Treatment methods for pediatric patients using upadacitinib

Abstract

This disclosure relates to a method for treating diseases in pediatric patients using upadacitinib, a JAK1 selective inhibitor. The diseases or disorders covered include idiopathic arthritis (pcJIA), systemic juvenile idiopathic arthritis (SJIA), juvenile psoriatic arthritis (JPsA), atopic dermatitis (AD), juvenile ankylosing spondylitis (JAS), juvenile non-radiographic spondyloarthritis (nr-axSpA), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), ulcerative colitis (UC), and Crohn's disease (CD). The treatment method generally involves administering a therapeutically effective dose of upadacitinib to pediatric patients in a stable liquid pharmaceutical composition or solid dosage form, based on the patient's body weight.

Description

[Technical Field]

[0001] This application claims the interests of U.S. Provisional Patent Application No. 63 / 491,665 filed on 22 March 2023 and U.S. Provisional Patent Application No. 63 / 623,994 filed on 23 January 2024, both of which are incorporated herein by reference in their entirety.

[0002] This disclosure relates to a method for treating a disease in pediatric patients using upadacitinib, a JAK1 selective inhibitor. [Background technology]

[0003] Upadacitinib is approved as a JAK1 selective inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiological spondyloarthritis, and ulcerative colitis in adults. It is also approved as a JAK1 selective inhibitor for the treatment of atopic dermatitis in adults and adolescents aged 12 years or older and weighing 40 kg or more. Furthermore, clinical trials are underway for its use in the treatment of Crohn's disease, hidradenitis suppurativa, and systemic lupus erythematosus in adults. On the other hand, its use in pediatric patients under 12 years of age or pediatric patients under 18 years of age weighing less than 40 kg has not yet been evaluated. [Overview of the project] [Problems that the invention aims to solve]

[0004] While the pharmacokinetics, safety, and tolerability of upadacitinib are already known in adults, they have not yet been studied in pediatric patients under 12 years of age or pediatric patients under 18 years of age weighing less than 40 kg. Since the identified diseases mentioned above also occur in pediatric patients, providing a safe and effective dosage of upadacitinib in pediatric patients is desirable in the art. In particular, it is necessary to establish a weight-based dosing regimen that achieves plasma exposure levels in pediatric patients equivalent to the dosages in adults that have shown efficacy (i.e., 15 mg and 30 mg QD). Furthermore, tablet formulations are difficult for young pediatric patients to swallow, which may result in decreased patient adherence and reduced therapeutic effect. [Means for solving the problem]

[0005] (Summary of Disclosure) This disclosure provides a method for treating diseases or disorders in pediatric patients requiring upadacitinib. Target diseases or disorders include idiopathic arthritis (pcJIA), systemic juvenile idiopathic arthritis (SJIA), juvenile psoriatic arthritis (JPsA), atopic dermatitis (AD), juvenile ankylosing spondylitis (JAS), juvenile non-radiographic spondyloarthritis (nr-axSpA), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), ulcerative colitis (UC), and Crohn's disease (CD). The treatment method generally involves administering a therapeutically effective dose of upadacitinib to pediatric patients in a stable liquid pharmaceutical composition or solid dosage form, based on the patient's body weight. In particular, in pediatric patients requiring upadacitinib, a method is provided herein that includes administering a therapeutically effective dose of upadacitinib in a weight-based amount as a stable liquid pharmaceutical composition twice daily or as a sustained-release tablet once daily.

[0006] In one embodiment, a method is provided for treating a pediatric patient having polyarticular course juvenile idiopathic arthritis (pcJIA). The method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In other embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0007] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0008] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0009] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0010] In some embodiments, when the weight of the pediatric patient is about 30 kg or more, the method comprises administering to the pediatric patient a therapeutically effective amount of upadacitinib, wherein: (i) upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) upadacitinib is administered twice daily at a dose of 12 mg (12 mg BID).

[0011] In some embodiments, when the weight of the pediatric patient is from about 10 kg to less than about 20 kg, the method comprises administering upadacitinib twice daily at a dose of 3 mg (3 mg BID). When the weight of the pediatric patient is from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 4 mg (4 mg BID). Further, when the weight of the pediatric patient is about 30 kg or more, the method comprises administering upadacitinib twice daily at a dose of 6 mg or once daily at a dose of 15 mg (6 mg BID or 15 mg QD).

[0012] In some embodiments, when the weight of the pediatric patient is from about 10 kg to less than about 20 kg, the method comprises administering upadacitinib twice daily at a dose of 6 mg (6 mg BID). When the weight of the pediatric patient is from about 20 kg to less than about 30 kg, the method comprises administering upadacitinib twice daily at a dose of 8 mg (8 mg BID). Further, when the weight of the pediatric patient is about 30 kg or more, the method comprises administering upadacitinib twice daily at a dose of 8 mg or once daily at a dose of 30 mg (8 mg BID or 30 mg QD).

[0013] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0014] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0015] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0016] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0017] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL.

[0018] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL.

[0019] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0020] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0021] In some embodiments, pcJIA is a polyarticular JIA that is rheumatoid factor positive or rheumatoid factor negative.

[0022] In some embodiments, pediatric patients have a history of having arthritis in at least five joints within the first six months of the disease.

[0023] In some embodiments, pediatric patients do not have a diagnosis of enthesitis-associated arthritis (ERA) or juvenile psoriatic arthritis (JPSA).

[0024] In some embodiments, pediatric patients have the following: a) Five or more active joints defined by the presence of swollen joints not due to deformity; or b) If swelling is absent, the joints must have limited range of motion (LOM) in addition to pain during movement and / or tenderness on palpation, and LOM must be present in at least three active joints.

[0025] In some embodiments, pediatric patients receive 20 mg / m² for at least 8 weeks prior to the start of administration. 2 The following stable doses of methotrexate are being administered.

[0026] In some embodiments, pediatric patients are administered oral glucocorticoids at a stable dose of 10 mg / day or less or 0.2 mg / kg / day or less (whichever is lower) for at least one week prior to the start of administration.

[0027] In some embodiments, pediatric patients achieve one or more of the following: JIA ACR Pediatric 30 / 50 / 70 / 90 / 100 response, change in JADAS 10 / 27 / 71 response from baseline, low disease activity based on JADAS criteria, or remission based on JADAS criteria. In some embodiments, pediatric patients achieve one or more of the above at 8, 10, 12, 14, 16, 18, 20, 22, 24, 48, or 52 weeks after the first daily administration. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 30 response at 12 weeks after the first daily administration. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 50 response at 12 weeks after the first daily administration. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 70 response at 12 weeks after the first daily administration. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 90 response at 12 weeks after the first daily administration. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 100 response within 12 weeks after the first daily dose.

[0028] In some embodiments, pediatric patients achieve the JIA ACR Pediatric 30 response at 24 weeks after the first daily dose. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 50 response at 24 weeks after the first daily dose. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 70 response at 24 weeks after the first daily dose. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 90 response at 24 weeks after the first daily dose. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 100 response at 24 weeks after the first daily dose.

[0029] In some embodiments, pediatric patients achieve the JIA ACR Pediatric 30 response at 48 weeks after the first daily dose. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 50 response at 48 weeks after the first daily dose. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 70 response at 48 weeks after the first daily dose. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 90 response at 48 weeks after the first daily dose. In some embodiments, pediatric patients achieve the JIA ACR Pediatric 100 response at 48 weeks after the first daily dose.

[0030] In another embodiment, a method for treating systemic juvenile idiopathic arthritis (SJIA) in pediatric patients is provided. The method comprises administering a therapeutically effective dose of upadacitinib to a pediatric patient. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0031] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0032] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0033] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0034] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0035] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0036] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0037] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0038] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0039] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0040] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0041] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL.

[0042] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL.

[0043] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0044] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0045] In another embodiment, a method for treating atopic dermatitis (AD) in pediatric patients is provided. The method comprises administering a therapeutically effective dose of upadacitinib to the child. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0046] In some embodiments, if the pediatric patient is under 12 years of age and weighs between approximately 10 kg and approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0047] In some embodiments, if the pediatric patient is under 12 years of age and weighs less than approximately 20 kg to approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0048] In some embodiments, if the pediatric patient is under 12 years of age and weighs about 30 kg or more, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0049] In some embodiments, if the pediatric patient is under 12 years of age and weighs about 30 kg or more, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0050] In some embodiments, if the pediatric patient is under 12 years of age and weighs between approximately 10 kg and less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient is under 12 years of age and weighs between approximately 20 kg and less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient is under 12 years of age and weighs 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0051] In some embodiments, if the pediatric patient is under 12 years of age and weighs between approximately 10 kg and less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient is under 12 years of age and weighs between approximately 20 kg and less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient is under 12 years of age and weighs 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0052] In some embodiments, if the pediatric patient is under 12 years of age and weighs between approximately 10 kg and less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient is under 12 years of age and weighs between approximately 20 kg and less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient is under 12 years of age and weighs 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0053] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0054] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0055] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0056] In some embodiments, when the pediatric patient is 12 years of age or older and weighs less than approximately 40 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0057] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0058] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0059] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0060] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL.

[0061] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL.

[0062] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0063] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0064] In some embodiments, pediatric patients achieve an EASI 75 response at 12 weeks after the first daily dose. In some embodiments, pediatric patients achieve an EASI 90 response at 12 weeks after the first daily dose. In some embodiments, pediatric patients achieve an EASI 100 response at 12 weeks after the first daily dose. In some embodiments, pediatric patients achieve an Investigator's Global Assessment scale for Atopic Dermatitis (vIGA-AD) score of 0 or 1 at 12 weeks after the first daily dose.

[0065] In another embodiment, a method for treating juvenile psoriatic arthritis (JPsA) in pediatric patients is provided. The method comprises administering a therapeutically effective dose of upadacitinib to the child. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0066] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0067] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0068] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0069] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0070] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0071] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0072] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0073] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0074] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0075] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0076] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL.

[0077] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL.

[0078] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0079] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0080] In another embodiment, a method for treating juvenile ankylosing spondylitis (JAS) in pediatric patients is provided. The method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0081] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0082] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0083] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0084] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0085] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0086] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0087] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0088] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0089] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0090] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0091] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL.

[0092] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL.

[0093] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0094] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0095] In another embodiment, a method is provided for treating axial spondyloarthritis (nr-axSpA) in pediatric patients that does not meet radiographic criteria. The method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0096] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0097] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0098] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0099] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0100] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0101] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0102] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0103] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0104] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0105] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0106] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL.

[0107] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL.

[0108] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0109] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as sustained-release tablets.

[0110] In another embodiment, a method for treating hidradenitis suppurativa (HS) in pediatric patients is provided. The method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0111] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0112] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0113] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0114] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0115] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0116] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0117] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0118] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0119] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0120] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0121] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL.

[0122] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL.

[0123] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0124] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0125] In another embodiment, a method for treating systemic lupus erythematosus (SLE) in pediatric patients is provided. The method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0126] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0127] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0128] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0129] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0130] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0131] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0132] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0133] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0134] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0135] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0136] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL.

[0137] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL.

[0138] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0139] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0140] In yet another embodiment, a method for treating ulcerative colitis (UC) in pediatric patients is provided. The method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0141] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0142] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0143] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0144] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0145] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0146] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0147] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0148] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0149] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0150] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0151] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL.

[0152] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL.

[0153] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0154] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0155] In yet another embodiment, a method for treating Crohn's disease in pediatric patients is provided. The method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective dose of upadacitinib is administered to the pediatric patient as a solid dosage form.

[0156] In some embodiments, when the weight of a pediatric patient is between approximately 10 kg and less than approximately 20 kg, the method comprises administering a therapeutically effective dose of upadacitinib, where: (i) Upadacitinib is administered twice daily at a dose of 3 mg (3 mg BID); or (ii) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID).

[0157] In some embodiments, if the weight of a pediatric patient is between approximately 20 kg and less than approximately 30 kg, the method comprises administering a therapeutically effective dose of upadacitinib to the pediatric patient, where: (i) Upadacitinib is administered twice daily at a dose of 4 mg (4 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0158] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID).

[0159] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered twice daily at a dose of 6 mg (6 mg BID); or (ii) Upadacitinib is administered at a dose of 12 mg twice daily (12 mg BID).

[0160] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 3 mg twice daily (3 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 4 mg twice daily (4 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 6 mg twice daily or at a dose of 15 mg once daily (6 mg BID or 15 mg QD).

[0161] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 8 mg twice daily or at a dose of 30 mg once daily (8 mg BID or 30 mg QD).

[0162] In some embodiments, if the pediatric patient weighs approximately 10 kg to less than approximately 20 kg, the method includes administering upadacitinib at a dose of 6 mg twice daily (6 mg BID). If the pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib at a dose of 8 mg twice daily (8 mg BID). Furthermore, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib at a dose of 12 mg twice daily or at a dose of 30 mg once daily (12 mg BID or 30 mg QD).

[0163] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a stable oral pharmaceutical solution.

[0164] In some embodiments, pediatric patients are administered upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily as a stable oral pharmaceutical solution.

[0165] In some embodiments, the oral solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0166] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL.

[0167] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL.

[0168] In some embodiments, if the weight of the pediatric patient is approximately 30 kg or more, the method includes administering a therapeutically effective dose of upadacitinib to the pediatric patient, wherein: (i) Upadacitinib is administered once daily at a dose of 15 mg (15 mg QD); or (ii) Upadacitinib is administered once daily at a dose of 30 mg (30 mg QD).

[0169] In some embodiments, the therapeutically effective dose of upadacitinib is administered to pediatric patients as a sustained-release tablet.

[0170] In yet another embodiment, a stable oral pharmaceutical formulation is provided comprising: upadacitinib or a pharmaceutically acceptable salt or solid form thereof, buffers and / or pH adjusters, preservatives, sweeteners, and water.

[0171] In some embodiments, the stable oral pharmaceutical formulation contains anhydrous free base upadacitinib at a concentration of approximately 0.5 mg / mL.

[0172] In some embodiments, the stable oral pharmaceutical formulation contains anhydrous free base-type upadacitinib at a concentration of approximately 1 mg / mL.

[0173] In some embodiments, the buffering agent is selected from the group consisting of citrates, phosphates, tartrates, succinates, formates, acetates, and combinations thereof.

[0174] In some embodiments, the pH adjuster is selected from the group consisting of citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof.

[0175] In some embodiments, the preservative is selected from the group consisting of sodium benzoate, benzoic acid, propylparaben, sodium metabisulfite, potassium sorbate, parahydroxybenzoic acid, parahydroxybenzoate, and combinations thereof.

[0176] In some embodiments, the sweetener is selected from the group consisting of sucralose, acesulfame potassium, sodium saccharin, neotame, sucrose, maltitol, xylitol, and combinations thereof.

[0177] In some embodiments, the stable oral pharmaceutical formulation contains anhydrous free base upadacitinib, citric acid, sodium citrate, sodium benzoate, sucralose, and water.

[0178] In some embodiments, the stable oral pharmaceutical solution has a pH in the range of about 2 to about 5. In some embodiments, the stable oral pharmaceutical solution has a pH in the range of about 3 to about 4. In some embodiments, the stable oral pharmaceutical solution has a pH in the range of about 2.5 to about 3.5. [Brief explanation of the drawing]

[0179] [Figure 1] Figure 1 is a schematic diagram of a clinical trial in pediatric polyarticular juvenile idiopathic arthritis patients according to a non-limiting embodiment of the present disclosure. [Figure 2] Figure 2 is a graph showing the mean plasma concentration-time profiles of upadacitinib in pediatric patients with polyarticular juvenile idiopathic arthritis according to a non-limiting embodiment of the present disclosure. [Figure 3-1] Figures 3A to 3E are graphs showing the efficacy of upadacitinib at week 12 in pediatric polyarticular juvenile idiopathic arthritis patients, stratified by age group, based on various evaluation indicators, according to non-limiting embodiments of the present disclosure. [Figure 3-2]Figures 3A to 3E are graphs showing the efficacy of upadacitinib at week 12 in pediatric polyarticular juvenile idiopathic arthritis patients, stratified by age group, based on various evaluation indicators, according to non-limiting embodiments of the present disclosure. [Figure 4] Figure 4 is a schematic diagram of a clinical trial in a child with atopic dermatitis according to a non-limiting embodiment of the present disclosure. [Figure 5-1] Figures 5A–5D are graphs showing the mean plasma concentration-time profiles of upadacitinib in pediatric patients with atopic dermatitis according to non-limiting embodiments of the present disclosure. [Figure 5-2] Figures 5A–5D are graphs showing the mean plasma concentration-time profiles of upadacitinib in pediatric patients with atopic dermatitis according to non-limiting embodiments of the present disclosure. [Figure 6] Figure 6 is a schematic diagram of a clinical trial in a patient with juvenile polyarticular idiopathic arthritis in children, according to a non-limiting embodiment of the present disclosure. [Figure 7] Figure 7 is a schematic diagram showing the treatment of patients in the clinical study of Example 1. [Figure 8] Figures 8A to 8C are graphs showing the mean plasma concentration-time profiles of various formulations of upadacitinib in pediatric polyarticular juvenile idiopathic arthritis patients, according to non-limiting embodiments of the present disclosure. [Figure 9-1] Figures 9A to 9E are a series of graphs illustrating the efficacy of upadacitinib at 12 weeks in pediatric polyarticular juvenile idiopathic arthritis patients, stratified by age group based on various evaluation indicators, according to non-limiting embodiments of the present disclosure. [Figure 9-2] Figures 9A to 9E are a series of graphs illustrating the efficacy of upadacitinib at 12 weeks in pediatric polyarticular juvenile idiopathic arthritis patients, stratified by age group based on various evaluation indicators, according to non-limiting embodiments of the present disclosure. [Figure 10A]Figure 10A is a graph showing the efficacy of upadacitinib over time up to week 48 in pediatric polyarticular juvenile idiopathic arthritis patients according to a non-limiting embodiment of the present disclosure, based on the JIA ACR response rate. [Figure 10B] Figure 10B is a graph showing the efficacy of upadacitinib over time up to week 48 in pediatric polyarticular juvenile idiopathic arthritis patients according to a non-limiting embodiment of the present disclosure, based on the JADAS-27 [CRP] response rate. [Figure 10C] Figure 10C is a graph showing the efficacy of upadacitinib over time up to week 48 in pediatric patients with polyarticular juvenile idiopathic arthritis, according to a non-limiting embodiment of the present disclosure, based on the mean change in C-CHAQ from baseline. [Figure 10D] Figure 10D is a graph showing the efficacy of upadacitinib over time to week 48 in a pediatric patient with polyarticular juvenile idiopathic arthritis, according to a non-limiting embodiment of the present disclosure, based on the mean change in the total number of active joints from baseline. [Modes for carrying out the invention]

[0180] I. Definition The section headings used in this section and throughout this disclosure are not intended to be limiting.

[0181] When a range of numbers is enumerated, each intermediate number within that range is also explicitly intended with the same precision. For example, in the range 6 to 9, 7 and 8 are intended in addition to 6 and 9, and in the range 6.0 to 7.0, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly intended. Similarly, all enumerated ratios also encompass all sub-ratios included in the broader ratio.

[0182] The singular forms "a," "an," and "the" can refer to multiple objects unless the context explicitly indicates otherwise.

[0183] The term "about" generally refers to a range of values ​​that a person skilled in the art would consider equivalent to the enumerated values ​​(i.e., a range that has the same function or result). In many cases, the term "about" may also include numbers rounded to the nearest significant figure.

[0184] Unless the context requires otherwise, the terms “comprise,” “comprises,” and “comprising” are used with a fundamental and clear understanding that they are to be interpreted comprehensively, not exclusively. The applicant intends each term to be interpreted in this way in the interpretation of this patent (including the claims below).

[0185] The term "AUC" refers to the area under the curve. AUC is the definite integral of a curve that represents the change in drug concentration in plasma as a function of time.

[0186] The term “C max "This refers to the reference drug, T max This refers to the plasma concentration in , and is expressed herein as ng / mL. This concentration is obtained by orally administering the dosage form or pharmaceutical composition (e.g., the dosage form or composition of this disclosure) once or a predetermined number of times. Unless otherwise specified, C max This refers to the overall maximum observed concentration.

[0187] As used herein, terms such as “treat,” “treatment,” and “therapy” are intended to include means of treatment for a disease or disorder that produce a clinically desirable or beneficial effect, including, but not limited to, the reduction or alleviation of one or more symptoms, the regression, slowing or cessation of the progression of the disease or disorder.

[0188] As used herein, the term "pediatric patient" refers to a human patient under the age of 18. In this specification, the terms "patient" and "subject" are used synonymously.

[0189] "Pharmacopoecitable salts" refer to salts obtained by reaction with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g., sulfonic acid, carboxylic acid, organophosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, monomalic acid, monooxalic acid, tartaric acid (e.g., monotartaric acid (e.g., (+)- or (-)-tartaric acid or mixtures thereof)), amino acids (e.g., (+)- or (-)-amino acids or mixtures thereof)) that retain the biological efficacy and properties of the free base. These salts can be prepared by methods known to those skilled in the art. Examples of pharmaceutically acceptable salts of upadacitinib are given in WO2017 / 066775, which is incorporated herein by reference in its entirety.

[0190] II. JAK1 Inhibition Upadacitinib (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide) or its pharmaceutically acceptable salt or solid form is an oral inhibitor of Janus kinase (JAK) and exhibits specific selectivity for the JAK1 receptor. The structure of upadacitinib is shown below.

[0191] [ka]

[0192] The dose strengths of upadacitinib enumerated in this application are based on the weight of anhydrous free base upadacitinib contained in the active ingredient delivered to the patient. For example, the terms "15 mg of upadacitinib" or "UPA 15 mg" refer to 15 mg of neutral upadacitinib free base present in the active ingredient, excluding co-forms of solvates or hydrates (including hemihydrates) containing solvents or water molecules that may be present in the active ingredient, and pharmaceutically acceptable salt counteranions. Therefore, for example, an administration of "15 mg of upadacitinib" may include an administration of 15.4 mg of crystalline upadacitinib free base hemihydrate. This hemihydrate contains a co-form of 1 / 2 molecule of water per molecule of upadacitinib free base, thereby delivering 15 mg of anhydrous free base upadacitinib to the patient. Similarly, the terms "30 mg of upadacitinib" or "UPA 30 mg" refer to 30 mg of neutral upadacitinib free base present in the active ingredient, excluding co-formed components of solvates or hydrates (including hemihydrates) containing solvents or water molecules that may be present in the active ingredient, and pharmaceutically acceptable salt counteranions. Therefore, for example, a dose of "30 mg of upadacitinib" may include a dose of 30.7 mg of crystalline upadacitinib free base hemihydrate. This hemihydrate contains a co-formed component of 1 / 2 molecule of water per molecule of upadacitinib free base, thereby delivering 30 mg of anhydrous free base upadacitinib to the patient.

[0193] III. Pharmaceutical Compositions and Routes of Administration Upadacitinib may be administered to human patients on its own, or in the form of a pharmaceutical composition mixed with a biocompatible carrier or excipient in doses to treat or improve the diseases or conditions described herein. These compound mixtures may also be administered to patients as simple mixtures or as appropriately formulated pharmaceutical compositions.

[0194] The pharmaceutical compositions of this disclosure can be produced by methods known on their own, for example, by conventional mixing, dissolving, granulation, dragée production, wet grinding, emulsification, encapsulation, encapsulation, or freeze-drying processes.

[0195] The pharmaceutical compositions for use relating to this disclosure can be formulated by conventional methods using one or more physiologically acceptable carriers, which include excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation. Appropriate formulation depends on the selected route of administration.

[0196] In some embodiments, the pharmaceutical composition is in capsule form. In some embodiments, the pharmaceutical composition is in tablet form. In some embodiments, the tablet is a controlled-release formulation, such as a sustained-release tablet formulation (also referred to herein as a modified-release formulation or sustained-release formulation). Examples of solid dosage forms containing upadacitinib are described in WO2017 / 066775, which is incorporated herein by reference in its entirety.

[0197] In some embodiments, the composition is a stable liquid pharmaceutical composition. In some embodiments, the stable liquid pharmaceutical composition is a stable oral solution. In some embodiments, the stable liquid pharmaceutical composition is a stable oral suspension. A suitable stable liquid pharmaceutical composition comprises upadacitinib or a pharmaceutically acceptable salt or solid form thereof, further comprising excipients such as buffers, preservatives, sweeteners, flavorings, pH adjusters, and solvents. In some embodiments, the stable liquid pharmaceutical composition is a stable oral pharmaceutical solution comprising upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water. In some embodiments, the stable liquid pharmaceutical composition is a stable oral pharmaceutical suspension comprising upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0198] The concentration of upadacitinib in a stable liquid pharmaceutical composition may vary. Upadacitinib is bitter and difficult to mask at high concentrations to maintain palatability (see, for example, Example 6), and is generally present at concentrations of about 1 mg / mL or less. In some embodiments, the stable pharmaceutical composition is an oral solution containing upadacitinib at a concentration in the range of about 0.3 mg / mL to about 1.2 mg / mL (e.g., about 0.3 to about 0.7 mg / mL or about 0.8 to about 1.2 mg / mL). In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, for example, in the range of about 0.8, about 0.9, or about 1.0 mg / mL to about 1.1, or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, in the range of about 0.3, about 0.4, or about 0.5 mg / mL to about 0.6, or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0199] In some embodiments, the oral solution contains a pH adjuster. Suitable pH adjusters include acids such as inorganic or organic acids. Inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, and phosphoric acid. As used herein, the term "organic acid" refers to organic (i.e., carbon skeleton) compounds characterized by acidic properties. Generally, organic acids are relatively weak acids (they do not completely dissociate in water), such as carboxylic acids (-CO2H). In some embodiments, the pH adjuster is an organic acid. Suitable organic acids include benzoic acid, toluic acid, salicylic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-(4-isobutylphenyl)propionic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, L-ascorbic acid, L-aspartic acid, α-methylbutyric acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and f Examples of pH adjusters include, but are not limited to, oacids, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphorylic acid, glycolic acid, hippuric acid, isobutyric acid, isovaleric acid, lactobionic acid, lauric acid, levulinic acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oleic acid, palmitic acid, pamoic acid, phenylacetic acid, pyroglutamic acid, pyruvic acid, sebacic acid, stearic acid, tartaric acid, and undecylenic acid. In some embodiments, the pH adjuster is selected from citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof. In some embodiments, the pH adjuster is citric acid.

[0200] In some embodiments, the stable liquid pharmaceutical composition contains a buffer. Suitable buffers include, but are not limited to, citrates, phosphates, tartrates, succinates, glycinates, glycerophosphates, formates, and acetates. In some embodiments, the buffer is selected from the group consisting of citrates, phosphates, tartrates, succinates, formates, acetates, and combinations thereof. In some embodiments, the buffer is selected from the group consisting of citrates and phosphates. In some embodiments, the buffer is sodium citrate.

[0201] The amounts of pH adjusters and / or buffers may vary. Generally, their concentrations are adjusted to give the desired pH range of the resulting stable liquid pharmaceutical composition. In some embodiments, the stable liquid pharmaceutical composition has a pH in the range of about 2 to about 5, about 3 to about 4, about 2 to about 3, about 4 to about 5, about 2.0 to about 2.5, about 2.5 to about 3.0, about 3.0 to about 3.5, about 3.5 to about 4.0, about 4.0 to about 4.5, about 4.5 to about 5.0, about 3.0 to about 3.1, about 3.0 to about 3.2, about 3.0 to about 3.3, about 3.1 to about 3.2, about 3.1 to about 3.3, about 3.1 to about 3.4, about 3.1 to about 3.5, about 3.2 to about 3.3, about 3.2 to about 3.4, about 3.2 to about 3.5, about 3.3 to about 3.4, or about 3.3 to about 3.5. In some embodiments, the stable liquid pharmaceutical composition has a pH of about 3.0, about 3.1, or about 3.2.

[0202] In some embodiments, the stable liquid pharmaceutical composition contains a preservative. Suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, ascorbic acid, potassium sorbate, 4-hydroxybenzoic acid, 4-hydroxybenzoate, methylparaben, propylparaben, sodium metabisulfite, and combinations thereof. In some embodiments, the preservative is selected from the group consisting of sodium benzoate, benzoic acid, propylparaben, sodium metabisulfite, potassium sorbate, parahydroxybenzoic acid, parahydroxybenzoate, and combinations thereof.

[0203] In some embodiments, the stable liquid pharmaceutical composition contains a sweetener. The sweetener may be in natural or artificial form, or a combination of natural and artificial forms, and any sweetener or combination thereof can be used. Examples of natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, and honey. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame potassium, and neotame. In some embodiments, the sweetener contains one or more sugar alcohols. Sugar alcohols are polyols derived from monosaccharides or disaccharides that are partially or completely hydrogenated. Sugar alcohols have, for example, about 4 to about 20 carbon atoms and include erythritol, arabitol, ribitol, isomalt, maltitol, dolucitol, isitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrolyzed starch hydrolysates). In some embodiments, the sweetener is selected from the group consisting of sucralose, acesulfame potassium, sodium saccharin, neotame, sucrose, maltitol, xylitol, and combinations thereof.

[0204] In some embodiments, the stable oral pharmaceutical solution contains one or more flavoring agents. Any aromatic or fragrant substance that can modify the taste, aroma, or both of the solution may be used. The flavoring agents may be natural or synthetic. Suitable flavoring agents include, but are not limited to, flavor compositions exhibiting the flavors of cherry, orange, lemon, lime, bubblegum, grape, strawberry, and mango.

[0205] In some embodiments, the stable oral pharmaceutical solution contains a flavor modifier. Suitable flavor modifiers include, but are not limited to, salts such as sodium chloride and monoammonium glycyrrhizinate to enhance sweetness.

[0206] In some embodiments, the stable pharmaceutical composition is an oral solution containing upadacitinib, citric acid, sodium citrate, sodium benzoate, a sweetener, and water.

[0207] In some embodiments, the stable pharmaceutical composition contains citric acid in an amount ranging from about 0.1 to about 1 mg / mL.

[0208] In some embodiments, the stable pharmaceutical composition contains an amount of sodium citrate ranging from about 0.01 to about 1 mg / mL.

[0209] In some embodiments, the stable pharmaceutical composition contains sodium benzoate in an amount ranging from about 0.01 to about 0.1 mg / mL.

[0210] In some embodiments, the stable pharmaceutical composition contains a sweetener in an amount ranging from about 1 to about 50 mg / mL.

[0211] In a particular embodiment, the stable pharmaceutical composition is an oral solution having the formulation shown in Table 1.

[0212] [Table 1]

[0213] The pH of a stable oral solution may vary. In some embodiments, the stable oral solution has a pH in the range of about 2 to about 5. In some embodiments, the stable oral solution has a pH in the range of about 3 to about 4. In some embodiments, the stable oral solution has a pH in the range of about 2.5 to about 3.5.

[0214] IV. Administration to Children In some embodiments, the pediatric patient is under 18 years of age. In some embodiments, the pediatric patient is under 12 years of age. In some embodiments, the pediatric patient is under 6 years of age. In some embodiments, the pediatric patient is in the age range of approximately 2 to under 6 years, approximately 6 to under 12 years, or approximately 12 to under 18 years. In some embodiments, the pediatric patient is in the age range of approximately 2 to 18 years, for example, approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years. In some embodiments, the pediatric patient is 2 years of age or older. In some embodiments, the pediatric patient is in the age range of approximately 2 to under 12 years.

[0215] In some embodiments, the pediatric patient has a weight of at least about 10 kg. In some embodiments, the pediatric patient has a weight of about 10 kg to less than about 30 kg, for example, about 20 kg to less than about 20 kg or about 20 kg to less than about 30 kg. In some embodiments, the pediatric patient has a weight of 30 kg or more. In some embodiments, the pediatric patient is in the age range of about 2 years to less than 12 years and has a weight of less than 40 kg. In some embodiments, the pediatric patient is 12 years of age or older and has a weight of less than 40 kg.

[0216] In some embodiments, when a pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, the method includes administering upadacitinib 3 mg twice daily (3 mg BID) as an oral solution.

[0217] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL. For example, it may contain concentrations ranging from about 0.8, about 0.9, or about 1.0 mg / mL to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0218] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and a 3 mg dose is administered twice daily (BID) as approximately 3 mL of the approximately 1 mg / mL solution.

[0219] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, in the range of about 0.3, about 0.4, or about 0.5 mg / mL to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0220] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and a 3 mg dose is administered twice daily (BID) as approximately 6 mL of the approximately 0.5 mg / mL solution.

[0221] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution.

[0222] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL. For example, it may contain concentrations ranging from about 0.8, about 0.9, or about 1.0 mg / mL to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0223] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and a 6 mg dose is administered twice daily (BID) as approximately 6 mL of the approximately 1 mg / mL solution.

[0224] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, in the range of about 0.3, about 0.4, or about 0.5 mg / mL to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0225] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and a 6 mg dose is administered twice daily (BID) as approximately 12 mL of the approximately 0.5 mg / mL solution.

[0226] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, when a pediatric patient weighs approximately 20 kg to less than 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution.

[0227] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL. For example, it may contain concentrations ranging from about 0.8, about 0.9, or about 1.0 mg / mL to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0228] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and an 8 mg dose is administered twice daily (BID) as approximately 8 mL of the approximately 1 mg / mL solution.

[0229] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, in the range of about 0.3, about 0.4 or about 0.5 mg / mL to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0230] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, and a dose of 8 mg is administered twice daily (BID) as about 16 mL of the about 0.5 mg / mL solution.

[0231] In some embodiments, when a pediatric patient has a body weight of about 30 kg or more, the method includes administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.

[0232] In some embodiments, when a pediatric patient has a body weight of about 30 kg or more, the method includes administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.

[0233] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL. For example, it may contain at a concentration of about 0.8, about 0.9 or about 1.0 mg / mL to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0234] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, and a dose of 6 mg is administered twice daily (BID) as about 6 mL of the about 1 mg / mL solution.

[0235] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, and a dosage of 12 mg is administered twice daily (BID) as about 12 mL of the about 1 mg / mL solution.

[0236] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, containing in the range of about 0.3, about 0.4 or about 0.5 mg / mL to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0237] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, and a dosage of 6 mg is administered twice daily (BID) as about 12 mL of the about 0.5 mg / mL solution.

[0238] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, and a dosage of 12 mg is administered twice daily (BID) as about 24 mL of the about 0.5 mg / mL solution.

[0239] In some embodiments, when a pediatric patient has a body weight of about 30 kg or more, the method includes administering 15 mg of upadacitinib once daily (15 mg QD) as a sustained-release tablet.

[0240] In some embodiments, when a pediatric patient has a body weight of about 30 kg or more, the method includes administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.

[0241] In some embodiments, when a pediatric patient has a body weight of about 30 kg or more, the method includes administering 12 mg of upadacitinib twice daily (12 mg BID) as an oral solution.

[0242] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL. For example, it may contain concentrations ranging from about 0.8, about 0.9, or about 1.0 mg / mL to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0243] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and an 8 mg dose is administered twice daily (BID) as approximately 8 mL of the approximately 1 mg / mL solution.

[0244] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, in the range of about 0.3, about 0.4, or about 0.5 mg / mL to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0245] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and an 8 mg dose is administered twice daily (BID) as approximately 16 mL of the approximately 0.5 mg / mL solution.

[0246] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0247] The highest concentration (C) achieved by the above administration max ) may vary depending, for example, the dosage, the patient's body weight, and the metabolism of upadacitinib in individual patients.

[0248] In some embodiments, when the immediate-release oral solution described herein is administered to pediatric subjects twice a day (BID), the average C of upadacitinib max is achieved in the range of about 20 to about 160 ng / mL.

[0249] In some embodiments, when administered to pediatric subjects at a dose of 3 mg or 4 mg twice a day (3 mg or 4 mg BID), the average C of upadacitinib max is achieved in the range of about 25 to about 50 ng / mL. For example, it is achieved in the range of about 25 to about 35, about 25 to about 33, about 25 to about 31, about 25 to about 29, or about 25 to about 27 ng / mL.

[0250] In some embodiments, when administered to pediatric subjects at a dose of 6 mg or 8 mg twice a day (6 mg or 8 mg BID), the average C of upadacitinib max is achieved in the range of about 40 to about 100 ng / mL. For example, it is achieved in the range of about 40 to about 95, about 40 to about 90, about 40 to about 85, about 40 to about 80, about 40 to about 75, about 40 to about 70, about 40 to about 65, about 40 to about 60, about 40 to about 55, about 40 to about 50, or about 40 to about 45 ng / mL.

[0251] In some embodiments, when the 15 mg sustained-release tablet described herein is administered to pediatric subjects once a day (15 mg QD), the average C of upadacitinib max is achieved in the range of about 45 to about 50 ng / mL. For example, it is achieved in the range of about 45 to about 49, about 45 to about 48, about 45 to about 46, or about 45 to about 46 ng / mL.

[0252] In some embodiments, when the 30 mg sustained-release tablet described herein is administered to pediatric subjects once a day (30 mg QD), the average C of upadacitinib max is achieved in the range of about 150 to about 160 ng / mL. For example, it is achieved in the range of about 152 to about 159, about 153 to about 158, about 154 to about 156, or about 154 to about 155 ng / mL.

[0253] The average 24-hour exposure (AUC) achieved by the above-mentioned administration. 0-24 ) may vary depending on factors such as the dosage, patient weight, feeding conditions (postprandial / fasting), and the individual patient's metabolism of upadacitinib.

[0254] In some embodiments, when the immediate-release oral solution described herein was administered twice daily to pediatric subjects, the mean AUC of upadacitinib was observed. 0-24 This is achieved in the range of approximately 200 to 700 ng·h / mL.

[0255] In some embodiments, when upadacitinib was administered to pediatric subjects at a dose of 3 mg or 4 mg (3 mg BID or 4 mg BID) twice daily, the mean AUC of upadacitinib was observed. 0-24 This can be achieved, for example, in the range of approximately 220 to 270 ng·h / mL. For example, it may also be approximately 220 to 265, 220 to 260, 220 to 255, 220 to 250, 220 to 245, 220 to 240, 220 to 235, 220 to 230, or 220 to 225 ng·h / mL.

[0256] In some embodiments, when upadacitinib was administered to pediatric subjects at a dose of 6 mg or 8 mg (6 mg BID or 8 mg BID) twice daily, the mean AUC of upadacitinib was observed. 0-24 This is achieved in the range of approximately 340 to 590 ng·h / mL. For example, approximately 340 to 580, approximately 340 to 570, approximately 340 to 560, approximately 340 to 550, approximately 340 to 540, approximately 340 to 530, approximately 340 to 520, approximately 340 to 510, approximately 340 to 500, approximately 340 to 490, approximately 340 to 480, approximately 340 to 470, approximately 340 to 460. The mean AUC of upadacitinib may be approximately 340-450, 340-440, 340-430, 340-420, 340-410, 340-400, 340-390, 340-380, 340-370, 340-360, 340-350, or 340-345 ng·h / mL. In some embodiments, when upadacitinib was administered to pediatric subjects at a dose of 6 mg or 8 mg twice daily, the mean AUC was approximately 340-450, 340-440, 340-430, 340-420, 340-410, 340-400, 340-390, 340-380, 340-370, 340-360, 340-350, or 340-345 ng·h / mL.0-24 is achieved in the range of about 570 to about 590 ng·h / mL. For example, it may be about 570 to about 590, about 570 to about 588, about 570 to about 586, about 570 to about 584, about 570 to about 582 or about 570 to about 580 ng·h / mL.

[0257] In some embodiments, when the 15 mg sustained-release tablet described herein is administered once daily (15 mg QD) to pediatric subjects, the average AUC of upadacitinib 0-24 is achieved in the range of about 45 to about 50 ng·h / mL. For example, it may be about 45 to about 49, about 46 to about 48 or about 47 to about 48 ng·h / mL.

[0258] In some embodiments, when the 30 mg sustained-release tablet described herein is administered once daily (30 mg QD) to pediatric subjects, the average AUC of upadacitinib 0-24 is achieved in the range of about 650 to about 680 ng·h / mL. For example, it may be about 660 to about 670 or about 665 to about 670 ng·h / mL. [[ID=1�]]

[0259] The disclosed method generally involves orally administering upadacitinib to a patient daily for a period of time. In some embodiments, the administration is continued at the same dosage and frequency throughout the treatment period. The length of the treatment period can vary. For example, the treatment period may be at least 14 days, at least 1 month, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 5 years, 10 years, 20 years, 50 years or more. In some embodiments, the treatment period is 12 weeks. In some embodiments, the treatment period is 156 weeks. In some embodiments, the treatment period is at least 156 weeks.

[0260] V. Treatment of Pediatric Patients Suffering from Polyarticular Juvenile Idiopathic Arthritis In some embodiments, the pediatric patient suffers from polyarticular juvenile idiopathic arthritis (pcJIA), which includes rheumatoid factor-positive or -negative polyarticular JIA, extended oligoarticular JIA, or systemic JIA with active arthritis and without active systemic symptoms.

[0261] Nonsteroidal anti-inflammatory drugs (NSAIDs) are the foundation of JIA treatment and are considered the least toxic treatments in children. While NSAIDs provide symptom relief, they are not considered to have disease-modifying effects. Among disease-modifying antirheumatic drugs (DMARDs), methotrexate (MTX) and sulfasalazine are effective for JIA, while hydroxychloroquine, D-penicillamine, and auranofin are not. The majority of children respond to MTX therapy, which has an acceptable toxicity profile, but remission is rare. Systemic corticosteroid administration is used to some extent in JIA conditions in general, but it is undesirable, especially in JIA, due to its many adverse effects. Systemic and intra-articular corticosteroids are used in combination with NSAIDs and DMARDs in the treatment of JIA. Intra-articular (IA) corticosteroid injections are recommended for JIA patients with active arthritis, with or without additional combination therapy. However, IA steroids are frequently used and often induce long-term remission in children with oligoarthritis-type joint arthritis (JIA).

[0262] Currently, numerous potent biological agents are available for the treatment of juvenile invasive intravascular infection (JIA), and these can induce remission in JIA as monotherapy or in combination with MTX or other synthetic disease-modifying agents. However, many patients fail to achieve remission or low disease activity with these agents, or lose their response over time. Furthermore, given the potential safety concerns associated with the immunomodulatory effects of biological agents, and the fact that all biological agents are administered by injection, there is a need for novel oral treatment options with a better benefit / risk profile in the treatment of JIA. Therefore, it is desirable to provide alternative therapies for the treatment of pediatric JIA.

[0263] JAK inhibition is known to inhibit the IL-6 pathway, and IL-6 is known to be involved in the pathogenesis of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). See, for example, Ou et al., Clin. Rheumatol., 2002, vol. 21, pp. 52-56; Mangge et al., Arthritis Rheum., 1995, vol. 38 (no. 2), pp. 211-220; and Mellins et al., Nat. Rev. Rheumatol., 2011, vol. 7 (no. 7), pp. 416-426. In particular, inhibition of JAK1 subtypes blocks the signaling of many important inflammatory cytokines known to be involved in inflammatory disorders, namely interleukin (IL)-2, IL-6, IL-7, and IL-15. By modulating these inflammatory cytokine pathways, upadacitinib offers the potential for effective treatment of inflammatory or autoimmune disorders. While not intended to be constrained by any particular theory, based on its differentiated selectivity profile in JAK inhibition, upadacitinib is thought to offer an improved benefit / risk profile compared to other less selective JAK inhibitors or other treatment strategies for patients with inflammatory diseases. In particular, upadacitinib is thought to offer therapeutic benefits in pcJIA.

[0264] In adults, the area under the steady-state 0-24 hour plasma upadacitinib concentration curve (AUC) 0-24 The exposure levels were model-estimated to be 362 ng·h / mL when 15 mg was administered once daily (QD) and 720 ng·h / mL when 30 mg was administered once daily. Accordingly, pediatric doses to achieve such exposure are disclosed herein as disclosed above.

[0265] As disclosed herein, a prototype oral solution formulation was developed to enable appropriate and flexible administration in young pediatric patients. When upadacitinib oral solution (1 mg / mL) was administered twice at 6 mg intervals of 12 hours, compared to a single dose of upadacitinib 15 mg once daily under fasting conditions (used in the Phase 3 RA trial), C maxThe ratio was approximately 30% higher, and the AUC was approximately 20% higher. These results supported the selection of the upadacitinib dose for pediatric subjects in the study of Example 1.

[0266] Accordingly, in one embodiment, a method is provided for treating pcJIA in pediatric patients using the weight-based pediatric doses disclosed herein above. The method generally involves administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's weight.

[0267] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0268] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0269] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0270] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0271] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0272] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0273] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0274] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0275] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0276] In some embodiments, pediatric patients have a history of arthritis affecting at least five joints within six months of the onset of the disease (however, according to ILAR (International Federation of Rheumatology Associations) criteria, in the case of extensive oligoarticular JIA, four joints or less within six months of onset, and more than four joints thereafter).

[0277] In some embodiments, pediatric patients do not have a diagnosis of enthesitis-associated arthritis (ERA) or juvenile psoriatic arthritis (JPSA).

[0278] In some embodiments, pediatric patients have five or more active joints. Active joints are defined as joints exhibiting swelling not due to deformation, or, if swelling is not observed, joints with limited range of motion (LOM), pain during movement, and / or tenderness on palpation, and furthermore, limited range of motion is present in at least three active joints.

[0279] In some embodiments, pediatric patients are administered methotrexate (MTX). In such embodiments, patients receive 20 mg / m² for at least 8 weeks prior to the start of administration. 2 The following stable doses are required.

[0280] In some embodiments, pediatric patients are administered oral glucocorticoids. In such embodiments, the patient must receive a stable dose not exceeding 10 mg / day or 0.2 mg / kg / day, whichever is lower, for at least one week prior to the start of administration.

[0281] In some embodiments, the patient achieves one or more of the following: a JIA ACR pediatric 30 / 50 / 70 / 90 / 100 response, a change in the JADAS 10 / 27 / 71 response from baseline, or low disease activity or remission based on JADAS criteria. In some embodiments, the patient achieves one or more of the JIA ACR pediatric 30 / 50 / 70 / 90 / 100 responses at 12, 24, or 48 weeks.

[0282] In some embodiments, pediatric patients do not have persistent or active uveitis within 3 months prior to the start of treatment. The patient does not have any of the following conditions requiring treatment with parenteral antiinfective drugs: active TB infection, chronic relapsing infection and / or active viral infection, active hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection, or β-D-glucan positivity.

[0283] In some embodiments, pediatric patients have not received intra-articular or parenteral corticosteroids within four weeks prior to the start of administration.

[0284] In some embodiments, pediatric patients do not have a history of: malignant tumors other than successfully treated non-melanoma skin cancer or localized intraepithelial carcinoma of the cervix; recurrent or disseminated herpes zoster (including a single episode); disseminated herpes simplex (including a single episode); human immunodeficiency virus (HIV) infection; organ transplantation requiring persistent immunosuppression; gastrointestinal perforation (excluding appendicitis or penetrating injury); diverticulitis or a significantly increased risk of gastrointestinal perforation; or a history of exposure to JAK inhibitors.

[0285] In some embodiments, pediatric patients are not using known moderate or potent inhibitors of drug-metabolizing enzymes (e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, paroxetine) or inducers (e.g., carbamazepine, rifampin, phenobarbital, phenytoin).

[0286] In some embodiments, pediatric patients are not using biological agents (etanercept, infliximab, adalimumab, abatacept, golimumab, tocilizumab, ustekinumab, certolizumab pegol, canakinumab, anakinra).

[0287] In some embodiments, pediatric patients are not using JAK inhibitors (e.g., commercially available upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], ruxolitinib [Jakafi®], baricitinib [Olumiant®], peficitinib [Smyraf®], abrocitinib [PF-04965842], or filgotinib).

[0288] In some embodiments, pediatric patients have moderate to severely active pcJIA.

[0289] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0290] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors.

[0291] VI. Treatment of pediatric patients with systemic juvenile idiopathic arthritis (SJIA) In some embodiments, pediatric patients have systemic juvenile idiopathic arthritis (SJIA). This disease is sometimes referred to as Still's disease or systemic juvenile rheumatoid arthritis. Although officially classified as a subset of juvenile idiopathic arthritis (JIA), its pathophysiology is most closely related to autoinflammatory disorders. SJIA affects not only the joints but also other parts of the body, such as the liver, lungs, and heart. Its course is highly diverse, typically beginning with spikes of fever and a rash that last for several months, accompanied by varying degrees of joint pain and arthritis. Currently, there is no cure for SJIA, but remission is achievable. Traditionally, the typical treatment goals for pediatric SJIA patients have been pain relief and symptom control, using nonsteroidal anti-inflammatory drugs (NSAIDs) and / or high doses of oral or intravenous corticosteroids. In recent years, biological agents and nonbiological disease-modifying antirheumatic drugs (DMARDs) have become available. However, in the treatment of SJIA, providing alternative, safe, well-tolerated, and effective non-biological disease-modifying agent (DMARD) therapies for pediatric patients remains desirable in the art.

[0292] JAK inhibition is known to inhibit the IL-6 pathway, and IL-6 is known to be involved in the pathogenesis of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). See, for example, Ou et al., Clin. Rheumatol., 2002, vol. 21, pp. 52-56; Mangge et al., Arthritis Rheum., 1995, vol. 38 (no. 2), pp. 211-220; and Mellins et al., Nat. Rev. Rheumatol., 2011, vol. 7 (no. 7), pp. 416-426. In particular, inhibition of JAK1 subtypes blocks the signaling of many important inflammatory cytokines known to be involved in inflammatory disorders, namely interleukin (IL)-2, IL-6, IL-7, and IL-15. By modulating these inflammatory cytokine pathways, upadacitinib offers the potential for effective treatment of inflammatory or autoimmune disorders. While not intended to be constrained by any particular theory, based on its differentiated selectivity profile in JAK inhibition, upadacitinib is thought to offer an improved benefit / risk profile compared to other less selective JAK inhibitors or other treatment strategies for patients with inflammatory diseases. In particular, upadacitinib is thought to offer therapeutic benefits in SJIA.

[0293] Pediatric doses that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above (i.e., based on body weight). Accordingly, in one embodiment, a method is provided herein for treating SJIA in pediatric patients using the body weight-based pediatric doses disclosed above. This method generally involves administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or as a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0294] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0295] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0296] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0297] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0298] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0299] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0300] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0301] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0302] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0303] In some embodiments, pediatric patients have moderate to severely active sJIA.

[0304] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0305] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors.

[0306] VII. Treatment of pediatric patients with atopic dermatitis In some embodiments, pediatric patients have atopic dermatitis (AD; also known as atopic eczema). AD is an inflammatory, itchy, chronic or chronically relapsing skin disease. Common clinical features include erythema, edema, dry skin (xerosis), erosions / scratches, exudation and crusting, and lichenification, but these vary depending on the patient's age and the chronicity of the lesions. Itching is a major feature of the disease and places a significant burden on patients and their families (Williams, N.Engl.J.Med., 2005, Vol. 352 (No. 22), pp. 2314-2324). AD is one of the most common skin diseases, affecting up to 20% of children. In approximately 70% of cases, Alzheimer's disease (AD) develops in children under 5 years of age (Williams et al., Atopic dermatitis: the epidemiology, causes, and prevention of atopic eczema, Cambridge University Press, Cambridge, UK, 2000, pp. 41-59). For patients with moderate to severe AD who are resistant to topical therapy, long-term oral treatment options are limited. Many conventional oral immunosuppressive therapies are used off-label, have limited efficacy data, and are unsuitable for long-term treatment due to their safety profile. Therefore, providing a safe, well-tolerated, and effective AD treatment for pediatric patients is desirable in this field.

[0307] Pediatric doses (i.e., based on body weight) that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above and in Example 1 below. Accordingly, in one embodiment, a method is provided herein for treating AD in pediatric patients using the body weight-based pediatric doses disclosed above. The method generally involves administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0308] In some embodiments, a body weight-based pediatric dose provides an exposure level consistent with the efficacy of treating AD in adult patients.

[0309] In some embodiments, when the pediatric patient is under 12 years of age and weighs between approximately 10 kg and less than 20 kg, the method includes administering upadacitinib 3 mg twice daily (3 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0310] In some embodiments, when the pediatric patient is under 12 years of age and weighs between approximately 10 kg and less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0311] In some embodiments, when the pediatric patient is under 12 years of age and weighs between approximately 20 kg and less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0312] In some embodiments, when the pediatric patient is under 12 years of age and weighs between approximately 20 kg and less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0313] In some embodiments, if the pediatric patient is under 12 years of age and weighs about 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, and the 6 mg dose is administered twice daily as about 6 mL of a solution containing about 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, and the 6 mg dose is administered twice daily as about 12 mL of a solution containing about 0.5 mg / mL.

[0314] In some embodiments, if the pediatric patient is under 12 years of age and weighs about 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, and the 8 mg dose is administered twice daily as about 8 mL of a solution containing about 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, and the 8 mg dose is administered twice daily as about 16 mL of a solution containing about 0.5 mg / mL.

[0315] In some embodiments, if the pediatric patient is under 12 years of age and weighs about 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, and the 12 mg dose is administered twice daily as about 12 mL of a solution containing about 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, and the 12 mg dose is administered twice daily as about 24 mL of a solution containing about 0.5 mg / mL.

[0316] In some embodiments, if the pediatric patient is under 12 years of age and weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0317] In some embodiments, when the pediatric patient is 12 years of age or older and weighs less than approximately 40 kg, the method includes administering upadacitinib 8 mg orally twice daily (8 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0318] In some embodiments, if the pediatric patient is 12 years of age or older and weighs less than approximately 40 kg, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0319] In some embodiments, pediatric patients achieve one or more vIGA-AD scores of 0 or 1, or at least a 75% (EASI 75), 90% (EASI 90), or 100% (EASI 100) improvement in the Eczema Area Severity Index (EASI). In some embodiments, pediatric patients achieve one or more vIGA-AD scores of 0 or 1, or an improvement of EASI 75, EASI 90, or EASI 100 at 8, 10, 12, 14, 16, 18, 20, 22, 24, 48, or 52 weeks after the first daily dose. In some embodiments, pediatric patients achieve EASI 75 at 12 weeks after the first daily dose. In some embodiments, pediatric patients achieve EASI 90 at 12 weeks after the first daily dose. In some embodiments, pediatric patients achieve an EASI of 100 12 weeks after the first daily dose. In some embodiments, pediatric patients achieve a vIGA-AD score of 0 or 1 12 weeks after the first daily dose. In some embodiments, pediatric patients achieve a vIGA-AD score of 0 12 weeks after the first daily dose. In some embodiments, pediatric patients achieve a vIGA-AD score of 1 12 weeks after the first daily dose.

[0320] In some embodiments, the pediatric patient has severe atopic dermatitis (AD).

[0321] In some embodiments, pediatric patients have moderate to severely active pcJIA.

[0322] In some embodiments, pediatric patients showed an inadequate response to one or more topical corticosteroids (TCS).

[0323] In some embodiments, pediatric patients showed an inadequate response to one or more biological agents.

[0324] VIII. Treatment of pediatric patients with juvenile psoriatic arthritis In some embodiments, pediatric patients have juvenile psoriatic arthritis (JPsA). JPsA is a chronic systemic inflammatory disease characterized by the coexistence of arthritis and psoriasis, and is classified as a subtype of spondyloarthritis (SpA). Its course is usually characterized by repeated exacerbations and remissions. If left untreated, JPsA patients may develop persistent inflammation, progressive joint impairment, functional impairment, and a shortened lifespan. Initial treatment of musculoskeletal symptoms consists of nonsteroidal anti-inflammatory drugs (NSAIDs) and topical corticosteroid injections, while topical therapy is used for the initial treatment of psoriasis. For subjects who are inadequately responsive to these measures or who experience toxicity, systemic therapy with non-biological disease-modifying antirheumatic drugs (non-biological DMARDs) (e.g., methotrexate [MTX], leflunomide [LEF], sulfasalazine [SSZ]) and cyclosporine A is recommended. Subsequently, antitumor necrosis factor (TNF) therapy is recommended for subjects who do not show a sufficient response. Furthermore, in selected PsA patients, other biological therapies such as IL-12 / 23 inhibitors or IL-17 inhibitors are recommended as alternatives to anti-TNF inhibitors. See, for example, Gossec et al., Ann Rheum Dis. (2016), Vol. 75, pp. 499-510; Coates et al., Arthritis Rheumatol. (2016), Vol. 68, pp. 1060-1071. However, despite the beneficial results obtained with currently available biological therapies, approximately 40% of patients do not achieve at least a 20% improvement in the American College of Rheumatology (ACR) score, and the clinical remission rate for PsA patients who have received currently available biological therapies is only 58%-61% after one year of treatment, with only about 43% achieving sustained remission (maintenance for at least one year).For example, see Gossec et al., Ann Rheum Dis. (2016), Vol. 75, pp. 499-510; Alamanos et al., J Rheumatol. (2003), Vol. 30, pp. 2641-2644; Savolainen et al., J Rheumatol. (2003), Vol. 30, pp. 2460-2468; Sandborn, Dig Dis. (2010), Vol. 28, pp. 536-542; Saber et al., Arthritis Res Therapy (2010), Vol. 12: R94; Perrotta et al., J Rheumatol. (2016), Vol. 43, pp. 350-355.

[0325] Therefore, there remains a clear medical need for further treatment options for juvenile psoriatic arthritis (JPsA). Thus, providing safe, well-tolerated, and effective JPsA treatments for pediatric patients is desirable in this art.

[0326] Pediatric doses (i.e., based on body weight) that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above and in Example 1 below. Accordingly, in one embodiment, a method for treating JPsA in pediatric patients is provided herein using the body weight-based pediatric doses disclosed above. The method generally involves administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or as a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0327] In some embodiments, a body weight-based pediatric dose provides an exposure level consistent with the efficacy of JPsA treatment in adult patients.

[0328] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0329] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0330] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0331] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0332] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0333] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0334] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0335] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0336] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0337] In some embodiments, pediatric patients have moderate to severe JPsA.

[0338] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0339] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors.

[0340] IX. Treatment of pediatric patients with juvenile ankylosing spondylitis In some embodiments, pediatric patients have juvenile ankylosing spondylitis (JAS). JAS is a chronic inflammatory rheumatic disease that primarily affects the axial skeleton and is characterized by chronic lower back pain (including nocturnal lower back pain), morning stiffness, enthesitis, peripheral arthritis, and extra-articular symptoms.

[0341] The long-term debilitating nature of AS often leads to irreversible structural damage, negatively impacting patients' lives. Since there is no cure for AS, the primary goal of treatment is to maximize the patient's quality of life by controlling disease signs and symptoms, preventing structural damage, and maintaining physical function, ideally achieving sustained clinical remission, or at least low disease activity. The first-line treatment for AS is nonsteroidal anti-inflammatory drugs (NSAIDs), and for patients who do not respond well to NSAIDs, biomedical disease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosis factor (TNF) inhibitors or interleukin-17 (IL-17) inhibitors, are recommended. While TNF inhibitors and IL-17 inhibitors are effective in some AS patients, there are still patients for whom individual treatment goals are not met by either of these approved treatments. AS is a difficult disease to treat, as evidenced by the low efficacy of IL-6 inhibitors (tocilizumab and sarilumab), IL-12 / 23 inhibitors (ustekinumab), and T-cell blocking inhibitors (abatacept). See, for example, Sieper et al., Ann. Rheum. Dis., 2014, Vol. 73, pp. 95-100; Sieper et al., Ann. Rheum. Dis., 2015, Vol. 74, pp. 1051-1057; Deodhar et al., Arthritis and Rheumatology, 2019, Vol. 71, pp. 258-270; and Song et al., Ann. Rheum. Dis., 2011, Vol. 70, pp. 1108-1110.

[0342] Therefore, there remains a clear medical need for additional treatment options for juvenile ankylosing spondylitis (JAS). Thus, in this field, it is desirable to provide a safe, well-tolerated, and effective treatment for AS in pediatric patients.

[0343] Pediatric doses (i.e., based on body weight) that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above and in Example 1 below. Accordingly, in one embodiment, a method for treating JAS in pediatric patients is provided herein using the body weight-based pediatric doses disclosed above. The method generally involves administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0344] In some embodiments, a body weight-based pediatric dose provides an exposure level consistent with the efficacy of JAS treatment in adult patients.

[0345] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0346] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0347] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0348] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0349] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0350] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0351] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0352] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0353] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0354] In some embodiments, pediatric patients have moderate to severely active JAS.

[0355] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0356] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors.

[0357] Treatment of pediatric patients with axial spondyloarthritis that does not meet the XX line criteria In some embodiments, pediatric patients have axial spondyloarthritis (nr-axSpA) that does not meet the radiographic criteria. nr-axSpA is a chronic inflammatory rheumatic disease that primarily affects the axial skeleton and is characterized by chronic lower back pain (including nocturnal lower back pain), morning stiffness, enthesitis, peripheral arthritis, and extra-articular symptoms. nr-axSpA is considered an "early form" of ankylosing spondylitis (AS) and shares many characteristics with it.

[0358] Because nr-axSpA has a long-term nature that causes functional impairment, it often leads to irreversible structural damage, negatively impacting the patient's life. Since there is no cure for nr-axSpA, the main goal of treatment is to maximize the patient's quality of life by controlling the signs and symptoms of the disease, preventing structural damage, and maintaining physical function, ideally achieving sustained clinical remission, or at least low disease activity. The first-line treatment for AS is nonsteroidal anti-inflammatory drugs (NSAIDs), and for patients who do not respond well to NSAIDs, biological disease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosis factor (TNF) inhibitors or interleukin-17 (IL-17) inhibitors, are recommended. While TNF inhibitors and IL-17 inhibitors are effective in some AS patients, there are still patients for whom individual treatment goals are not met by either of these approved treatments. AS is a difficult disease to treat, as evidenced by the low efficacy of IL-6 inhibitors (tocilizumab and sarilumab), IL-12 / 23 inhibitors (ustekinumab), and T-cell blocking inhibitors (abatacept). See, for example, Sieper et al., Ann. Rheum. Dis., 2014, Vol. 73, pp. 95-100; Sieper et al., Ann. Rheum. Dis., 2015, Vol. 74, pp. 1051-1057; Deodhar et al., Arthritis and Rheumatology, 2019, Vol. 71, pp. 258-270; and Song et al., Ann. Rheum. Dis., 2011, Vol. 70, pp. 1108-1110. Therefore, in this art, it is desirable to provide a safe, well-tolerated, and effective treatment for nr-axSpA in pediatric patients.

[0359] Pediatric doses (i.e., based on body weight) that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above and in Example 1 below. Accordingly, in one aspect of the present invention, a method is provided herein for treating nr-axSpA in pediatric patients using the body weight-based pediatric doses disclosed above. The method generally involves administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0360] In some embodiments, a body weight-based pediatric dose provides an exposure level consistent with the efficacy of nr-axSpA treatment in adult patients.

[0361] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0362] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0363] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0364] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0365] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0366] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0367] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0368] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0369] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0370] In some embodiments, pediatric patients have moderate to severely active axial spondyloarthritis (nr-axSpA) that does not meet the radiographic criteria.

[0371] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0372] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors.

[0373] XI. Treatment of pediatric patients with hidradenitis suppurativa In some embodiments, pediatric patients have hidradenitis suppurativa (HS). HS is a debilitating skin disorder involving the apocrine glands (sweat glands located in specific areas of the body surface) and hair follicles, characterized by swollen, painful, chronically inflammatory lesions and nodules. HS is localized to body parts containing apocrine glands, such as the armpits, areola, groin, perineum, perianal, and perinatal regions. Immunological abnormalities of hair follicles are suspected to be involved in the pathogenesis of this disease. HS is a recurrent or chronic inflammatory condition, particularly common in young adults, with an average age of onset of 23 years. This disease is not fully understood, and it is thought that patients underreport their cases. However, it is estimated that approximately 1% of the general population in Western Europe is affected, and women are 2 to 5 times more likely to be affected than men (Naldi, L., Epidemiology, Hidradenitis Suppurativa (edited by Jemec et al.), Springer (Heidelberg), 2006).

[0374] Hidradenitis suppurativa (HS) is characterized by recurrent inflammatory nodules, abscesses, and fistulas that develop when the openings of apocrine glands become blocked by sweating or when the glands are underdeveloped and unable to discharge properly. The trapped secretions push sweat and bacteria into the surrounding tissue, causing subcutaneous induration, inflammation, and infection. HS lesions (i.e., nodules, abscesses, and fistulas) are painful and may have a foul odor due to purulent discharge. The combination of these signs and symptoms results in significant disability and social stigma for patients, severely impacting their quality of life.

[0375] Current treatments for moderate to severe HS include short- or long-term oral or topical antibiotics, retinoids, intralesional steroids, oral steroids, immunosuppressants such as cyclosporine or methotrexate, radiotherapy, laser therapy, and the tumor necrosis factor α (TNF-α) antagonist adalimumab. However, adalimumab is the only approved treatment for HS, and other TNF antagonists such as etanercept have failed to improve HS over a 24-week treatment period (Adams et al., Arch Dermatol. Vol. 146 (No. 5), pp. 501-504, 2010). Given the limited success of HS treatment and the debilitating nature of the disease, there is an urgent need for an effective treatment. Therefore, providing a safe, well-tolerated, and effective HS treatment for pediatric patients is desirable in this field.

[0376] Pediatric doses (i.e., based on body weight) that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above and in Example 1 below. Accordingly, in one embodiment, a method is provided herein for treating HS in pediatric patients using the body weight-based pediatric doses disclosed above. The method generally involves administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0377] In some embodiments, a body weight-based pediatric dose provides an exposure level consistent with the efficacy of HS treatment in adult patients.

[0378] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0379] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0380] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0381] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0382] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0383] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0384] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0385] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0386] In some embodiments, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet. In some embodiments, the pediatric patient has moderate to severe HS.

[0387] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0388] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors.

[0389] XII. Treatment of pediatric patients with systemic lupus erythematosus In some embodiments, pediatric patients have systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by antibodies against nuclear and cytoplasmic antigens, multi-organ inflammation, diverse clinical symptoms, and a course of repeated relapses and remissions. SLE causes widespread inflammation and tissue damage in affected organs, which may include the joints, skin, brain, lungs, kidneys, and blood vessels. Symptoms of SLE vary depending on the affected organ but may include fatigue, rash, fever, and joint pain or swelling.

[0390] Currently, there is no cure for SLE, and existing treatments focus on improving quality of life by controlling symptoms and minimizing relapses, primarily through the use of immunosuppressants such as hydroxychloroquine and corticosteroids, as well as immunomodulators such as belimumab and aniflorumab. However, despite these treatments, there remains a significant unmet treatment need among SLE patients. Therefore, providing safe, well-tolerated, and effective SLE treatments for pediatric patients is desirable in this field.

[0391] Pediatric doses (i.e., based on body weight) that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above and in Example 1 below. Accordingly, in one embodiment, a method for treating SLE in pediatric patients is provided herein using the body weight-based pediatric doses disclosed above. The method generally involves administering upadacitinib to the pediatric patient as a stable oral pharmaceutical formulation or a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0392] In some embodiments, a body weight-based pediatric dose provides an exposure level consistent with the efficacy of treating SLE in adult patients.

[0393] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0394] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0395] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0396] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0397] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0398] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0399] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0400] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0401] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0402] In some embodiments, pediatric patients have moderate to severely active SLE.

[0403] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0404] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors.

[0405] XIII. Treatment of pediatric patients with ulcerative colitis In some embodiments, pediatric patients have ulcerative colitis (UC). UC is one of the two major types of inflammatory bowel disease (IBD) of unknown cause. UC is a chronic and relapsing inflammatory disease of the large intestine, characterized primarily by inflammation and ulcer formation in the mucosa, and sometimes in the submucosa of the intestine. Typical clinical symptoms of UC include bloody diarrhea accompanied by rectal urgency and tenesmus. The clinical course is characterized by repeated exacerbations and remissions. Despite the existence of existing treatment options, there remains a significant unmet therapeutic need in UC patients. Therefore, providing a safe, well-tolerated, and effective treatment for UC in pediatric patients is desirable in the art.

[0406] Pediatric doses that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above (i.e., based on body weight). Accordingly, in one embodiment, a method is provided herein for treating UC in pediatric patients using the body weight-based pediatric doses disclosed above. This method comprises treating pediatric patients with ulcerative colitis by administering upadacitinib as a stable oral pharmaceutical formulation or as a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0407] In some embodiments, a body weight-based pediatric dose provides an exposure level consistent with the effectiveness of UC treatment in adult patients.

[0408] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0409] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0410] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0411] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0412] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0413] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0414] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0415] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0416] In some embodiments, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, if the pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet. In some embodiments, the pediatric patient has moderate to severely active UC.

[0417] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0418] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors.

[0419] XIV. Treatment of pediatric patients with Crohn's disease In some embodiments, pediatric patients have Crohn's disease (CD). CD is one of the two major forms of inflammatory bowel disease (IBD) of unknown cause. CD is characterized by severe symptoms such as abdominal pain, diarrhea, weight loss / malnutrition, and fatigue, and follows a progressive course, leading to complications such as fistulas, strictures, and abscesses. Approximately 80% of patients diagnosed with CD require at least one surgical procedure related to the disease at some point (Munkholm P, Langholz E, Davidsen M et al., Gastroenterology. 1993, Vol. 105 (No. 6), pp. 1716-1723). Despite the existence of existing treatment options, there remains a significant unmet treatment need in patients with CD. Therefore, providing a safe, well-tolerated, and effective treatment for CD in pediatric patients is desirable in the art.

[0420] Pediatric doses that achieve exposure levels consistent with efficacy in adult patients are disclosed herein as described above (i.e., based on body weight). Accordingly, in one embodiment, a method is provided herein for treating UC in pediatric patients using the body weight-based pediatric doses disclosed above. This method comprises treating pediatric patients with ulcerative colitis by administering upadacitinib as a stable oral pharmaceutical formulation or as a sustained-release tablet. The amount of upadacitinib administered, the dosage form of the oral formulation, and the frequency of administration (e.g., once or twice daily) vary depending on the patient's body weight.

[0421] In some embodiments, a body weight-based pediatric dose provides an exposure level consistent with the effectiveness of UC treatment in adult patients.

[0422] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering 3 mg of upadacitinib as an oral solution twice daily (3 mg BID). In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered twice daily as approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0423] In some embodiments, when a pediatric patient weighs approximately 10 kg to less than 20 kg, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0424] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 4 mg twice daily (4 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered twice daily as approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0425] In some embodiments, when a pediatric patient weighs approximately 20 kg to less than approximately 30 kg, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0426] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 6 mg twice daily (6 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered twice daily as approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0427] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 8 mg twice daily (8 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered twice daily as approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered twice daily as approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0428] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 12 mg twice daily (12 mg BID) as an oral solution. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered twice daily as approximately 12 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered twice daily as approximately 24 mL of a solution containing approximately 0.5 mg / mL.

[0429] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0430] In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 15 mg once daily (15 mg QD) as a sustained-release tablet. In some embodiments, when a pediatric patient weighs approximately 30 kg or more, the method includes administering upadacitinib 30 mg once daily (30 mg QD) as a sustained-release tablet.

[0431] In some embodiments, pediatric patients have moderate to severely active CD.

[0432] In some embodiments, pediatric patients showed an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

[0433] In some embodiments, pediatric patients showed an inadequate response to one or more TNF inhibitors. [Examples]

[0434] Example 1: Evaluation of the pharmacokinetics and safety of upadacitinib in pediatric subjects with polyarticular juvenile idiopathic arthritis.

[0435] Test plan This study was a phase 1, multi-dose, open-label trial conducted in three parts, involving approximately 124 pediatric subjects aged 2 to under 18 years with polyarticular juvenile idiopathic arthritis (pcJIA). A schematic diagram of the study is shown in Figure 1. Part 1 was a multi-dose, open-label, multi-cohort study. In the 12 to under 18 year old age group (Group 1), two stages of multiple dose escalation levels (low and high doses) were evaluated, while in the two younger age groups (Group 2: 6 to under 12 years old, Group 3: 2 to under 6 years old), only one stage (low dose) was evaluated. Nine subjects were enrolled in each of the low-dose and high-dose cohorts in age group 1. Approximately 18 subjects were enrolled in each of the low-dose cohorts in age groups 2 and 3.

[0436] The dose of upadacitinib was administered according to the subject's body weight, based on three weight categories set for each dose level. At least 10 subjects weighing less than 30 kg were enrolled in this study. Subject recruitment was conducted using an age-based stepwise approach. Upon completion of Part 1, if the subject demonstrated benefit from the study drug, and, based on the investigator's clinical judgment, was not experiencing any persistent adverse events of particular interest or serious adverse events, and with the subject / family's consent, the subject was eligible to participate in Part 2, which involved open-label upadacitinib administration. Part 2 was an open-label, long-term extension study to evaluate the long-term safety and tolerability of upadacitinib. Part 2 subjects received open-label upadacitinib at the low-dose level set for each weight category. At week 156, if the investigator determined that the subject was still benefiting from the treatment, they were eligible to continue treatment until the end of the study. Part 3 was an additional safety cohort. This additional safety cohort enrolled approximately 70 subjects from all age groups between 2 and under 18 years of age, with the aim of evaluating the long-term safety and tolerability of upadacitinib without intensive pharmacokinetic sampling. Part 3 was opened to age groups that had completed enrollment in Part 1. Subjects in Part 3 received open-label upadacitinib at a low dose level set for each weight group, and followed the same visit schedule as subjects in Part 2 after baseline and screening visits, without intensive pharmacokinetic sampling. Dosages were adjusted during the study period for all weight groups after reviewing the results obtained from subjects who completed Part 1 of the study.

[0437] Eligibility Criteria • Subjects must be male or female, between 2 and under 18 years of age, and have a total weight of 10 kg or more at the time of screening. • Diagnosed with pcJIA (rheumatoid factor-positive or negative polyarticular JIA, extensive oligoarticular JIA, or systemic JIA with active arthritis but without active systemic symptoms), with a history of arthritis in at least 5 joints within the first 6 months of onset (in the case of extensive oligoarticular JIA: 4 joints or less within 6 months of onset, and more than 4 joints thereafter), according to ILAR criteria. • Subjects must not have been diagnosed with enthesitis-associated arthritis (ERA) or juvenile psoriatic arthritis (JPSA). • At the time of screening, there must be five or more active joints. An active joint is defined as a joint exhibiting swelling not due to deformation, or, if swelling is not observed, a joint with limited range of motion (LOM) in addition to pain during movement and / or tenderness on palpation, and LOM must be observed in at least three active joints. • If you are receiving methotrexate (MTX), take 20 mg / m² for at least 12 weeks immediately preceding the first day of the trial. 2 The following stable doses must be administered for at least 8 weeks prior to the first day of the study, including the first day of the study. In addition, subjects must receive folic acid or folinic acid in accordance with local standard care. If oral glucocorticoids are being administered, they must have been given a stable dose of 10 mg / day or 0.2 mg / kg / day (whichever is less) for at least one week prior to the first day of the study, including the first day of the study. • No history of exposure to JAK inhibitors. • No persistent or active uveitis within three months prior to the first day of the trial. • The participant must not have received intra-articular or parenteral corticosteroids within four weeks prior to the first day of the trial. • No history of malignant tumors, except for cases of cured non-melanoma skin cancer or localized carcinoma in situ of the cervix. • No history of drug or alcohol abuse deemed clinically significant by the principal investigator within the past six months. • No history of allergic reactions or severe hypersensitivity to the components of the test drug (and its excipients) and / or other drugs of the same class. • No current or past history of infectious diseases, including the following: • No history of recurrent or disseminated herpes zoster (including single outbreaks). • No history of disseminated herpes simplex (including single outbreaks). • Not infected with human immunodeficiency virus (HIV). • Subjects must not have active tuberculosis and must not meet the tuberculosis exclusion criteria (specific requirements for tuberculosis testing are described in the implementation procedure manual). • No active infection requiring parenteral antiinfective medication within 30 days prior to the first day of the trial, nor any active infection requiring oral antiinfective medication within 14 days prior to the first day of the trial. • No patients have chronically recurrent infections and / or active viral infections that would disqualify them from this study based on the clinical assessment of the principal investigator. • No active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. The definition is as follows: • HBV: In subjects positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), HBV deoxyribonucleic acid (DNA) PCR qualitative test showed positive detection sensitivity. • HCV: When HCV ribonucleic acid (RNA) is detected in subjects who are positive for hepatitis C virus antibodies (HCV Ab). • No history of organ transplantation requiring sustained immunosuppression. • No history of gastrointestinal perforation (excluding appendicitis or penetrating injury). Furthermore, patients with diverticulitis or those with a significantly increased risk of gastrointestinal perforation as determined by the principal investigator will be excluded. • The patient does not have any medical conditions that may interfere with drug absorption (including, but not limited to, short bowel syndrome). • No known moderate or potent drug-metabolizing enzyme inhibitors (e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, paroxetine) or inducers (e.g., carbamazepine, rifampin, phenobarbital, phenytoin) have been used within 30 days prior to the first dose of the study drug until the completion of Part 1 of the study. • No known potent cytochrome P450 3A isoform subfamily (CYP3A) inhibitors or inducers have been used systemically from the start of Part 2 or Part 3 of the study until the completion of the study.

[0438] Prohibited drugs and treatments In addition to the drugs listed in the eligibility criteria, the following are prohibited: • The use of biological agents must be discontinued by Study Day 1 (etanercept: 4 weeks, infliximab / adalimumab / abatacept: 8 weeks, golimumab: 10 weeks, tocilizumab / ustekinumab / certolizumab pegol: 12 weeks, canakinumab: 10 weeks, anakinra: 1 week). Use during the study period is also prohibited. Note: If drug concentrations of any of the above approved biological agents are adequately documented to be below the detection limit by market assays, the minimum drug-free period before baseline is not required. Immunosuppressant drugs must be discontinued for at least 30 days prior to administration of the investigational drug or for five times the drug's half-life, and are prohibited until the end of the clinical trial. • The use of known moderate or potent inhibitors of drug-metabolizing enzymes (e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, paroxetine) or inducers (e.g., carbamazepine, rifampin, phenobarbital, phenytoin) is prohibited from 30 days prior to the first dose of the study drug until the completion of Part 1 of the clinical trial. Furthermore, systemic administration of known potent CYP3A inhibitors or inducers is prohibited from the start of Part 2 or Part 3 until the completion of the clinical trial. • Live vaccines were not permitted in Part 1 of the clinical trial. If subjects and the principal investigator chose to administer live vaccines, appropriate precautions should have been taken and completed at least 4 weeks (8 weeks in Japan) prior to the first dose of the study drug, if possible. Although not a protocol requirement, vaccines recommended by regional guidelines should be considered. If live vaccines were required in Part 2 or Part 3, administration of the study drug should be discontinued from at least 4 weeks (8 weeks in Japan) prior to vaccination until at least 4 weeks (8 weeks in Japan) after vaccination. After that, administration may be resumed at the discretion of the principal investigator, provided that appropriate precautions are taken. The investigational drug must be discontinued within 30 days prior to the first dose of the drug or within five half-lives of the drug (whichever is longer). Its use during the clinical trial is also prohibited. JAK inhibitors (e.g., commercially available upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], ruxolitinib [Jakafi®], baricitinib [Olumiant®], peficitinib [Smyraf®], abrocitinib [PF-04965842], filgotinib) were prohibited during the clinical trial.

[0439] The following concomitant medications / treatments were permitted. • Stable dose administration of nonsteroidal anti-inflammatory drugs (NSAIDs) • Stable dose administration of low-dose glucocorticoids (prednisone equivalent to ≤0.2 mg / kg / day, with a maximum of 10 mg per day) • Stable dose administration of methotrexate (MTX) (body surface area 1 m²) 2 (Per serving: ≤20mg / week)

[0440] Investigational drug and treatment period The investigational drug was upadacitinib in the following dosage forms and doses: 7.5 mg tablets (oral), 15 mg tablets (oral), 30 mg tablets (oral), 1 mg / mL solution (oral), and 0.5 mg / mL solution (oral). In Part 1, doses were determined according to three body weight categories. Subjects were stratified by age group, and the dose over seven consecutive days was determined for each dose level based on the three body weight categories shown in Table 2. The doses evaluated in this study were predicted to provide plasma exposure equivalent to that obtained by administering 15 mg once daily (QD) and 30 mg once daily (QD) of the sustained-release formulation to adult RA subjects in each body weight category. Dosage selection was based on population pharmacokinetic analyses of upadacitinib in healthy adults and adult RA subjects, as well as pharmacokinetic simulations across body weight categories using body weight-based allometric scaling of upadacitinib pharmacokinetic parameters (volume of distribution and clearance parameters).

[0441] The doses selected in this study took into account the difference in oral bioavailability between the sustained-release tablet formulation and the oral solution. Based on population pharmacokinetic analysis across Phase 1 to Phase 3 trials, the median (90% predicted interval) mean plasma exposure of upadacitinib at the dosing interval for adult RA patients administered 15 mg once daily (QD) and 30 mg once daily (QD) of the sustained-release formulation were 15.1 ng / mL (8.96–32.7 ng / mL) and 30.0 ng / mL (18.1–63.8 ng / mL), respectively. Based on pharmacokinetic simulations, it was predicted that pediatric patients would also achieve exposure equivalent to that of adults (15 mg QD and 30 mg QD) at low and high doses within each weight category (Table 2). Furthermore, after reviewing the results of subjects who completed Part 1, dose adjustments were made during the study period for all weight categories.

[0442] [Table 2]

[0443] Participants in Part 2 received low-dose levels of upadacitinib as shown in Table 2 in an open-label manner. At week 156, if the principal investigator determined that the participant would benefit from continued treatment, they were given the option to continue treatment at a low-dose level corresponding to their weight category until the end of the study.

[0444] Dose adjustment criteria For each subject, the dose of upadacitinib in Part 1 was determined based on body weight at screening and the assigned study cohort. Where preliminary pharmacokinetic and clinical data (collected after intensive pharmacokinetic sampling on day 7 of Part 1) from at least four subjects in the cohort became available, these data were used, as necessary, to adjust the doses of subjects already enrolled (including those in Parts 2 and 3) and those to be enrolled in the future. Additional criteria were also considered in the decision-making process for dose adjustments in Part 1 to ensure safe and effective exposure.

[0445] In Part 2, subjects receiving upadacitinib continued to receive the same dose until their next scheduled visit (however, the principal investigator may adjust the dose earlier if deemed necessary). At the next scheduled visit, subjects in Part 2 received upadacitinib for the remainder of the study period according to the administration regimen shown in Table 2. Subjects weighing more than 30 kg were given the option of administering upadacitinib oral solution if they were unable to swallow tablets (see Table 2). For subjects who underwent a dose adjustment in Part 2, blood samples for upadacitinib pharmacokinetic analysis were collected before administration, and 1 and 2 hours after administration at an unscheduled visit 4 to 6 weeks after the dose adjustment visit. The times of the two most recent administrations and blood sample collections prior to the trough plasma pharmacokinetic sample taken immediately before administration were recorded in minutes. Blood samples for clinical testing were also collected at the same unscheduled visit.

[0446] In Parts 2 and 3, subjects were administered either a low-dose level corresponding to their weight category (see Table 2) or a dose determined based on data from Part 1. Changes in a subject's weight category were determined by the principal investigator during either the Part 2 or Part 3 trial visit. If the dose was adjusted due to a change in a subject's weight, blood samples for pharmacokinetic analysis were taken from subjects in Parts 2 and 3.

[0447] Research objectives and evaluation items Part 1: • To evaluate the pharmacokinetics, safety, and tolerability of upadacitinib after multiple administrations in pediatric subjects with pcJIA. • To evaluate the palatability of oral upadacitinib solution in pediatric subjects. • To evaluate the descriptive efficacy of upadacitinib in pcJIA. Part 2: • To evaluate the long-term safety and tolerability of upadacitinib in pediatric subjects with pcJIA who have completed Part 1. To evaluate the descriptive efficacy of upadacitinib in pcJIA. Part 3: To evaluate the long-term safety and tolerability of upadacitinib in pediatric subjects with pcJIA. To evaluate the descriptive efficacy of upadacitinib in pcJIA.

[0448] In Parts 2 and 3, subjects whose total number of active joints (joints with swelling not due to deformation, or joints with limited range of motion accompanied by pain, tenderness, or both) did not improve by 20% or more at two consecutive visits (from week 8 onward) compared to baseline, discontinued administration of the study drug and received treatment according to local standard care at the discretion of the principal investigator.

[0449] Safety evaluation items Safety assessments included the incidence of therapeutic adverse events (TEAEs), physical examination results, changes in vital signs, and clinical laboratory tests (hematology and chemistry), which were used as indicators of safety and tolerability throughout the entire study period.

[0450] Pharmacokinetic evaluation items Part 1 discusses the pharmacokinetic parameters (C) of upadacitinib. max , the time to reach the highest observed plasma concentration [T max ], Area under the plasma concentration-time curve within the dosing interval on day 7 [AUC tau The apparent oral clearance [CL / F] at steady state and half-life were calculated using the non-compartment method.

[0451] Effectiveness evaluation items The following efficacy parameters were collected and used to determine the American College of Rheumatology (ACR) response and the Juvenile Arthritis Disease Activity Score (JADAS) in juvenile arthritis: • Total number of active joints (definition: • Joints with swelling not due to deformation, or (Joints with limited range of motion [LOM] and accompanied by pain, tenderness, or both) • Number of joints with limited range of motion • Child Health Assessment Questionnaire (C-HAQ) • Overall assessment of disease activity by a physician (Visual Analog Scale [VAS]) • Patient / caregiver assessment of overall health status (VAS) • Erythrocyte sedimentation rate (ESR) • C-reactive protein (CRP)

[0452] Based on the parameters described above, the following composite efficacy endpoints were evaluated: JIA ACR Pediatric 30 / 50 / 70 / 90 / 100 Responses • Changes from baseline in JADAS 10 / 27 / 71 responses, as well as JADAS criteria for low disease activity and remission (if deemed useful and appropriate).

[0453] Example 2: Pharmacokinetics of upadacitinib in pediatric patients with polyarticular juvenile idiopathic arthritis (pcJIA); Interim results analysis of Example 1

[0454] the purpose The primary objective of this analysis was to characterize the pharmacokinetics of upadacitinib in a Phase 1 trial in children with pcJIA (pharmacokinetic analysis of Example 1).

[0455] method Patients diagnosed with pcJIA (N=51) were randomly assigned to one of the following four groups in an open-label, multi-dose study: Group 1: 12 to under 18 years old, low-dose group Group 2: 12 to under 18 years old, high-dose group Group 3: Children aged 6 to under 12 years, low-dose group Group 4: Children aged 2 to under 6 years, low-dose group

[0456] The low and high doses were designed to provide plasma exposure in children equivalent to that of the 15 mg once daily and 30 mg once daily sustained-release tablet formulations administered to adults, respectively. Patients received upadacitinib either as a twice-daily (BID) immediate-release (IR) oral solution or as a once-daily (QD) sustained-release (ER) tablet formulation, based on their body weight. Pharmacokinetic evaluations were performed at steady state on day 7 of the trial, after which all patients were able to continue the study at the low dose.

[0457] result A summary of the background data of the registered subjects is shown in Table 3. Pharmacokinetic results are reported from 49 patients whose drug concentrations were evaluable on day 7 of the trial.

[0458] In Group 1, the geometric mean maximum plasma concentration (C) of upadacitinib was max ) and AUC in the steady state 0-24 The values ​​were 35.1 ng / mL and 269 ng·hmL, respectively.

[0459] In Group 2, the geometric mean C of upadacitinib max and AUC 0-24 The values ​​were 69.8 ng / mL and 553 ng·hmL, respectively.

[0460] In Group 3, the geometric mean C of upadacitinib max and AUC 0-24 The values ​​were 51.0 ng / mL and 346 ng·hmL, respectively.

[0461] In Group 4, the geometric mean C of upadacitinib max and AUC 0-24 The values ​​were 46.6 ng / mL and 369 ng·hmL, respectively.

[0462] The median time to peak upadacitinib concentration was approximately 3 hours with the once-daily sustained-release tablet regimen and approximately 1 hour with the twice-daily immediate-release solution regimen. The harmonic mean functional half-lives were approximately 5 hours and 2 hours, respectively. Apparent oral clearance of upadacitinib increased with increasing body weight in pcJIA patients. The mean plasma concentration-time profiles of upadacitinib in each group are shown in Figure 2 by dosing regimen. Overall, these data demonstrate that plasma exposure to upadacitinib in pediatric pcJIA patients, using either sustained-release tablets or immediate-release solution in evaluated dosing regimens (both low and high doses), is comparable to that of targeted adult RA patients. These results support the use of body weight-based dosing regimens in pediatric trials of upadacitinib.

[0463] [Table 3]

[0464] Example 3: Safety and efficacy of upadacitinib in pediatric patients with polyarticular juvenile idiopathic arthritis (pcJIA): Interim analysis of an open-label phase 1 trial (analysis up to week 12, including interim results from Example 1)

[0465] the purpose The purpose of this study was to evaluate the safety and efficacy of upadacitinib in pediatric patients with pcJIA, separated by age group.

[0466] method This study was an open-label, three-part Phase 1 trial (NCT03725007) that enrolled pediatric patients (ages 2 to under 18 years) with five or more active joints in pcJIA at 31 sites located in North America, Europe, and Asia. Part 1: A two-stage multiple escalation UPA dose group (low-dose group: oral solution 3 mg or 4 mg twice daily or tablet 15 mg once daily; high-dose group: oral solution 6 mg or 8 mg or tablet 30 mg) was administered for 7 days based on weight groups (10 kg to under 20 kg, 20 kg to under 30 kg, ≥ 30 kg) and age groups (2 to under 6 years, 6 to under 12 years, 12 to under 18 years). Part 2 (long-term extension of Part 1): The low-dose group (oral solution 3 mg or 4 mg or tablet 15 mg) was administered for up to 156 weeks based on weight groups. Part 3 (Additional Safety Cohort): The low-dose group was administered similarly. Efficacy endpoints included ACR response (30 / 50 / 70), Pediatric Health Assessment Questionnaire (C-HAQ), and 27-point Juvenile Arthritis Disease Activity Score (JADAS-27) at 12 weeks in patients treated in Parts 1 and 2. This report is an interim analysis.

[0467] result A total of 57 pediatric patients (mean [standard deviation] age 9.5 [4.4] years, 78.9% female, mean [standard deviation] weight 38.1 [20.4] kg) received UPA. In Part 1, 8 out of 51 patients (15.7%) reported adverse events (AEs) over a 7-day period, but no serious AEs or AEs leading to discontinuation of treatment were observed. In Parts 2 and 3, 52 out of 57 patients (91.2%) reported AEs, the majority of which were mild to moderate (see Table 4). The incidence of AEs was generally highest in the patient group aged 12 to under 18 years. The most common and noteworthy AEs were elevated creatine phosphokinase (6 / 57 patients, 10.5%), liver dysfunction (3 / 57 patients, 5.3%), and neutropenia (2 / 57 patients, 3.5%). Of the 19 patients aged 12 to under 18 years, 6 (31.6%) reported serious adverse events (AEs), and 2 (10.5%) reported AEs leading to treatment discontinuation. No deaths were reported. In all age groups, a high proportion of patients achieved ACR30, ACR50, and ACR70 responses at 12 weeks (see Figures 3A, 3B, and 3C, respectively). In Figures 3A-3C, the numbers on the bar graphs represent the proportion of patients who responded and (n / N). Furthermore, improvements in C-HAQ and JADAS-27 scores from baseline to 12 weeks were observed in all age groups (see Figures 3D and 3E, respectively). Overall, upadacitinib was safe and well-tolerated in pediatric patients with pcJIA and was associated with improved disease activity in a high proportion of patients at 12 weeks in this interim analysis.

[0468] [Table 4]

[0469] Example 4: Pharmacokinetics, safety, and tolerability of upadacitinib in pediatric patients with atopic dermatitis The purpose of this study was to clarify the pharmacokinetics (PK), safety, and tolerability of upadacitinib in pediatric patients with severe atopic dermatitis (AD).

[0470] method This study was an open-label, multi-dose trial. Thirty-five AD patients were enrolled in the following four cohorts: • Cohort 1: Children aged 6 to under 12 years, low-dose group • Cohort 2: Ages 6 to under 12, high-dose group • Cohort 3: Children aged 2 to under 6 years, low-dose group • Cohort 4: Children aged 2 to under 6 years, high-dose group

[0471] Upadacitinib was administered based on body weight as an oral solution twice daily (BID) or as a sustained-release tablet once daily (QD). Low and high doses were designed to provide plasma exposure equivalent to the adult doses of 15 mg and 30 mg once daily, respectively, in pediatric patients. PK evaluation was performed on day 7 after the initial dose. Safety evaluation was conducted throughout the study period. Exploratory efficacy endpoints were collected at predetermined time points.

[0472] result Geometric mean C in a steady state max The AUC for 0-24 hours was 33.1 and 35.2 ng / mL, and 249 and 264 ng·h / mL, respectively, in Cohort 1 and Cohort 3. In Cohort 2 and Cohort 4, it was 95.5 and 101 ng / mL, and 523 and 625 ng·h / mL, respectively.

[0473] Upadacitinib was generally safe and well-tolerated. The most common adverse events (AEs) were COVID-19 infection, headache, and abdominal discomfort. No new safety risks were observed compared to the known safety profile of upadacitinib.

[0474] In the 29 patients for whom interim efficacy evaluation results were available at week 12, 34.5% achieved a validated investigator global assessment scale score of 0 or 1 for atopic dermatitis, and 69.0% achieved at least a 75% improvement in the Eczema Area and Severity Index (EASI). Overall, these findings support further consideration of the use of a weight-based dosing regimen for upadacitinib in pediatric AD patients in a Phase 3 clinical trial.

[0475] Example 5: Treatment of pediatric patients with severe atopic dermatitis with upadacitinib This study is an open-label, multi-dose, phase 1 trial, currently ongoing, that evaluates the pharmacokinetics (PK), safety, and tolerability of upadacitinib in pediatric subjects with severe atopic dermatitis (AD).

[0476] Test design A schematic diagram of the test design is shown in Figure 4. As shown in Figure 4, the test consisted of two parts.

[0477] Part 1 was a multi-dose, open-label, multi-cohort study consisting of two multiple-stage multiple-escalation dose groups (low-dose and high-dose levels) in two age groups (Group 1: 6 to under 12 years, Group 2: 2 to under 6 years). Upadacitinib was administered according to predefined weight categories set for each dose level, based on the subjects' body weight, with at least four subjects in each weight category (see Table 5). The objective of Part 1 was to evaluate the pharmacokinetics, efficacy, safety, and tolerability of upadacitinib at multiple doses in pediatric subjects with severe atopic dermatitis, as well as to evaluate the palatability of the oral upadacitinib solution in pediatric subjects.

[0478] Part 2 was a multi-dose, open-label, long-term extension study evaluating the long-term safety and tolerability of upadacitinib. Participants in Part 2 received open-label upadacitinib at low dose levels corresponding to their weight category.

[0479] [Table 5]

[0480] Participants who completed Part 1 had the option to enroll in Part 2 and receive open-label low-dose upadacitinib. In Part 2, the use of topical medication for Alzheimer's disease was permitted at the discretion of the principal investigator during the study period. Participants who showed a worsening of 25% or more compared to their baseline EASI score at two consecutive regular visits from week 4 onwards, or who did not show at least a 50% improvement compared to baseline at two consecutive visits (from week 8 onwards), discontinued the study drug and received treatment at the discretion of the principal investigator and according to local standard treatment.

[0481] Key Eligibility Criteria Enrollment was limited to male and female subjects aged 2 to under 12 years at the time of screening, with a baseline total weight of 10 kg or more. The criteria for AD were as follows: • The patient must have been diagnosed with Alzheimer's disease (AD) at least 6 months prior to baseline. • Meets the diagnostic criteria for Alzheimer's and Rajka's Alzheimer's disease (AD). • The disease is active and meets all of the following disease activity criteria at screening and baseline visits: • Eczema Area Severity Index (EASI) score of 21 or higher; • AD's validated investigator global assessment scale (vIGA-AD) score is 4; • The area affected by Alzheimer's disease covers more than 15% of the body surface area. • A history of inadequate response to or poor tolerance of topical corticosteroids (TCS) and / or topical calcineurin inhibitors (TCI) within 12 months prior to baseline visit, or a medical inappropriateness for the use of TCS or TCI.

[0482] Test population: Between January 31, 2019, and March 18, 2022, a total of 32 subjects were enrolled in this study and received at least one dose of upadacitinib. Enrollment for Cohort 4 is currently underway. An additional 20 subjects failed screening. The most common reason for failing pre-screening was that subjects did not meet the Hanifine and Rajka criteria for AD. One subject (3.1%) discontinued upadacitinib in Part 1, and ten subjects (32.3%) discontinued it in Part 2. The main reasons for discontinuation in Part 2 were insufficient efficacy (n=4, 12.9%) and adverse events (n=3, 9.7%).

[0483] The median exposure to upadacitinib for all subjects was 7.0 days (range: 1–9 days) in Part 1 and 170 days (range: 1–770 days) in Part 2 (see Table 6).

[0484] [Table 6]

[0485] Background data (Table 7) and baseline disease characteristics (Table 8) for all enrolled subjects are shown below. The majority of subjects treated with upadacitinib were female (n=18, 56.3%), Caucasian (n=19, 59.4%), and had a median age of 6.0 years (range: 2–11 years).

[0486] Preliminary analysis of clinical pharmacokinetics A summary of the pharmacokinetic (PK) parameters of upadacitinib on day 7 is shown in Figures 5A–5D and Table 9. In cohorts 1, 2, 3, and 4, 9, 8, 6, and 0 subjects received upadacitinib with the initial dosing regimen defined in the protocol, respectively, while 0, 0, 2, and 6 subjects received the revised dosing regimen. Furthermore, one subject enrolled in cohort 3 withdrew consent before PK evaluation and was therefore not included in the PK analysis. For the analysis of plasma concentration-time profiles and pharmacokinetic parameters, data from all these subjects were summarized by cohort and dosage form (see Figures 5A–5D and Table 9).

[0487] Preliminary analysis of clinical efficacy Clinical efficacy parameters were collected as exploratory endpoints and used to facilitate a benefit-risk assessment to justify low-dose upadacitinib administration in the continuation of Part 2 (evaluation of long-term safety and tolerability). Formal statistical comparisons were not planned. Since all cohorts received low-dose upadacitinib in Part 2, efficacy assessments were summarized for the entire population.

[0488] The pharmacodynamic activity of upadacitinib was demonstrated by efficacy outcome measures evaluating improvement from baseline to multiple study time points. At week 12, a validated investigator global assessment scale (vIGA-AD) score of 0 or 1 (at least two-step improvement from baseline) for atopic dermatitis was achieved in 9 out of 27 subjects (33.3%) in the overall cohort population at the data cutoff (Table 10). This means that the skin achieved a “clear” or “nearly clear” state. Notably, despite the fact that 10 subjects in cohorts 1, 2, and 3 required dose increases to reach sufficient upadacitinib plasma exposure, efficacy was observed in the overall population.

[0489] At week 12, an at least 75% change in the Eczema Area and Severity Index (EASI) from baseline (EASI 75) was achieved in 19 out of 27 subjects (70.4%) in the overall cohort population at the data cutoff (Table 11). The mean and median percentage change in EASI scores from baseline at week 12 for the overall cohort population were -79.8% and -82.9%, respectively, at the data cutoff (Table 12). Tables 10-12 describe the results for the overall population, the cohort aged 2-6 years, the cohort aged 6-12 years, subjects enrolled in the initial dosing scheme, and subjects enrolled after the dosing scheme was readjusted to reach the target upadacitinib plasma exposure.

[0490] Furthermore, efficacy outcomes were also summarized for eight subgroups from cohorts 3 and 4 treated with the revised upadacitinib dosing scheme from the start of the trial. Although efficacy data at week 12 were available for only seven of these subjects, all achieved an EASI 75 response at week 12. The percentage changes from baseline in EASI 75, vIGA-AD 0 / 1, and EASI score in these subjects were consistent with the results for the overall population at each time point. In addition, for 10 subjects enrolled in the protocol prior to version 3.0 and subsequently receiving dose increases at different time points due to dosing modifications based on protocol version 4.0, the response rates, measured as EASI 75 and vIGA-AD score 0 / 1 (with at least a two-step improvement from baseline), showed numerical improvement at 12 weeks after dose increase.

[0491] [Table 7]

[0492] [Table 8]

[0493] [Table 9]

[0494] [Table 10]

[0495] [Table 11]

[0496] [Table 12]

[0497] Example 6: Upadacitinib immediate-release liquid formulation For use in children, oral solutions were developed to improve acceptability (palatability and ease of swallowing), stability, and formulation suitability. Specifically, stable oral pharmaceutical solutions of upadacitinib (1 mg / mL and 0.5 mg / mL) were prepared. Upadacitinib exhibits good solubility at low pH (see Table 13). Therefore, low pH buffers such as citrate, phosphate, tartrate, and formate are suitable for preparing oral solutions. Buffers with a higher pH range, such as succinate and acetate, can also be used (see Example 7), but these result in oral suspensions. Citrate buffer was selected because its pKa (approximately 3.1) approximates the final pH of the oral solution, making it preferable. Therefore, formulations based on liquid solubility were developed by adding citrate and sodium citrate to completely dissolve upadacitinib.

[0498] Upadacitinib exhibits a strong bitter taste at concentrations above 0.1 mg / mL. Formulations that are tolerable and have a good palatability have a bitterness intensity of less than 1.0. Therefore, the bitterness of upadacitinib can be reduced by using sweeteners, bitterness masking agents, or taste modifiers, as well as flavoring agents. Sweeteners such as acesulfame potassium, sodium saccharin, sucralose, neotame, sucrose, maltitol, and xylitol, or combinations thereof, are suitable for this oral solution. Taste modifiers such as sodium chloride, citric acid, and monoammonium glycyrrhizinate are also suitable for this oral solution. Flavoring agents such as cherry, orange, bubblegum, strawberry, and mango can improve the palatability of the formulation.

[0499] Upadacitinib oral solution contains water and sweeteners, which may cause microbial growth. Furthermore, this oral solution is a multi-dose formulation. Therefore, preservatives are added to the formulation to prevent microbial growth. Depending on the final pH of the oral solution, sodium benzoate and propylparaben are suitable preservatives. Sodium metabisulfite, benzoic acid, parahydroxybenzoic acid, potassium sorbate, and parahydroxybenzoic acid can also be used depending on the final pH of the oral solution or suspension.

[0500] Upadacitinib 1 mg / mL oral solution C contains citric acid, sodium citrate, sucralose, sodium benzoate, and water. This 1 mg / mL oral solution C was colorless and transparent or pale yellow. The compositions of specific 1 mg / mL and 0.5 mg / mL oral solutions are shown in Table 14.

[0501] [Table 13]

[0502] [Table 14]

[0503] Example 7: Upadacitinib immediate-release or sustained-release liquid formulation (suspension) To accommodate higher dose strength or higher pH, immediate-release oral suspensions are prepared. The buffers, preservatives, and sweeteners listed in Example 6 may be used in this formulation. Generally, sustained-release liquid formulations are prepared to achieve sustained release of upadacitinib for once-daily administration using release rate modifiers such as ion exchange resins. The liquid formulation contains an upadacitinib-ion exchange resin complex, in which upadacitinib or a pharmaceutically acceptable salt thereof is bonded to an ion exchange resin. Suitable ion exchange resins include, but are not limited to, sulfonated copolymers containing styrene and divinylbenzene. In some such embodiments, the mobile or exchangeable cation is sodium. An exemplary cation exchange resin is AmberLite® IRP69 (DuPont).

[0504] Example 8: Safety and efficacy of upadacitinib in pediatric patients with polyarticular juvenile idiopathic arthritis (pcJIA): Interim analysis of an open-label phase 1 trial (analysis up to week 48, including interim results from Example 1) This embodiment provides additional data up to week 48 for the test described in Example 1.

[0505] the purpose The purpose of this study was to evaluate the pharmacokinetics, efficacy, and safety of upadacitinib in pediatric patients with polyarticular juvenile idiopathic arthritis (pcJIA).

[0506] method As described in Example 1 above, this study was an open-label Phase 1 trial in patients aged 2 to under 18 years of age with pcJIA. Patients received a dose of upadacitinib determined based on body weight, either as an oral solution twice daily (BID) or as a sustained-release tablet once daily (QD) (see Table 15). The study included a 7-day pharmacokinetic evaluation followed by long-term efficacy and safety evaluations over up to 156 weeks, and also included an additional long-term safety cohort. This interim analysis includes all pharmacokinetic, safety, and efficacy data collected up to week 48, excluding patients enrolled in the long-term safety cohort. A schematic diagram of the study design, including body weight categories, is shown in Figure 6.

[0507] [Table 15]

[0508] result Patients and Outcomes A summary of patient outcomes is shown in Figure 7. A summary of patient background data and disease characteristics is shown in Table 16. As shown in Table 16, the majority of enrolled patients were female (45 / 57 cases, 78.9%) and had RF-negative polyarticular JIA (42 / 57 cases, 73.7%). The ages of enrolled patients ranged from 2 to 17 years, and the mean duration of illness was 3 years. At baseline, 23 patients (40.4%) were receiving methotrexate, 11 patients (19.3%) were receiving oral corticosteroids, and 14 patients (24.6%) reported a history of bDMARD use.

[0509] [Table 16]

[0510] Pharmacokinetics The mean plasma concentration-time profiles (by dose level and formulation) are shown in Figures 8A-8C, compared to the adult reference profiles simulated from pharmacokinetic analysis based on upadacitinib data obtained in the RA trial (Phase 3). The adult RA reference represents the median (dashed line) and (5th and 95th percentiles) (shaded areas) of model-predicted upadacitinib plasma concentrations in adult RA patients after QD tablet administration. These reference pharmacokinetic profiles were simulated using previously developed models for RA patients. The low-opacity symbols (12-24 hours) for the IR BID regimen are replicated from observed data (0-12 hours) to compensate for differences in administration frequency between the BID oral solution formulation and the QD tablet formulation.

[0511] Table 17 summarizes the steady-state pharmacokinetic parameters on day 7 after administration of upadacitinib to patients enrolled in Part 1. During pharmacokinetic evaluation, 13 patients in Group 3 and 12 patients in Group 4 received modified doses, while the other patients received their initial doses. max This was reached approximately 3 hours after administration with the ER tablet formulation and approximately 1 hour after administration with the IR oral solution formulation. The functional effects of upadacitinib 1 / 2 For ER tablets, the interval was approximately 5 hours within the QD dosing interval, and for IR solution, it was approximately 2 hours within the BID dosing interval.

[0512] [Table 17]

[0513] Effectiveness By the data cutoff date, 50 out of 51 patients from Part 1 and Part 2 had efficacy evaluation results at week 12, and 37 had efficacy evaluation results up to week 48. At that point, 35 out of 37 patients were being treated based on the revised upadacitinib administration scheme. The summaries of the JIA ACR30 / 50 / 70 response, C-HAQ, and JADAS-27CRP at week 12 are shown in Figures 9A-9E, respectively. Overall, the JIA ACR30 / 50 / 70 / 90 / 100 response rates at week 12 in patients from Part 1 and Part 2 were 91.8%, 89.8%, 69.4%, 49.0%, and 32.7%, respectively. By age group, the 2-6 year old and 6-12 year old groups showed similar improvements, while the 12-18 year old group showed a numerically lower rate of JIA ACR response compared to these younger groups, although the difference was not statistically significant. The response to upadacitinib was rapid, with 61.2% of patients achieving JIA ACR30 by week 1. The JIA ACR response further improved at week 24 and was generally maintained until week 48 (Figure 10A). Other key efficacy indicators (C-HAQ, total number of active joints, physician's visual assessment of disease activity (VAS), patient / guardian's visual assessment of overall health status (VAS), JADAS-27 CRP, JADAS-27 ESR, ESR, and CRP) are summarized in Table 18. At week 12, these efficacy indicators showed improvement from baseline in all age groups, and consistent baseline changes were observed across age groups. Changes in JADAS-27 ESR were similar to those in JADAS-27 CRP. At week 12, 29 out of 50 patients (58%) achieved a JADAS-27 CRP ≤ 3.8, and 16 patients (32%) achieved a JADAS-27 CRP ≤ 1. The proportion of patients achieving these responses further increased at week 24 and was largely maintained until week 48 (Figures 10B, 10C, and 10D).

[0514] [Table 18] TIFF2026511037000020.tif146170

[0515] Consideration In this open-label Phase 1 trial, upadacitinib administered at fixed doses according to body weight categories was effective and well-tolerated in pediatric patients with pcJIA. Furthermore, the pharmacokinetics of upadacitinib observed in pediatric patients with pcJIA using the once-daily (QD) extended-release (ER) formulation and the twice-daily (BID) immediate-release (IR) formulation were consistent with the characteristic pharmacokinetics of each formulation in adult patients.

[0516] The initial dosing regimen for upadacitinib was selected using pharmacokinetic data of upadacitinib in adult RA patients and allometric scaling of clearance and volume of distribution based on body weight, with the goal of ensuring that upadacitinib exposure in pcJIA patients was equivalent to the optimal exposure in adult RA patients. Preliminary population pharmacokinetic analyses in this study showed that apparent oral clearance in pediatric patients was underestimated when a typical index (0.75) was used for upadacitinib clearance estimates obtained from adult RA patients to describe the relationship between body weight and clearance. Therefore, a revised dosing regimen was developed and applied to young pediatric patients (mostly 6 to under 12 years and 2 to under 6 years), enabling the achievement of upadacitinib exposure comparable to the target exposure in adult RA patients. Based on previous analyses, the median area under the steady-state plasma concentration-time curve (AUC) (5th and 95th percentiles) for upadacitinib in adult RA patients participating in the Phase 3 trial was 358 (234, 701) ng·h / mL after daily administration of 15 mg ER tablets and 708 (466, 1332) ng·h / mL after daily administration of 30 mg ER tablets. In this study, the median target exposure (AUC) for adults was... 0-24 Relative upadacitinib AUC by group compared to ) 0-24 The median exposure ranged from approximately 0.77 to 1.07 (Table 19). In particular, in the young pediatric patient group, where the majority of patients received the revised dose, the observed upadacitinib exposure was almost identical to the target exposure in adult patients, with a ratio of 1.01.

[0517] In this study, the BID oral solution of the IR formulation was used in patients weighing less than 30 kg or in patients unable to swallow tablets. Although the pharmacokinetic profile differed depending on the administration frequency, the AUC of upadacitinib was also observed. 0-24 If equivalent outcomes are achieved, the BID oral solution is expected to demonstrate equivalent efficacy to the QD tablets in pcJIA. This is supported by exposure-response analyses of the primary efficacy endpoint previously conducted in adult RA patients. Specifically, a model built on data obtained using the BID capsule formulation in the Phase 2 trial accurately predicted the efficacy observed with the QD tablet formulation in the Phase 3 trial. These analyses showed equivalent AUC. 0-24 The BID IR regimen and QD ER regimen of upadacitinib, which provide this information, are expected to achieve comparable efficacy responses.

[0518] Based on a descriptive analysis of efficacy endpoints, this study showed improvements in disease activity, pain, function, and overall health status in pcJIA patients at week 12 and these improvements were largely maintained until week 48. Improvements were observed in all age groups of pcJIA patients (2 to under 18 years of age), with patients aged 2 to under 12 years showing a numerically higher response rate than patients aged 12 to under 18 years. Notably, the majority of the oldest group had a long disease duration and a history of bDMARD use. In contrast, the majority of the younger group had a short disease duration and no history of bDMARD use (see Table 16). Furthermore, no patients had a history of uveitis, and no cases of uveitis were observed during this study. The safety profile of upadacitinib in pediatric pcJIA patients was largely consistent with the known safety profile in adults and adolescents with inflammatory conditions.

[0519] Overall, upadacitinib was well-tolerated and effective in pcJIA patients across all age groups from 2 to under 18 years, achieving plasma exposure levels comparable to those in adult RA patients with the evaluated dosing regimens. No new safety risks were observed in pcJIA patients, and based on the safety and efficacy results to date in this study, the benefit-risk profile of upadacitinib was assessed as favorable.

[0520] [Table 19]

Claims

1. A method for treating polyarticular juvenile idiopathic arthritis (pcJIA) in pediatric patients, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (ii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

2. The method according to claim 1, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to the pediatric patient as a stable oral pharmaceutical solution.

3. The method according to claim 2, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

4. The method according to claim 2 or 3, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

5. The method according to any one of claims 1 to 4, wherein upadacitinib is administered to a pediatric patient once daily in a dose of 15 mg or 30 mg as a sustained-release tablet.

6. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 30 response 12 weeks after the first daily administration.

7. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 50 response 12 weeks after the first daily administration.

8. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 70 response 12 weeks after the first daily administration.

9. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 90 response 12 weeks after the first daily administration.

10. A method for treating systemic juvenile idiopathic arthritis (SJIA) in a pediatric patient, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (iii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

11. The method according to claim 10, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to the pediatric patient as a stable oral pharmaceutical solution.

12. The method according to claim 11, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

13. The method according to claim 11 or 12, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

14. The method according to claim 10, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

15. A method for treating atopic dermatitis (AD) in a child patient under 12 years of age, comprising administering a therapeutically effective dose of upadacitinib to the child patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (iii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

16. The method according to claim 15, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to the pediatric patient as a stable oral pharmaceutical solution.

17. The method according to claim 16, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

18. The method according to claim 16 or 17, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

19. The method according to claim 15, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

20. The method according to any one of claims 15 to 19, wherein the pediatric patient achieves an EASI 75 response 12 weeks after the first daily administration.

21. The method according to any one of claims 15 to 19, wherein the pediatric patient achieves an EASI 90 response 12 weeks after the first daily administration.

22. The method according to any one of claims 15 to 19, wherein the pediatric patient achieves an EASI 100 response 12 weeks after the first daily administration.

23. The method according to any one of claims 15 to 19, wherein the pediatric patient achieves a physician-administered global assessment scale (vIGA-AD) score of 0 or 1 at 12 weeks after the first daily administration.

24. A method for treating psoriatic arthritis (PsA) in a pediatric patient, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (iii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

25. The method according to claim 24, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to the pediatric patient as a stable oral pharmaceutical solution.

26. The method according to claim 25, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

27. The method according to claim 25 or 26, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

28. The method according to claim 24, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

29. A method for treating ankylosing spondylitis (AS) in a pediatric patient, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (iii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

30. The method according to claim 29, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to the pediatric patient as a stable oral pharmaceutical solution.

31. The method according to claim 30, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

32. The method according to claim 30 or 31, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

33. The method according to claim 29, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

34. A method for treating axial spondyloarthritis (nr-axSpA) in pediatric patients that does not meet radiographic criteria, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient. If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (iii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

35. The method according to claim 34, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to the pediatric patient as a stable oral pharmaceutical solution.

36. The method according to claim 35, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

37. The method according to claim 35 or 36, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

38. The method according to claim 34, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

39. A method for treating hidradenitis suppurativa in a pediatric patient, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (iii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

40. The method according to claim 39, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to a pediatric patient as a stable oral pharmaceutical solution.

41. The method according to claim 40, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

42. The method according to claim 40 or 41, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

43. The method according to claim 39, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

44. A method for treating systemic lupus erythematosus in a pediatric patient, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (iii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

45. The method according to claim 44, wherein upadacitinib in doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 8 mg twice daily is administered to the pediatric patient as a stable oral pharmaceutical solution.

46. The method according to claim 45, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

47. The method according to claim 45 or 46, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

48. The method according to claim 44, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

49. A method for treating ulcerative colitis in a pediatric patient, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (ii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

50. The method according to claim 49, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to a pediatric patient as a stable oral pharmaceutical solution.

51. The method according to claim 50, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

52. The method according to claim 50 or 51, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

53. The method according to claim 49, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

54. A method for treating Crohn's disease in a pediatric patient, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If the weight of the aforementioned pediatric patient is between approximately 10 kg and less than approximately 20 kg, (i) administer upadacitinib at a dose of 3 mg twice daily, or (ii) Administer upadacitinib at a dose of 6 mg twice daily; If the weight of the aforementioned pediatric patient is between approximately 20 kg and less than approximately 30 kg, (i) administer upadacitinib at a dose of 4 mg twice daily, or (ii) Administer upadacitinib at a dose of 8 mg twice daily; If the weight of the aforementioned pediatric patient is approximately 30 kg or more, (i) Administer upadacitinib at a dose of 6 mg twice daily. (ii) Administer upadacitinib at a dose of 12 mg twice daily. (iii) Administer upadacitinib at a dose of 15 mg once daily, or (iv) Administer upadacitinib at a dose of 30 mg once daily. Methods that include...

55. The method according to claim 54, wherein upadacitinib in a dose of 3 mg twice daily, upadacitinib in a dose of 4 mg twice daily, upadacitinib in a dose of 6 mg twice daily, upadacitinib in a dose of 8 mg twice daily, or upadacitinib in a dose of 12 mg twice daily is administered to a pediatric patient as a stable oral pharmaceutical solution.

56. The method according to claim 55, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

57. The method according to claim 55 or 56, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

58. The method according to claim 54, wherein upadacitinib in a dose of 15 mg or 30 mg once daily is administered to the pediatric patient as a sustained-release tablet.

59. A stable oral pharmaceutical solution comprising upadacitinib or a pharmaceutically acceptable salt or solid form thereof, buffers and / or pH adjusters, preservatives, sweeteners, and water.

60. A stable oral pharmaceutical solution according to claim 59, comprising anhydrous free base upadacitinib at a concentration of approximately 0.5 mg / mL.

61. A stable oral pharmaceutical solution according to claim 59, comprising anhydrous free base upadacitinib at a concentration of approximately 1 mg / mL.

62. The stable oral pharmaceutical solution according to claim 59, wherein the buffering agent is selected from the group consisting of citrate, phosphate, tartrate, succinate, formate, acetate, and combinations thereof.

63. The stable oral pharmaceutical solution according to claim 59, wherein the pH adjusting agent is selected from the group consisting of citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof.

64. The stable oral pharmaceutical solution according to claim 59, wherein the preservative is selected from the group consisting of sodium benzoate, benzoic acid, propylparaben, sodium metabisulfite, potassium sorbate, hydroxyparabenzoic acid, hydroxyparabenzoate salts, and combinations thereof.

65. The stable oral pharmaceutical solution according to claim 59, wherein the sweetener is selected from the group consisting of sucralose, acesulfame potassium, saccharin sodium, neotame, sucrose, maltitol, xylitol, and combinations thereof.

66. A stable oral pharmaceutical solution according to claim 59, comprising anhydrous free base upadacitinib, citric acid, sodium citrate, sodium benzoate, sucralose, and water.

67. A stable oral pharmaceutical solution according to claim 59, having a pH in the range of approximately 2 to approximately 5.

68. A stable oral pharmaceutical solution according to claim 59, having a pH in the range of approximately 3 to approximately 4.

69. A stable oral pharmaceutical solution according to claim 59, having a pH in the range of approximately 2.5 to approximately 3.

5.

70. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 30 response 24 weeks after the first daily administration.

71. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 50 response 24 weeks after the first daily administration.

72. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 70 response 24 weeks after the first daily administration.

73. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 90 response 24 weeks after the first daily administration.

74. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 30 response at 48 weeks after the first daily administration.

75. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 50 response at 48 weeks after the first daily administration.

76. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 70 response at 48 weeks after the first daily administration.

77. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR pediatric 90 response at 48 weeks after the first daily administration.

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