Maripasvir compositions and uses thereof

Abstract

The present disclosure provides novel methods and compositions for the use of Mariobavir in the treatment of pediatric and teenager patient populations. The present disclosure also provides compositions of Maripasvir in powder form for oral suspensions, which are useful in patients who are difficult to swallow pills, including pediatric and teenager patient populations.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 470,161, filed May 31, 2023; U.S. Provisional Application No. 63 / 525,228, filed July 6, 2023; and U.S. Provisional Application No. 63 / 633,277, filed April 12, 2024, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Cytomegalovirus (CMV) is a member of the herpesvirus family. Human cytomegalovirus (HCMV) infection is common, with 40% to 100% of adults showing serological evidence of prior infection. However, severe HCMV disease occurs almost exclusively in individuals with compromised or immature immune systems. CMMV remains a significant problem for patients undergoing various types of transplants involving the use of potent immunosuppressive chemotherapy, including hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT).

[0004] Currently available systemic anti-CMV agents include intravenous (IV) ganciclovir, oral valganciclovir (a prodrug of ganciclovir with improved bioavailability), IV foscarnet sodium, IV cidofovir, letermovir (IV and oral), and maribavir (oral). In the transplant setting, ganciclovir is the most extensively studied drug in the prevention and treatment of CMV infection or disease. Despite all of these drugs being effective anti-CMV agents, their use is limited by respective toxicities, most notably bone marrow suppression with ganciclovir / valganciclovir, and kidney impairment with foscarnet sodium and cidofovir. These toxicities are of particular concern in transplant patients whose bone marrow has been depleted or significantly suppressed (stem cell transplant (SCT) patients), who receive ongoing chemotherapy, particularly aimed at suppressing their immune system to prevent organ rejection (SOT patients) or graft versus host disease (GVHD; in SCT patients), or who can be on other therapies that have potential toxicity to the kidneys or other organs (SOT and SCT patients). The development of antiviral resistance to currently available anti-CMV agents is also a persistent clinical problem in SOT and HSCT patients, which leads to graft loss and even death in some transplant patients. Letermovir is a newer agent that targets the CMV deoxyribonucleic acid (DNA) terminase; however, it is indicated for the prevention of CMV reactivation and disease in seropositive adult recipients of allogeneic HSCT [R+]. Ganciclovir IV is indicated in the European Union (EU) for adults and adolescents at least 12 years of age for the treatment of CMV disease in immunocompromised patients, while maribavir is approved in the United States (US) for use in adults and pediatric patients at least 12 years of age and weighing at least 35 kg with post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet sodium, with or without genotypic resistance. There is no approved agent for the treatment of CMV infection or disease in pediatric patients <12 years of age and / or weighing less than 35 kg. SUMMARY

[0005] Maribavir is a benzimidazole ribonucleoside and is an orally available antiviral agent against CMV. Maribavir is also known by its trade name LIVTENCITY™. Typically, patients (e.g., adults and / or pediatric patients at least 12 years of age and weighing at least 35 kg) are administered 400 mg maribavir tablets orally twice daily. However, in some aspects, the present disclosure recognizes that many pediatric and adolescent patients are less than 12 years of age and / or weigh less than 35 kg and / or can have difficulty swallowing pills. The present disclosure provides, among other things, methods and compositions for treating such patient populations.

[0006] The present disclosure also provides methods for treating a CMV infection or disease in a patient less than 12 years old, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising maribavir (e.g., an oral liquid formulation). The present disclosure also provides methods for treating a CMV infection or disease in a patient less than 6 years old, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising maribavir (e.g., an oral liquid formulation). In some embodiments, the pharmaceutical composition comprises maribavir, a sweetener, and a flavoring agent. In some embodiments, the present disclosure provides methods of treating a CMV infection or disease in a patient having a CMV infection or disease, comprising orally administering maribavir to the patient, wherein the patient is less than 6 years old.

[0007] In some embodiments, the present disclosure relates to a pharmaceutical composition for oral administration, wherein the composition contains coated particles comprising an active substance (e.g., maribavir) that has an unpleasant taste and / or bitter taste when orally administered. In some embodiments, the present disclosure relates to a pharmaceutical composition containing bitter taste masked coated particles comprising maribavir. In some embodiments, such pharmaceutical composition is in a form suitable for an aqueous suspension. In some embodiments, the pharmaceutical composition is a powder, e.g., a powder for an oral suspension. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1 Flavor profile method definitions and scales for quantitative comparison of sensory information are shown.

[0009] Figure 2 Percent dissolution of formulated batches of maribavir of different particle sizes is shown. DETAILED DESCRIPTION

[0010] Maribavir ((2S,3S,4R,5S)-2-(5,6-dichloro-2-(isopropylamino)-1H- benzo[d]imidazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol) is a compound having the following chemical structure:

[0011] is an effective and orally bioavailable antiviral agent for the treatment of CMV infection or disease in transplant recipients. Pharmaceutically acceptable salts of maribavir are also within the scope of the present disclosure, e.g., in the compositions and methods described herein. Transplant recipients are at high risk for CMV infection or disease. While maribavir is approved for the treatment of CMV in adults and adolescents at least 12 years of age and weighing at least 35 kg, many pediatric and adolescent patients are less than 12 years of age and / or weigh less than 35 kg (collectively, “pediatric patients”), and many patients have difficulty swallowing pills. The present disclosure encompasses the recognition that novel dosing and / or formulations are needed in order to treat CMV in pediatric patients, and provides such methods and formulations. The present disclosure also encompasses the recognition that adult patients who have difficulty swallowing pills need novel formulations, and provides such formulations.

[0012] A previous study evaluating the palatability of maribavir characterized it as having a strong and persistent bitter taste and secondary aromatic off-taste at clinically relevant doses, which poses a taste-masking challenge for pediatric patients, particularly those too young to swallow tablets (e.g., less than 6 years of age). To provide a palatable pediatric use formulation, a taste-masking strategy was explored that minimizes the availability of maribavir in the oral cavity. The taste-masking method uses a polymer to coat the maribavir substance, where the polymer is insoluble at neutral pH (i.e., the pH of saliva) but soluble at acidic pH (i.e., the pH of gastric fluid). By encapsulating maribavir inside a coating polymer, it is believed that maribavir will not be perceived in the oral cavity, but will be released appropriately in the stomach for absorption as a powder substance for liquid suspension.

[0013] In the first part (“Part 1”) of a clinical study (NCT04131556), two maribavir oral suspension formulations were tested, each containing the same coating polymer but in different amounts. The palatability and bioavailability of maribavir for the formulations relative to the tablet formulation were evaluated. Based on the pharmacokinetic results from Part 1 of the study, a second part of the study was planned to test the dose proportionality of one of the two formulations and the effect of food on the rate and extent of absorption of the selected formulation. However, the study was terminated after Part 1 because “based on planned interim analysis of Part 1 data, the palatability of both pediatric formulations was unacceptable.”

[0014] While not wishing to be bound by theory, the unacceptable palatability of the formulations tested in NCT04131556 can be due to the inability of the formulations to fully mask the strong bitter taste of the active drug substance. Accordingly, the present disclosure includes a previously unrecognized source of the problem. The present disclosure provides, among other things, novel formulations that overcome the previous failed attempts to produce a palatable oral liquid formulation of maraviroc. More specifically, using a similar polymer coating technique as the previously tested formulations, but by making modifications to other aspects of the formulation, the present disclosure unexpectedly provides compositions that improve the liquid suspension formulation to an acceptable palatability. Such compositions are also characterized by a dissolution profile that is expected to provide bioavailability of the maraviroc active ingredient that is comparable to oral maraviroc tablets. Slow dissolution rates can be undesirable because they can result in lower bioavailability and, thus, require higher dosages and / or less desirable taste characteristics, affecting compliance and therapeutic efficacy.

[0015] In some embodiments, the provided pharmaceutical compositions suitable for oral administration comprise maraviroc, a pH-sensitive polymer coating, a sweetener, a flavoring agent, and one or more excipients (e.g., a diluent, a disintegrant, or a suspending agent), which can then be made into a liquid suspension. Such pharmaceutical compositions comprise intragranular particles having a particle size found to be useful for optimal dissolution. The provided oral liquid formulations can be administered to patients who are unable to swallow tablets (e.g., patients less than 6 years old, or adult patients who have difficulty swallowing pills) to treat CMV.

[0016] The methods provided by the present disclosure include treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maraviroc to the patient, wherein the patient is at least 12 years old and less than 18 years old, and wherein the amount of maraviroc administered is based on body weight (e.g., 100 mg twice a day for a patient weighing at least 10 kg and less than 14 kg; 200 mg twice a day for a patient weighing at least 14 kg and less than 25 kg; or 400 mg twice a day for a patient weighing at least 25 kg).

[0017] The methods provided by the present disclosure also include treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maraviroc to the patient, wherein the patient is at least 6 years old and less than 12 years old, and wherein the amount of maraviroc administered is based on body weight (e.g., 100 mg twice a day for a patient weighing at least 10 kg and less than 14 kg; 200 mg twice a day for a patient weighing at least 14 kg and less than 25 kg; or 400 mg twice a day for a patient weighing at least 25 kg).

[0018] Further, the present disclosure provides methods for treating CMV infection or disease in a patient less than 6 years old, the methods comprising administering a therapeutically effective amount of a pharmaceutical composition comprising maralixibat (e.g., an oral liquid formulation). In some embodiments, the pharmaceutical composition comprises maralixibat, a sweetener, and a flavoring agent. In some embodiments, the amount of maralixibat administered is based on body weight (e.g., 50 mg once daily for a patient weighing between about 5 and 7 kg; 50 mg twice daily for a patient weighing between about 7 and 10 kg; 100 mg twice daily for a patient weighing between about 10 and 14 kg; 200 mg twice daily for a patient weighing between about 14 and 25 kg; and 400 mg twice daily for a patient weighing greater than or equal to about 25 kg).

[0019] In some embodiments, the provided methods further comprise the step of confirming clearance of CMV viremia in the patient. In some embodiments, clearance of CMV viremia is defined as a plasma CMV DNA concentration below the lower limit of quantification (e.g., < 137 international units per milliliter [IU / mL] in a sample taken at least 5 days apart after 2 consecutive baselines).

[0020] Definitions The term“about,” when used herein in connection with a value, refers to a value that is similar in context to the reference value. In general, one of skill in the art familiar with the context will understand the degree of relevant variation encompassed by“about” in that context. For example, in some embodiments, the term“about” can encompass a range of values within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the reference value (i.e., ± 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%). For example, a dose comprising“about 200 mg” of maralixibat encompasses any amount of maralixibat in the range of 180 mg to 220 mg. The terms“about,”“approximately,” and the symbol“~” are used interchangeably herein and have the same meaning.

[0021] As used herein, the terms "administering" and "administration" generally refer to the application of a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., in some embodiments, the target site can be the site of a disease or injury, and / or the site of a responsive process, cell, tissue, etc.). As will be appreciated by persons skilled in the art upon reading the disclosure herein, in some embodiments, one or more particular routes of administration can be feasible and / or available in the practice of the present disclosure. In some embodiments, administration can be oral. In some embodiments, administration can involve only a single dose. In some embodiments, administration can involve the application of a fixed number of doses. In some embodiments, administration can involve intermittent (e.g., multiple doses spaced apart in time) and / or periodic (e.g., individual doses spaced apart by a common time period) dosing.

[0022] As used herein, the term "reference" describes a standard or control against which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or assayed substantially contemporaneously with the test or assay of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, the reference or control is assayed or characterized under similar conditions or circumstances as where the evaluation is taking place, as will be appreciated by persons skilled in the art. Persons skilled in the art will understand when there is sufficient similarity to justify reliance on and / or comparison to a particular possible reference or control.

[0023] As used herein, the terms "treat," "treatment," and "treating" refer to partially or completely alleviating, inhibiting, ameliorating, and / or abating a disorder or condition, or one or more symptoms of the disorder or condition. In some embodiments, treatment can be administered after one or more symptoms have developed. In some embodiments, the term "treatment" includes halting progression of a disease or disorder. Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence. Accordingly, in some embodiments, the term "treatment" includes preventing or delaying the recurrence or reoccurrence of a disease or disorder.

[0024] Dosing Regimen Provided herein are methods of treating a patient having CMV, comprising administering maralibavir to the patient (e.g., by administering a composition comprising and / or delivering maralibavir as described herein). In some embodiments, the provided methods comprise administering to the patient about 400 mg of maralibavir orally twice per day. In some embodiments, the provided methods comprise administering to the patient about 200 mg of maralibavir orally twice per day. In some embodiments, the provided methods comprise administering to the patient about 100 mg of maralibavir orally twice per day. In some embodiments, the provided methods comprise administering to the patient about 50 mg of maralibavir orally twice per day. In some embodiments, the provided methods comprise administering to the patient about 50 mg of maralibavir orally once per day.

[0025] Maralibavir can be administered with or without food. In some embodiments, maralibavir is administered as a 200 mg tablet. In some embodiments, maralibavir is administered as a 200 mg liquid suspension for oral ingestion. In some embodiments, maralibavir is administered as a 50 mg liquid suspension for oral ingestion.

[0026] In some embodiments, maralibavir can be administered with an antacid. In some embodiments, the provided pharmaceutical compositions can be administered with an antacid. In some embodiments, the provided pharmaceutical compositions are administered to a patient in need thereof, wherein the patient has received or is receiving an antacid. In some embodiments, the antacid is omeprazole, esomeprazole, rabeprazole, lansoprazole, a benzimidazole, pantoprazole, cimetidine, ranitidine, or famotidine. In some embodiments, maralibavir is administered with rabeprazole. In some embodiments, maralibavir is administered to a patient in need thereof, wherein the patient is receiving or has received rabeprazole.

[0027] In some embodiments, the amount of maribavir administered is based on patient weight. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maribavir to the patient, wherein the patient is at least 12 years old and less than 18 years old, and wherein the amount of maribavir administered is 100 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 200 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 400 mg twice a day for a patient weighing at least 25 kg. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maribavir to the patient, wherein the patient is at least 12 years old and less than 18 years old, and wherein the amount of maribavir administered is 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is concurrently administered an anticonvulsant. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maribavir to the patient, wherein the patient is at least 12 years old and less than 18 years old, and wherein the amount of maribavir administered is 200 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 400 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 800 mg twice a day for a patient weighing at least 25 kg, wherein the patient is concurrently administered carbamazepine. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maribavir to the patient, wherein the patient is at least 12 years old and less than 18 years old, and wherein the amount of maribavir administered is 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is concurrently administered carbamazepine.In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is at least 12 years old and less than 18 years old, and wherein the amount of maralixibat administered is 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is co-administered phenobarbital. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is at least 12 years old and less than 18 years old, and wherein the amount of maralixibat administered is 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is co-administered phenytoin. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is at least 6 years old and less than 12 years old, and wherein the amount of maralixibat administered is 100 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 200 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 400 mg twice a day for a patient weighing at least 25 kg. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is at least 6 years old and less than 12 years old, and wherein the amount of maralixibat administered is 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is co-administered an anticonvulsant agent.In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is at least 6 years old and less than 12 years old, and wherein the amount of maralixibat administered is 200 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 400 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 800 mg twice a day for a patient weighing at least 25 kg, wherein the patient is also administered carbamazepine. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is at least 6 years old and less than 12 years old, and wherein the amount of maralixibat administered is 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is also administered carbamazepine. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is at least 6 years old and less than 12 years old, and wherein the amount of maralixibat administered is 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is also administered phenobarbital. In some embodiments, provided are methods of treating a CMV infection or disease in a patient having the CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is at least 6 years old and less than 12 years old, and wherein the amount of maralixibat administered is 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is also administered phenytoin.In some embodiments, the disclosure provides methods of treating a CMV infection or disease in a patient having a CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is less than 6 years old, and wherein the amount of maralixibat administered is 50 mg once daily for a patient weighing between about 5 and 7 kg, 50 mg twice daily for a patient weighing between about 7 and 10 kg, 100 mg twice daily for a patient weighing at least 10 kg and less than 14 kg, 200 mg twice daily for a patient weighing at least 14 kg and less than 25 kg, or 400 mg twice daily for a patient weighing at least 25 kg. In some embodiments, the disclosure provides methods of treating a CMV infection or disease in a patient having a CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is less than 6 years old, and wherein the amount of maralixibat administered is 150 mg once daily for a patient weighing between about 5 and 7 kg, 150 mg twice daily for a patient weighing between about 7 and 10 kg, 300 mg twice daily for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice daily for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice daily for a patient weighing at least 25 kg, wherein the patient is also administered an anticonvulsant. In some embodiments, the disclosure provides methods of treating a CMV infection or disease in a patient having a CMV infection or disease, comprising orally administering maralixibat to the patient, wherein the patient is less than 6 years old, and wherein the amount of maralixibat administered is 100 mg once daily for a patient weighing between about 5 and 7 kg, 100 mg twice daily for a patient weighing between about 7 and 10 kg, 200 mg twice daily for a patient weighing at least 10 kg and less than 14 kg, 400 mg twice daily for a patient weighing at least 14 kg and less than 25 kg, or 800 mg twice daily for a patient weighing at least 25 kg, wherein the patient is also administered carbamazepine.In some embodiments, the disclosure provides a method of treating a CMV infection or disease in a patient having a CMV infection or disease, comprising orally administering maralixine to the patient, wherein the patient is less than 6 years old, and wherein the amount of maralixine administered is 150 mg once a day for a patient weighing between about 5 and 7 kg, 150 mg twice a day for a patient weighing between about 7 and 10 kg, 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is also administered carbamazepine. In some embodiments, the disclosure provides a method of treating a CMV infection or disease in a patient having a CMV infection or disease, comprising orally administering maralixine to the patient, wherein the patient is less than 6 years old, and wherein the amount of maralixine administered is 150 mg once a day for a patient weighing between about 5 and 7 kg, 150 mg twice a day for a patient weighing between about 7 and 10 kg, 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is also administered phenobarbital. In some embodiments, the disclosure provides a method of treating a CMV infection or disease in a patient having a CMV infection or disease, comprising orally administering maralixine to the patient, wherein the patient is less than 6 years old, and wherein the amount of maralixine administered is 150 mg once a day for a patient weighing between about 5 and 7 kg, 150 mg twice a day for a patient weighing between about 7 and 10 kg, 300 mg twice a day for a patient weighing at least 10 kg and less than 14 kg, 600 mg twice a day for a patient weighing at least 14 kg and less than 25 kg, or 1200 mg twice a day for a patient weighing at least 25 kg, wherein the patient is also administered phenytoin.

[0028] In some embodiments, the disclosure provides a method of treating a CMV infection or disease in a patient having a CMV infection or disease, the method comprising orally administering maralixine to the patient, wherein the patient is less than 12 years old, and wherein the amount of maralixine administered is 50 mg once a day for a patient weighing between about 5 and 7 kg, 50 mg twice a day for a patient weighing between about 7 and 10 kg, 100 mg twice a day for a patient weighing between about 10 and 14 kg, 150 mg twice a day for a patient weighing between about 14 and 20 kg, 200 mg twice a day for a patient weighing between about 20 and 26 kg, 300 mg twice a day for a patient weighing between about 26 and 34 kg, or 400 mg twice a day for a patient weighing more than about 34 kg, wherein the patient is unable or has difficulty swallowing tablets.

[0029] In some embodiments, the disclosure provides a method of treating a CMV infection or disease in a patient having a CMV infection or disease, the method comprising orally administering maralixine to the patient, wherein the patient is less than 6 years old (optionally wherein maralixine is formulated as a powder for an oral suspension), and wherein the amount of maralixine administered is 50 mg once a day for a patient weighing between about 5 and 7 kg, 50 mg twice a day for a patient weighing between about 7 and 10 kg, 100 mg twice a day for a patient weighing between about 10 and 14 kg, 200 mg twice a day for a patient weighing between about 14 and 25 kg, and 400 mg twice a day for a patient weighing more than or equal to about 25 kg.

[0030] In some embodiments, the disclosure provides a method of treating a CMV infection or disease in a patient having a CMV infection or disease, the method comprising orally administering maralixine to the patient, wherein the patient is at least 6 years old and less than 12 years old (optionally wherein maralixine is formulated as a powder for an oral suspension), and wherein the amount of maralixine administered is 100 mg twice a day for a patient weighing between about 10 and 14 kg, 200 mg twice a day for a patient weighing between about 14 and 25 kg, and 400 mg twice a day for a patient weighing more than or equal to about 25 kg.

[0031] Skilled artisans will appreciate that dosing can be adjusted based on observed pharmacokinetics (PK) (e.g., mean and individual area under the curve (AUC), minimum concentration (Cmin), or Cmax in children compared to target AUC, Cmin, and Cmax ranges based on adult data). For example, if AUC and Cmin are consistently found to be below 128 h*pg / mL and 4.9 pg / mL in subjects weighing such that they initially receive 200 mg BID of maralibavir, the dosing regimen can be adjusted to 400 mg BID. Alternatively, if AUC exceeds 776 h*pg / mL or Cmax exceeds 70 pg / mL in patients weighing such that they receive 400 mg BID of maralibavir, the dose should be adjusted to 200 mg BID. In some embodiments, the mean AUC according to the provided methods is in the range of 128 to 380 h*pg / mL.

[0032] In some embodiments, the provided methods and compositions are used to treat CMV infection or disease in patients less than 6 years of age.

[0033] Doses can vary depending on the needs of the patient and the compound used. In the context of the present disclosure, the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Dosages and intervals can be adjusted to provide levels of the administered compound that are sufficient to effectively treat the particular clinical indication being addressed. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0034] In some embodiments, the provided methods include administering maralibavir to a patient in need thereof in a therapeutically effective amount. In some embodiments, the provided methods include administering maralibavir to a patient in need thereof according to a regimen determined to achieve one or more particular effects (e.g., particular maximum concentrations and / or particular area under the curve and / or particular half-lives and / or particular target exposures, e.g., for a particular portion of time between doses) in a relevant patient population. In some such embodiments, the relevant patient population is those patients less than 6 years of age. In some embodiments, the relevant patient population is those patients weighing less than 35 kg.

[0035] In some embodiments, the particular effect is or includes a particular mean maximum concentration (Cmax) 最大 ), which can be extrapolated from studies in other patient populations, including adults. In some embodiments, the particular effect is or includes a particular mean plasma concentration maintained for a particular period of time, which can be extrapolated from studies in other patient populations, including adults. In some embodiments, the particular effect is or includes a particular mean Cmin, which can be extrapolated from studies in other patient populations, including adults.最大 and maintaining a certain average plasma concentration over a certain period of time, the certain average C 最大 and maintaining a certain average plasma concentration over a certain period of time can be extrapolated from studies in other patient populations, including adults. In some embodiments, the certain effect is or includes a certain average area under the curve (AUC (0168) ), the certain average area under the curve (AUC 1 / 2 ), the certain half-life (t

[0036] In some embodiments, maribavir is administered daily. In some embodiments, maribavir is administered daily for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks.

[0037] Patients As described above, the provided methods include treating a patient having a cytomegalovirus (CMV) infection or disease, including administering maribavir to the patient, wherein the patient is less than 18 years old. In some embodiments, the patient has a post-transplant CMV infection or disease. In some embodiments, the patient is a transplant recipient. In some embodiments, the patient is a hematopoietic stem cell transplant recipient. In some embodiments, the patient is a solid organ transplant recipient (e.g., liver, kidney, lung, heart, pancreas, intestinal tract). In some embodiments, prior to treatment with maribavir, the patient does not have a CMV tissue invasive disease involving the central nervous system (CNS) or retina.

[0038] In some embodiments, the patient to whom the provided dosing regimen is administered has a tissue invasive disease.

[0039] In some embodiments, the patient to whom the provided dosing regimen (i.e., for CMV) is administered has CMV syndrome. In some embodiments, CMV syndrome is characterized by detection of CMV in the blood by viral culture, antigenemia, or DNA or ribonucleic acid-based assays, and at least 2 of the following: a. Fever > 38°C for at least 2 days.

[0040] b. New or worsening malaise (toxicity grade > 2) or new or worsening fatigue (toxicity grade > 3) (National Cancer Institute: Common Terminology Criteria for Adverse Events, version 4.0).

[0041] c. Leukopenia or neutropenia is found in 2 separate measurements at least 24 hours apart, defined as a white blood cell (WBC) count < 3,500 cells per microliter (pL) if the WBC count prior to the onset of clinical symptoms was > 4,000 cells / pL, or a decrease of > 20% if the WBC count prior to the onset of clinical symptoms was < 4,000 cells / pL. The corresponding neutrophil count is < 1,500 cells / pL or a decrease of > 20% if the neutrophil count prior to the onset of symptoms was < 1,500 cells / pL.

[0042] d. > 5% atypical lymphocytes.

[0043] e. Thrombocytopenia, defined as a platelet count < 100,000 cells / pL if the platelet count prior to the onset of clinical symptoms was > 15,000 cells / mL, or a decrease of > 20% if the platelet count prior to the onset of clinical symptoms was < 115,000 cells / mL.

[0044] f. Liver transaminases (alanine aminotransferase or aspartate aminotransferase) are elevated to 2 times the upper limit of normal (applicable to non-liver transplant recipients).

[0045] In some embodiments, the patient is less than 18 years old. In some embodiments, the patient is at least 12 years old and less than 18 years old. In some embodiments, the patient is less than 12 years old. In some embodiments, the patient is less than 6 years old. In some embodiments, the patient is an adult patient (i.e., 18 years old or older) who has difficulty swallowing a pill.

[0046] In some embodiments, the patient weighs less than 35 kg. In some embodiments, the patient weighs at least 25 kg. In some embodiments, the patient weighs less than 25 kg. In some embodiments, the patient weighs 10-25 kg. In some embodiments, the patient weighs at least 5 kg.

[0047] The skilled artisan is aware of methods to diagnose a patient for a CMV infection or disease. In some embodiments, a patient has a CMV infection or disease has a CMV deoxyribonucleic acid (DNA) screening value of > 1365 international units per milliliter (IU / mL) in whole blood or > 455 IU / mL in plasma by quantitative polymerase chain reaction (qPCR) in 2 consecutive assessments at least 1 day apart within 14 days of the first dose of maribavir.

[0048] In some embodiments, the patient is refractory to treatment for the CMV infection or disease with one or more other drugs. In some embodiments, the patient is refractory to treatment for the CMV infection or disease with one or more other drugs and has genotypic resistance. In some embodiments, the patient is refractory to treatment for the CMV infection or disease with one or more other drugs and does not have genotypic resistance. In some embodiments, the patient is refractory to treatment with one or more of ganciclovir, valganciclovir, cidofovir, or foscarnet sodium. In some embodiments, the patient is refractory to treatment with ganciclovir or valganciclovir. In some embodiments, the patient is refractory to treatment with ganciclovir. In some embodiments, the patient is refractory to treatment with valganciclovir.

[0049] In some embodiments, the patient is selected based on one or more inclusion criteria described in Example 1 or Example 2.

[0050] In some embodiments, the treatment methods disclosed herein exclude treatment of a patient who meets one or more exclusion criteria described in Example 1 or Example 2.

[0051] In some embodiments, the methods of the application comprise administering maribavir and co-administering a drug to a patient in need thereof (e.g., a CYP3A4 inducer (such as carbamazepine, phenytoin, or phenobarbital), a p-glycoprotein inducer (P-gp), an immunosuppressant, an antacid, an antiarrhythmic agent such as digoxin, ganciclovir, or valganciclovir).

[0052] In some embodiments, the patient is receiving or has received a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir, and the methods provided comprise a step of discontinuing administration of the CYP3A4 inducer prior to administration of maribavir. In some embodiments, the patient is receiving or has received a cytochrome P450 3A4 (CYP3A4) inducer, and the methods provided comprise a step of increasing the amount of maribavir administered to the patient. In some embodiments, the CYP3A4 inducer is a strong CYP3A4 inducer. In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, avasimibe, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John’s wort. In some embodiments, the CYP3A4 inducer is selected from the group consisting of rifampin, rifabutin, and St. John’s wort. In some embodiments, the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenytoin, and phenobarbital.

[0053] In some embodiments, the patient is receiving or has received an immunosuppressant. In some embodiments, the provided methods include a step of monitoring the level of the immunosuppressant (e.g., compared to a reference or standard level) after the initiation of the administration of maralibavir. In some embodiments, the provided methods further include a step of reducing the amount of the immunosuppressant administered to the patient. In some embodiments, the provided methods further include a step of monitoring the level of the immunosuppressant (e.g., compared to a reference or standard level) after the cessation of the administration of maralibavir. In some embodiments, the provided methods further include a step of increasing the amount of the immunosuppressant administered to the patient (e.g., to the amount of the immunosuppressant administered prior to the initiation of the administration of maralibavir). In some embodiments, the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, and sirolimus.

[0054] In some embodiments, the patient is receiving or has received digoxin. In some embodiments, the provided methods further include a step of monitoring the level of the digoxin. In some embodiments, the provided methods further include a step of reducing the amount of the digoxin administered to the patient.

[0055] In some embodiments, the patient is receiving or has received an antacid. In some embodiments, the antacid is omeprazole, esomeprazole, rabeprazole, lansoprazole, a benzimidazole, pantoprazole, cimetidine, ranitidine, or famotidine. In some embodiments, the antacid is rabeprazole. In some embodiments, the patient is receiving or has received an anticonvulsant. In some embodiments, the anticonvulsant is carbamazepine. In some embodiments, the anticonvulsant is phenytoin. In some embodiments, the anticonvulsant is phenobarbital.

[0056] Pharmaceutical Composition Suitable for Liquid Oral Formulation As described above, the present disclosure provides novel formulations suitable for liquid oral formulations of maralibavir. In some embodiments, the provided liquid suspension formulations are sufficient to reduce the bitter taste of maralibavir. To successfully achieve taste masking of the bitter taste of maralibavir, the provided formulations employ polymeric coating of maralibavir particles with other agents (e.g., sweeteners and flavoring agents). Such formulations can be administered to patients who are unable to swallow maralibavir tablet formulations. In some embodiments, the provided oral pharmaceutical compositions comprising maralibavir are suitable for administration to patients less than 6 years of age.

[0057] In some embodiments, a liquid formulation for oral administration is provided, the liquid formulation comprising a coated (e.g., taste-masked) granule comprising at least one pharmaceutically active substance and at least one pharmaceutically acceptable excipient, the liquid formulation prepared by mixing a dry formulation with a liquid vehicle prior to oral administration, thereby forming a suspension.

[0058] In some embodiments, a provided pharmaceutical composition comprises an active pharmaceutical ingredient, a diluent, and a disintegrant granulated into an intragranular composition (e.g., a granule). In some embodiments, the intragranular granule comprises an active pharmaceutical ingredient (e.g., maribavir), a diluent, and a disintegrant. In some embodiments, the intragranular granule comprises an active pharmaceutical ingredient (e.g., maribavir), microcrystalline cellulose, and crospovidone. In some embodiments, the intragranular composition is prepared by granulating (e.g., by a fluidized rotor granulator) an active pharmaceutical ingredient (e.g., maribavir), a diluent, and a disintegrant. In some embodiments, the intragranular composition is prepared by granulating (e.g., by a fluidized rotor granulator) an active pharmaceutical ingredient (e.g., maribavir), microcrystalline cellulose, and crospovidone.

[0059] In some embodiments, a provided pharmaceutical composition comprises maribavir in a composition comprising other excipients (e.g., croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, and crospovidone). In some embodiments, a provided pharmaceutical composition comprises a granule comprising maribavir, microcrystalline cellulose, and crospovidone.

[0060] In some embodiments, a provided pharmaceutical composition comprises a coating that encapsulates a maribavir-containing component of a composition. In some embodiments, a provided pharmaceutical composition comprises a coating that encapsulates a maribavir-containing component distributed within an extragranular composition. In some embodiments, a provided pharmaceutical composition comprises a mixture of coated intragranular particles within a matrix of an extragranular component.

[0061] In some embodiments, a provided pharmaceutical composition comprises: (i) an intragranular composition comprising maribavir, a diluent, and a disintegrant; (ii) an enteric coating of the intragranular composition, the enteric coating comprising a selectively soluble polymer; and (iii) an extragranular composition comprising a diluent, a suspending agent, a sweetener, and a flavoring agent.

[0062] In some embodiments, a provided pharmaceutical composition comprises: (i) an intragranular composition comprising maribavir, microcrystalline cellulose, and a disintegrant; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising a diluent, a suspending agent, a sweetener, and a flavoring agent.

[0063] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maribavir, microcrystalline cellulose, and crospovidone; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising a diluent, a suspending agent, a sweetener, and a flavoring agent.

[0064] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maribavir, a diluent, and crospovidone; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising a diluent, a suspending agent, a sweetener, and a flavoring agent.

[0065] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maribavir, a diluent, and a disintegrant; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising mannitol, a suspending agent, a sweetener, and a flavoring agent.

[0066] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maribavir, microcrystalline cellulose, and crospovidone; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising mannitol, a suspending agent, a sweetener, and a flavoring agent.

[0067] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maraviroc, microcrystalline cellulose, and crospovidone; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising mannitol, suspending agent, sucralose, and flavoring agent.

[0068] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maraviroc, microcrystalline cellulose, and crospovidone; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising mannitol, microcrystalline cellulose and sodium carboxymethyl cellulose, sucralose, and flavoring agent.

[0069] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maraviroc, microcrystalline cellulose, and crospovidone; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising mannitol, microcrystalline cellulose and sodium carboxymethyl cellulose, sucralose, and flavoring agent.

[0070] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maraviroc and at least one excipient; (ii) an enteric coating of the intragranular composition comprising a selectively soluble polymer; and (iii) an extragranular composition comprising (a) a diluent, (b) at least one sweetener or flavoring agent, and (c) other excipients; wherein the intragranular composition has a median particle size of between about 100 and 400 microns, wherein the coated intragranular composition has a median particle size of less than 500 microns, wherein the diluent has a dv50 (i.e., 50thpercentile) particle size of between about 30 and 180 microns.

[0071] In some embodiments, the provided pharmaceutical composition comprises: (i) an intragranular composition comprising maraviroc and at least one excipient; (ii) an enteric coating of the intragranular composition, the enteric coating comprising a selectively soluble polymer; and (iii) an extragranular composition comprising (a) mannitol, (b) at least one sweetener or flavoring agent, and (c) other excipients; wherein the intragranular composition has a median particle size of between about 100 and 400 microns, wherein the coated intragranular composition has a median particle size of less than 500 microns, wherein the mannitol has a dv50 (i.e., 50th percentile) particle size of between about 30 and 180 microns.

[0072] In some embodiments, the provided pharmaceutical composition comprises maribavir, a sweetener, and a flavoring agent. In some embodiments, the sweetener is a high intensity sweetener. In some embodiments, the sweetener is saccharin (e.g., sodium saccharin), aspartame, acesulfame potassium (Ace-K), sucralose, neotame, advantame, or a combination thereof. In some embodiments, the sweetener is or comprises a steviol glycoside or a Swingle / monk fruit extract. In some embodiments, the sweetener is glycyrrhizic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the sweetener is sucralose.

[0073] In some embodiments, the provided pharmaceutical composition comprises maribavir, a sweetener, and a flavoring agent. In some embodiments, the flavoring agent is a pediatric-friendly flavor profile (e.g., a fruit flavor).

[0074] As used herein, the term “flavor profile method” is a standard for quantitative sensory information evaluation. Flavors are evaluated in terms of five major components: characteristic attributes, attribute intensities, order of attribute appearance, aftertaste, and amplitude (overall impression of analyzable and non-analyzable flavor components). See CAUL, J.F. 1957. The profile method of flavor analysis., “Advances in Food Research” Mrak, E.M. and Stewart, G.F. Eds. Vol. 7, pp. 1-40. Academic Press, New York, NY; and KEANE, P. 1992. The flavor profile., ASTM Manual on Descriptive Analysis Testing” (Manual 13) Hootman, R.C. Ed. pp. 5-14. ASTM, Philadelphia, PA.

[0075] Several different types of coatings (e.g., enteric coatings comprising selectively soluble polymers) can be applied individually or in combination to the entire dosage form or to the particles, granules, or beads that make up the dosage form. Functional coatings such as enteric polymers can be used to prevent or delay dissolution until the dosage form leaves the stomach. Exemplary enteric coating materials include HPMCAS, HPMCP, CAP, CAT, carboxymethyl ethyl cellulose, carboxylic acid functionalized polymethacrylates, and carboxylic acid functionalized polyacrylates. Alternatively, “non-functional” coatings such as sugar-based coatings that facilitate swallowing can be used that do not substantially affect dissolution or other pharmacokinetic properties. In some embodiments, the maraviroc granules are coated with a polymer that is insoluble at neutral pH (e.g., the pH of saliva and the mouth) but soluble at acidic pH (e.g., the pH of the stomach). In some embodiments, the coating polymer is an aminomethacrylate copolymer (e.g., basic butylated methacrylate copolymer), Kollicoat Smartseal, methyl methacrylate, dimethylaminoethyl methacrylate copolymer, or a combination thereof. In some embodiments, the coating polymer is an aminomethacrylate copolymer. In some embodiments, the coating polymer is a basic butylated methacrylate copolymer. In some embodiments, the coating polymer is butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate polymer, or a combination thereof, e.g., butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer. In some embodiments, the coating polymer is Eudragit® E PO (e.g., Eudragit® E PO ReadyMix, i.e., sodium lauryl sulfate, stearic acid, talc, silicon dioxide) (Eudragit® CAS Registry Number 24938-16-7).

[0076] Intra-coated Granule Composition In some embodiments, the provided pharmaceutical compositions for oral liquid administration comprise a granule component (e.g., an intra-granule composition within an enteric coating, provided within a combination of extra-granule components) derived from smaller micronized excipients and active pharmaceutical ingredients. In some embodiments, for example, the pharmaceutical compositions for oral liquid administration comprise maraviroc with other excipients suitable for liquid suspension formulations for oral administration. In some embodiments, maraviroc, a disintegrant, and a diluent are granulated into an intra-granule, which is further encased in a polymer coating that is insoluble at neutral pH but soluble at acidic pH (e.g., an enteric coating comprising selectively soluble polymers).

[0077] In some embodiments, the provided pharmaceutical composition comprises a component layer. In some embodiments, the layered pharmaceutical composition comprises a radially-graduated layer. In some embodiments, the layered pharmaceutical composition comprises a maralixibat layer and a coating layer. In some embodiments, the layered pharmaceutical composition comprises two or more layers. In some embodiments, the pharmaceutical composition layer is or comprises a pharmaceutically active ingredient, a diluent, and a disintegrant. In some embodiments, the pharmaceutical composition layer is a pH-sensitive polymer or copolymer. In some embodiments, the pH-sensitive polymer or copolymer intermediate layer is insoluble at pH 7 or about pH 7. In some embodiments, the pH-sensitive polymer or copolymer intermediate layer is soluble at or below about pH 5. In some embodiments, the provided pharmaceutical composition suitable for suspension in a liquid for oral administration comprises an intragranular layer and a pH-sensitive polymer coating that encases the intragranular layer. In some embodiments, the provided pharmaceutical composition suitable for suspension in a liquid for oral administration comprises an intragranular layer and a pH-sensitive polymer or copolymer coating, wherein the coated intragranular particles (e.g., particles within Eudragit®) are dispersed in an extragranular composition of excipients.

[0078] In some embodiments, the provided pharmaceutical composition is or comprises a granule. In some embodiments, the provided pharmaceutical composition is or comprises a multilayered granule. In some embodiments, the provided pharmaceutical composition comprises a selectively soluble layer (e.g., a pH-sensitive polymeric or copolymeric layer). In some embodiments, the provided pharmaceutical composition is or comprises a layered granule further comprising an active pharmaceutical ingredient within a pH-sensitive polymer or copolymer. In some embodiments, the layered pharmaceutical composition comprises maralixibat within a Eudragit® E PO coating.

[0079] In some embodiments, the provided pharmaceutical composition can be produced by a method of coating an intragranular composition comprising maralixibat with a coating layer comprising a pH-sensitive polymer or copolymer. In some embodiments, the provided pharmaceutical composition is a core granule comprising maralixibat, microcrystalline cellulose, and crospovidone, wherein the granule is encased by an enteric polymer layer (e.g., a selectively soluble polymer such as Eudragit®).

[0080] In some embodiments, the provided pharmaceutical composition comprises intragranular particles comprising an active pharmaceutical ingredient (e.g., maraviroc), a diluent (e.g., microcrystalline cellulose), and a disintegrant (e.g., crospovidone). In some embodiments, the provided pharmaceutical composition comprises intragranular particles comprising an active pharmaceutical ingredient (e.g., maraviroc), a diluent (e.g., microcrystalline cellulose), a disintegrant (e.g., crospovidone), and a coating comprising a pH-sensitive layer (e.g., Eudragit® E PO ReadyMix).

[0081] In some embodiments, the provided pharmaceutical composition comprises a diluent. In some embodiments, the diluent can be used individually or in combination throughout the dosage form or the particles, granules, or beads that make up the dosage form. In some embodiments, the diluent is selected from the group consisting of lactose, dextrin, glucose, sucrose, sorbitol, mannitol, xylitol, lactitol, isomalt, maltitol, microcrystalline cellulose, sodium carboxymethylcellulose, hydrogenated starch hydrolysate, calcium silicate, sodium silicate, potassium silicate, magnesium chloride, sodium chloride, potassium chloride, silicon dioxide, or a combination thereof. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is microcrystalline cellulose.

[0082] In some embodiments, the provided pharmaceutical composition comprises a glidant. In some embodiments, the provided pharmaceutical glidant is selected from the group consisting of ascorbic acid palmitate, calcium palmitate, stearic acid, magnesium stearate, colloidal silicon dioxide, starch, talc, lactose, dextrin, glucose, sucrose, sorbitol, mannitol, xylitol, lactitol, isomalt, maltitol, hydrogenated starch hydrolysate, calcium silicate, sodium silicate, potassium silicate, magnesium chloride, sodium chloride, potassium chloride, or silicon dioxide.

[0083] In some embodiments, the provided pharmaceutical composition comprises mannitol.

[0084] Intra-granule Composition Without wishing to be bound by a particular theory, particle size within a granular composition is generally described by the range distribution of the 10th, 50th, and 90thpercentiles of the composition. In the present disclosure and to those skilled in the art, particle size distribution is a measure of the variation in the size of particles in a pharmaceutical composition according to their size. In some embodiments, the expression of the distribution of particles of a particular size in a composition can assume that the shape of the particles is spherical or similar.

[0085] Without wishing to be bound by a particular theory, Applicants have observed that the particle size of the active pharmaceutical ingredient and / or excipients can have an impact on the dissolution of the active pharmaceutical ingredient and thus on the bioavailability. Accordingly, one aspect of the present disclosure is the recognition that controlling such particle size in a manner such as to impact the bioavailability of the active pharmaceutical ingredient (e.g., maribavir) in a patient, as well as other pharmacokinetic parameters, can be advantageous.

[0086] Maribavir Drug Substance Maribavir ((2S,3S,4R,5S)-2-(5,6-dichloro-2-(isopropylamino)-1H- benzo[d]imidazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol) is a compound having the following chemical structure:

[0087] is an effective and orally bioavailable antiviral agent for the treatment of CMV infection or disease in transplant recipients.

[0088] In some embodiments, the compositions of the present disclosure comprise a particular polymorphic form of maribavir. In some embodiments, the compositions of the present disclosure comprise Form VI of maribavir as described in US 6,482,939 (e.g., at least 90%, 95%, or 99% by weight of Form VI of maribavir). In some embodiments, the compositions of the present disclosure comprise maribavir Form VI substantially free of other polymorphic forms of maribavir. As used herein, the term “polymorphic form” includes solvates and hydrates.

[0089] In some embodiments, the provided compositions comprise Form VI of maribavir as described in US 6,482,939 (e.g., at least 90%, 95%, or 99% by weight of Form VI of maribavir). In some embodiments, the provided compositions comprise Form VI of maribavir as described in US 6,482,939 (e.g., at least 90%, 95%, or 99% by weight of Form VI of maribavir), and another polymorphic form of maribavir as described in US 6,482,939, US 8,546,344, or US 11,130,777. In some embodiments, the provided compositions comprise Form VI of maribavir as described in US 6,482,939 and an isopropyl acetate solvate of maribavir (e.g., as described in US 6,482,939, US 8,546,344, or US 11,130,777). In some embodiments, the provided compositions comprise Form VI of maribavir and less than 10%, 5%, 1%, or 0.5% by weight of another polymorphic form of maribavir, e.g., as described in US 6,482,939, US 8,546,344, or US 11,130,777. In some embodiments, the provided compositions comprise Form VI of maribavir and less than 10%, 5%, 1%, or 0.5% by weight of another polymorphic form of maribavir, e.g., as described in US 6,482,939, US 8,546,344, or US 11,130,777. In some embodiments, the provided compositions comprise Form VI of maribavir substantially free of other polymorphic forms, e.g., as described in US 6,482,939, US 8,546,344, or US 11,130,777. In some embodiments, the provided compositions comprise Form VI of maribavir synthesized and / or crystallized by the methods described in International Application PCT / US23 / 34933. In some embodiments, the provided compositions comprise Form VI of maribavir crystallized by using isopropyl acetate / toluene as the crystallization solvent. In some embodiments, the provided compositions comprise Form VI of maribavir crystallized by using maribavir seed crystals with a d(50) of the PSD between about 1.00 µm and about 10.00 µm. In some embodiments, the provided compositions comprise Form VI of maribavir crystallized by using maribavir seed crystals with a d(50) of the PSD between about 1.25 µm and about 9.00 µm. In some embodiments, the provided compositions comprise Form VI of maribavir crystallized by using maribavir seed crystals with a d(50) of the PSD between about 1.75 µm and about 8.00 µm.In some embodiments, the provided compositions comprise Form VI of maribavir, less than 0.05% of synthetic intermediate impurities (e.g., compounds 2, 3, and / or 4 as described in International Application PCT / US23 / 34933), less than 0.05% of enantiomeric impurities (e.g., D-maribavir as described in International Application PCT / US23 / 34933), and / or less than 0.05% of unspecified impurities, as measured by HPLC.

[0090] Particle Size In some embodiments, the provided pharmaceutical compositions comprise particles characterized by a particle size (e.g., expressed as an average diameter of irregular spheroid particles) expressed in terms of mean, percentile, and range of the composition of the particles (e.g., intra-granular particles, intra-coated granular particles, or other components of the provided pharmaceutical composition). In some embodiments, regular and irregular spheroid particles have an average diameter and size distribution as measured by laser diffraction. Other means of measuring particle size are known and include flow imaging microscopy, X-ray powder diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), dynamic vapor sorption (DVS), sieving, dynamic light scattering, and the like.

[0091] Intra-granule Composition Particle Size The present disclosure encompasses the recognition that intra-granular particle size plays an important role in the dissolution profile of the provided pharmaceutical compositions, and thus in the bioavailability of maribavir. For example, dissolution studies of maribavir granules (e.g., intra-coated granular compositions) at pH 2.5 (50 mM phosphate buffer) indicated that the percent dissolution was 10-15% higher for median particle sizes of 254 and 269 microns than for a median particle size of 345 microns after 5, 10, 15, and 20 minutes (see Figure 2 ).

[0092] In some embodiments, the intragranular pharmaceutical composition (e.g., comprising maraviroc, MCC, and crospovidone) has a median particle size of between about 100 and 400 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 350 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 320 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 300 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 280 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 260 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 240 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 220 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 200 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 180 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 150 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of between about 100 and 130 microns. In some embodiments, the intragranular pharmaceutical composition has a median particle size of about 150 microns or less.

[0093] As described above and herein, in some embodiments, the intragranular composition is coated with an enteric coating. In some embodiments, the median particle size of the coated intragranular pharmaceutical composition is about 500 microns or less. In some embodiments, the median particle size of the coated intragranular pharmaceutical composition is about 400 microns or less. In some embodiments, the median particle size of the coated intragranular pharmaceutical composition is about 300 microns or less. In some embodiments, the median particle size of the coated intragranular pharmaceutical composition is about 225-350 microns. In some embodiments, the median particle size of the coated intragranular pharmaceutical composition is about 250-325 microns, about 250-310 microns, about 250-300 microns, about 250-290 microns, about 250-280 microns, about 250-270 microns, or about 225-300 microns. In some embodiments, the median particle size of the coated intragranular pharmaceutical composition is about 250-300 microns.

[0094] In some embodiments, the dv50 (50th percentile; median) particle size of the drug composition within the coated granules comprises particles of about 250-400 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 250-380 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 250-350 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 250-340 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 250-320 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 250-300 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 260-400 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 270-400 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 280-400 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 290-400 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 300-400 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 320-400 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 350-400 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 150-260 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 175-260 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 200-260 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 225-260 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 250-260 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 250, 251, 252, 253, 254, 255, 256, 257, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, or 270 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 250 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granules comprises particles of about 251 microns.In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 252 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 253 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 254 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 255 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 256 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 257 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 258 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 259 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 260 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 261 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 262 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 263 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 264 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 265 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 266 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 267 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 268 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 269 microns. In some embodiments, the dv50 particle size of the drug composition within the coated granule comprises particles of about 270 microns.

[0095] In some embodiments, the dv90 (90th percentile) particle size of the drug composition within the coated granules comprises particles of about 350-500 microns. In some embodiments, the dv90 particle size of the drug composition within the coated granules comprises particles of about 350-475 microns. In some embodiments, the dv90 particle size of the drug composition within the coated granules comprises particles of about 350-450 microns. In some embodiments, the dv90 particle size of the drug composition within the coated granules comprises particles of about 350-425 microns. In some embodiments, the dv90 particle size of the drug composition within the coated granules comprises particles of about 350-400 microns. In some embodiments, the dv90 particle size of the drug composition within the coated granules comprises particles of about 350-375 microns.

[0096] In some embodiments, the dv10 (10th percentile) particle size of the drug composition within the coated granules comprises particles of about 100-300 microns. In some embodiments, the dv10 particle size of the drug composition within the coated granules comprises particles of about 120-300 microns. In some embodiments, the dv10 particle size of the drug composition within the coated granules comprises particles of about 150-300 microns. In some embodiments, the dv10 particle size of the drug composition within the coated granules comprises particles of about 175-300 microns. In some embodiments, the dv10 particle size of the drug composition within the coated granules comprises particles of about 200-300 microns. In some embodiments, the dv10 particle size of the drug composition within the coated granules comprises particles of about 225-300 microns. In some embodiments, the dv10 particle size of the drug composition within the coated granules comprises particles of about 250-300 microns. In some embodiments, the dv10 particle size of the drug composition within the coated granules comprises particles of about 260-300 microns. In some embodiments, the dv10 particle size of the provided drug composition comprises particles of about 270-300 microns. In some embodiments, the dv10 particle size of the drug composition within the coated granules comprises particles of about 280-300 microns.

[0097] Intra-coated Granule Dispersion in Extragranular Matrix In some embodiments, the provided intra-granular composition (e.g., maraviroc and excipients within the enteric layer) is further dispersed in an extra-granular component. In some embodiments, the provided pharmaceutical composition having an intra-granular component (e.g., maraviroc, diluent, and disintegrant) and a selectively soluble polymer coating is further dispersed in an extra-granular component to form a solid sol. In some embodiments, the provided pharmaceutical composition is a coated intra-granular composition that is further dispersed in an extra-granular component to form a solid sol. In some embodiments, the provided pharmaceutical composition is a solid sol for dispersion in water comprising: an active pharmaceutical ingredient within an enteric coating, a diluent, and a disintegrant, further comprising a diluent, a suspending agent, a sweetener, and a flavoring agent. In some embodiments, the provided pharmaceutical composition is a solid sol for dispersion in water comprising: maraviroc, microcrystalline cellulose, crospovidone, Eudragit® E PO, mannitol, sodium carboxymethylcellulose, sucralose, and a flavoring agent.

[0098] Input Particle Size Maribavir Particle Size In some embodiments, the median particle size (i.e., the 50th percentile or dv50) of maraviroc is about 1-24 microns. In some embodiments, the median particle size of maraviroc is about 1-18 microns. In some embodiments, the median particle size of maraviroc is about 1-12 microns. In some embodiments, the median particle size of maraviroc is about 1-6 microns. In some embodiments, the median particle size of maraviroc is about 1-3 microns. In some embodiments, the median particle size of maraviroc is about 3-18 microns. In some embodiments, the median particle size of maraviroc is about 6-18 microns.

[0099] In some embodiments, the dv90 (i.e., the 90th percentile) particle size of maraviroc is about 90 microns or less. In some embodiments, the dv90 particle size of maraviroc is about 60 microns or less. In some embodiments, the dv90 particle size of maraviroc is about 40 microns or less. In some embodiments, the dv90 particle size of maraviroc is about 30 microns or less. In some embodiments, the dv90 particle size of maraviroc is 25 microns or less. In some embodiments, the dv90 particle size of maraviroc is 15 microns or less. In some embodiments, the dv90 particle size of maraviroc is 10 microns or less.

[0100] Microcrystalline Cellulose In some embodiments, the microcrystalline cellulose (MCC) (e.g., Avicel® PH-105) has a dv10 (i.e., 10th percentile) particle size of about 1-50 microns. In some embodiments, the MCC has a dv10 particle size of about 1-40 microns. In some embodiments, the MCC has a dv10 particle size of about 1-30 microns. In some embodiments, the MCC has a dv10 particle size of about 1-20 microns. In some embodiments, the MCC has a dv10 particle size of about 1-10 microns. In some embodiments, the MCC has a dv10 particle size of about 1-5 microns.

[0101] In some embodiments, the MCC has a dv50 (i.e., 50th percentile) particle size of about 2-90 microns. In some embodiments, the MCC has a dv50 particle size of about 5-80 microns. In some embodiments, the MCC has a dv50 particle size of about 5-60 microns. In some embodiments, the MCC has a dv50 particle size of about 5-50 microns. In some embodiments, the MCC has a dv50 particle size of about 5-40 microns. In some embodiments, the MCC has a dv50 particle size of about 5-30 microns. In some embodiments, the MCC has a dv50 particle size of about 5-20 microns. In some embodiments, the MCC has a dv50 particle size of about 10-50 microns. In some embodiments, the MCC has a dv50 particle size of about 15-40 microns. In some embodiments, the MCC has a dv50 particle size of about 15-30 microns. In some embodiments, the MCC has a dv50 particle size of about 10-30 microns. In some embodiments, the MCC has a dv50 particle size of about 20-30 microns. In some embodiments, the MCC has a dv50 particle size of about 25-30 microns.

[0102] In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 10-150 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 10-120 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 10-90 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 10-75 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 10-60 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 10-50 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 10-40 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 20-90 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 20-75 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 20-60 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 30-60 microns. In some embodiments, the dv90 (i.e., 90th percentile) particle size of the MCC is about 40-60 microns.

[0103] Crospovidone In some embodiments, the dv10 (i.e., the 10th percentile) particle size of the cross-linked povidone (e.g., Polyplasdone™ XL-10) is about 2-48 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 8-48 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 16-48 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 8-48 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 2-36 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 2-24 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 2-12 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 2-36 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 2-16 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 4-16 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 8-16 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 10-16 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 6-12 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 8-12 microns. In some embodiments, the dv10 particle size of the cross-linked povidone is about 10-12 microns.

[0104] In some embodiments, the dv50 (i.e., the 50th percentile) particle size of the cross-linked povidone is about 5-120 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 10-120 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 15-120 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 20-120 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 5-100 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 5-80 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 5-60 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 5-40 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 10-50 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 10-40 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 10-30 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 20-30 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 25-30 microns. In some embodiments, the dv50 particle size of the cross-linked povidone is about 20-25 microns.

[0105] In some embodiments, the cross-linked povidone has a dv90 (i.e., 90th percentile) particle size of about 10-250 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 30-250 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 50-250 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 80-250 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 10-200 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 10-150 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 10-100 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 10-50 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 30-250 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 50-200 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 60-180 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 70-150 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 75-130 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 80-120 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 85-110 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 85-100 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 25-100 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 30-95 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 35-85 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 40-80 microns. In some embodiments, the cross-linked povidone has a dv90 particle size of about 45-75 microns.

[0106] Extragranular Components In some embodiments, the provided pharmaceutical composition comprises an intragranular composition within an extragranular matrix (e.g., composition) of coated granules. In some embodiments, the extragranular composition comprises a diluent, a suspending agent, a sweetener, and a flavoring agent. In some embodiments, the extragranular composition comprises mannitol (e.g., Pearlitol® 100 SD, microcrystalline cellulose, and sodium carboxymethyl cellulose (e.g., Avicel® CL-611), sucralose (Emprove®), and a flavoring agent (e.g., fruit flavor).

[0107] In some embodiments, the extragranular matrix comprises an excipient that inhibits particle segregation (e.g., a sugar alcohol such as mannitol). In some embodiments, the extragranular matrix comprises a flavoring agent that provides flavor masking during oral administration of the liquid suspension. In some embodiments, the extragranular matrix comprises one or more sweeteners. In some embodiments, the extragranular matrix comprises a suspending agent. In some embodiments, the extragranular matrix comprises a sugar alcohol. In some embodiments, the extragranular matrix comprises mannitol.

[0108] Particle Separation As discussed above, in some embodiments, the provided pharmaceutical composition comprises an active pharmaceutical ingredient and a pharmaceutically acceptable excipient. It will be appreciated that the intracoated granule pharmaceutical composition will have a statistical distribution of particle size, shape, density, etc. Particles of similar size tend to collect together through a phenomenon of particle segregation when continuously exposed to vibration, motion, humidity, gravity, and relative air flow. Particle segregation can result in a local statistical distribution of particle size, density, shape, or some other characteristic, and thus the amount of active drug (e.g., dose) of the pharmaceutical composition (e.g., intracoated granule pharmaceutical composition) within each subpopulation becomes spatially segregated rather than remaining a single homogenized statistical distribution. In order to maintain uniformity of the microparticulate pharmaceutical composition throughout the manufacturing and dosing processes, among other factors, control of such particle segregation behavior can be performed. The present disclosure encompasses the recognition that the addition of mannitol (e.g., as a diluent) is particularly useful for controlling particle segregation of the provided pharmaceutical composition. Methods of measuring particle segregation are known to the skilled person and include, by way of non-limiting example, ASTM standards D6940 and D6941.

[0109] Flowability In some embodiments, flowability is the relative movement of bulk particles (e.g., pharmaceutical composition) between adjacent particles or along a container wall or surface. In some embodiments, various characterization dimensions can represent flowability. In some embodiments, flowability is measured by angle of repose, compression index (Hausner ratio), flow in a rotating drum and through an orifice, shear cell or rheometry. In some embodiments, flowability is represented by means of flow angle or dynamic cohesion index, among others. The present disclosure encompasses the recognition that the addition of mannitol (e.g., as a diluent) is particularly useful for improving flowability of the provided pharmaceutical composition. In some embodiments, flowability can be improved by using a filling device with a vibration function.

[0110] Mannitol In some embodiments, the extragranular matrix (e.g., composition) of the provided pharmaceutical composition comprises a particle segregation inhibitor. In some embodiments, the particle segregation inhibitor is mannitol.

[0111] In some embodiments, the extragranular matrix of the provided pharmaceutical composition comprises a diluent particle separation inhibitor. In some embodiments, the extragranular matrix of the provided pharmaceutical composition comprises a sugar alcohol. In some embodiments, the extragranular matrix of the provided pharmaceutical composition comprises mannitol. In some embodiments, the extragranular matrix of the provided pharmaceutical composition comprises spray-dried mannitol.

[0112] In some embodiments, the dv10 (i.e., the 10th percentile) particle size of the mannitol (e.g., Pearlitol® 100 SD) is about 70 microns or less. In some embodiments, the dv10 particle size of the mannitol is about 60 microns or less. In some embodiments, the dv10 particle size of the mannitol is about 50 microns or less. In some embodiments, the dv10 particle size of the mannitol is about 40 microns or less. In some embodiments, the dv10 particle size of the mannitol is about 30 microns or less. In some embodiments, the dv10 particle size of the mannitol is about 20 microns or less. In some embodiments, the dv10 particle size of the mannitol is about 15 microns or less. In some embodiments, the dv10 particle size of the mannitol is about 10 microns or less.

[0113] In some embodiments, the dv50 (i.e., the 50th percentile) particle size of the mannitol is between about 30 and 180 microns. In some embodiments, the dv50 particle size of the mannitol is between about 50 and 150 microns. In some embodiments, the dv50 particle size of the mannitol is between about 70 and 130 microns. In some embodiments, the dv50 particle size of the mannitol is between about 80 and 120 microns. In some embodiments, the dv50 particle size of the mannitol is between about 90 and 110 microns. In some embodiments, the dv50 particle size of the mannitol is between about 95 and 95 microns. In some embodiments, the dv50 particle size of the mannitol is between about 50 and 110 microns. In some embodiments, the dv50 particle size of the mannitol is between about 60 and 110 microns. In some embodiments, the dv50 particle size of the mannitol is between about 70 and 110 microns. In some embodiments, the dv50 particle size of the mannitol is between about 80 and 110 microns. In some embodiments, the dv50 particle size of the mannitol is between about 90 and 150 microns. In some embodiments, the dv50 particle size of the mannitol is between about 90 and 140 microns. In some embodiments, the dv50 particle size of the mannitol is between about 90 and 130 microns. In some embodiments, the dv50 particle size of the mannitol is between about 90 and 120 microns. In some embodiments, the dv50 particle size of the mannitol is about 100 microns.

[0114] In some embodiments, the dv90 (90th percentile) particle size of the mannitol is about 150 microns or more. In some embodiments, the dv90 particle size of the mannitol is about 160 microns or more. In some embodiments, the dv90 particle size of the mannitol is about 170 microns or more. In some embodiments, the dv90 particle size of the mannitol is about 180 microns or more. In some embodiments, the dv90 particle size of the mannitol is about 185 microns or more. In some embodiments, the dv90 particle size of the mannitol is about 195 microns or more. In some embodiments, the dv90 particle size of the mannitol is about 200 microns. In some embodiments, the dv90 particle size of the mannitol is about 210 microns. In some embodiments, the dv90 particle size of the mannitol is about 225 microns.

[0115] In some embodiments, the provided pharmaceutical composition comprises spray-dried mannitol. In some embodiments, the provided pharmaceutical composition comprises amorphous mannitol.

[0116] In some embodiments, the provided pharmaceutical composition consists of maraviroc and excipients in some ratios expressed in w / w%. In some embodiments, the provided pharmaceutical composition consists of about 25-40% maraviroc, about 10-22% microcrystalline cellulose, about 0.5-4% crospovidone, and the rest comprising a coating polymer (e.g., an aminomethacrylate copolymer). In some embodiments, the provided pharmaceutical composition consists of about 25-40% maraviroc, about 10-22% microcrystalline cellulose, about 0.5-4% crospovidone, and about 34-65% coating polymer (e.g., Eudragit® E PO). In some embodiments, the provided pharmaceutical composition consists of about 30-40% maraviroc, about 15-22% microcrystalline cellulose, about 1-4% crospovidone, and about 34-54% coating polymer (e.g., Eudragit® E PO). In some embodiments, the provided pharmaceutical composition consists of about 25-37% maraviroc, about 10-18% microcrystalline cellulose, about 0.5-2.5% crospovidone, and about 42-65% coating polymer (e.g., Eudragit® E PO). In some embodiments, the provided pharmaceutical composition consists of about 31-37% maraviroc, about 14-18% microcrystalline cellulose, about 1.5-2.5% crospovidone, and about 42-54% coating polymer (e.g., Eudragit® E PO). In some embodiments, the provided pharmaceutical composition consists of about 32.5% maraviroc, about 15.5% microcrystalline cellulose, about 2% crospovidone, and about 50% coating polymer (e.g., Eudragit® E PO). In some embodiments, the provided pharmaceutical composition consists of about 36.1% maraviroc, about 17.2% microcrystalline cellulose, about 2.2% crospovidone, and about 44.4% coating polymer (e.g., Eudragit® E PO). In some embodiments, the provided pharmaceutical composition consists of about 10-25% maraviroc, about 5-40% suspending agent (e.g., microcrystalline cellulose and sodium carboxymethylcellulose), about 0.5-2% crospovidone, about 15-25% coating polymer (e.g., Eudragit® E PO), about 5-15% mannitol, about 5-25% sweetener (e.g., sucralose), and about 2-10% flavoring agent (e.g., fruit flavor). In some embodiments, the provided pharmaceutical composition consists of about 10-25% maraviroc, about 5-40% suspending agent (e.g., microcrystalline cellulose and sodium carboxymethylcellulose), about 0.5-2% crospovidone, about 15-25% coating polymer (e.g., Eudragit® E PO), about 5-15% mannitol, about 5-25% sweetener (e.g., sucralose), and about 2-10% flavoring agent (e.g., fruit flavor).In some embodiments, the provided pharmaceutical composition consists of about 12-22% maribavir, about 20-40% suspending agents (e.g., microcrystalline cellulose and sodium carboxymethyl cellulose), about 0.5-1.5% crospovidone, about 18-23% coating polymer (e.g., Eudragit® E PO), about 8-12% mannitol, about 10-20% sweetener (e.g., sucralose), and about 4-8% flavoring (e.g., fruit flavor). In some embodiments, the provided pharmaceutical composition consists of about 15-20% maribavir, about 25-40% suspending agents (e.g., microcrystalline cellulose and sodium carboxymethyl cellulose), about 1% crospovidone, about 19-21% coating polymer (e.g., Eudragit® E PO), about 9-11% mannitol, about 11-15% sweetener (e.g., sucralose), and about 5-7% flavoring (e.g., fruit flavor). In some embodiments, the provided pharmaceutical composition consists of about 15-20% maribavir, about 30-35% suspending agents (e.g., microcrystalline cellulose and sodium carboxymethyl cellulose), about 1% crospovidone, about 19-21% coating polymer (e.g., Eudragit® E PO), about 9-11% mannitol, about 11-15% sweetener (e.g., sucralose), and about 5-7% flavoring (e.g., fruit flavor). In some embodiments, the provided pharmaceutical composition consists of about 16.6% maribavir, about 33% suspending agents (e.g., microcrystalline cellulose and sodium carboxymethyl cellulose), about 1% crospovidone, about 20.3% coating polymer (e.g., Eudragit® E PO), about 10% mannitol, about 13.3% sweetener (e.g., sucralose), and about 5.8% flavoring (e.g., fruit flavor).

[0117] In some embodiments, the provided pharmaceutical composition consists of about 50 mg maribavir, about 23.9 mg microcrystalline cellulose (Avicel® PH105), about 3.1 mg crospovidone (Polyplasdone™ XL-10), about 61.5 mg Eudragit® E PO ReadyMix, about 30.1 mg mannitol, about 75 mg microcrystalline cellulose and sodium carboxymethyl cellulose (Avicel® CL-611), about 40 mg sucralose (Emprove), and about 17.5 mg of flavoring (e.g., fruit flavor).

[0118] In some embodiments, the provided pharmaceutical composition consists of about 200 mg maribavir, about 95.6 mg microcrystalline cellulose (Avicel® PH 105), about 12.4 mg croscarmellose sodium (Ac-Di-Sol®), about 246 mg Eudragit® E PO Ready Mix, about 120.4 mg mannitol, about 300 mg microcrystalline cellulose and sodium carboxymethyl cellulose (Avicel® CL-611), about 160 mg sucralose (Emprove), and about 70 mg of flavoring agent (e.g., fruit flavor).

[0119] Also provided are solid form formulations that are intended to be converted into liquid form formulations for oral administration shortly before use. Such liquid forms include solutions, suspensions, dispersions, colloids, sols, and emulsions. In addition to the active ingredient, these formulations can contain coloring, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickening agents, solubilizing agents, and the like.

[0120] In some embodiments, the provided maribavir formulation is an oral liquid formulation. In some embodiments, such formulations are prepared by suspending the provided solid pharmaceutical composition in a liquid, such as water.

[0121] The provided pharmaceutical formulations can be in unit dosage form. In such form, the formulation can be sub-divided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged formulation containing the discrete quantities of the formulation.

[0122] Viscosities greater than simple aqueous solutions can be desirable to reduce variability in dispensing the formulation, to reduce physical separation of components of a suspension or emulsion of the formulation, and / or to otherwise improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing.

[0123] In some embodiments, the provided pharmaceutical composition further comprises a viscosity enhancer, viscosity modifier, or suspending agent (e.g., microcrystalline cellulose and sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hypromellose, or a combination thereof). In some embodiments, the suspending agent is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., Avicel® CL-611).

[0124] In some embodiments, the provided pharmaceutical composition for liquid oral administration is packaged within a stick pack. In some embodiments, the stick pack container is resistant to air and moisture. In some embodiments, the stick pack container comprises laminated paper or aluminum. In some embodiments, the stick pack container is stable at room temperature and the provided pharmaceutical composition for liquid oral administration does not degrade. Stick packs are a packaging solution for powders, granules, and other formulations that provide a convenient portable unit dose solution for pharmaceuticals. Typically, stick packs are tubular in shape with an elongated configuration and typically have a continuous side seam.

[0125] Manufacturing Process The present disclosure also provides a method of manufacturing a ready-to-use pharmaceutical composition for liquid oral administration, the method comprising the steps of: i) granulating an active pharmaceutical ingredient and other excipients to form an intra-granular composition; ii) overcoating the intra-granular composition with a selectively soluble polymer to form a coated intra-granular composition; iii) blending the coated intra-granular composition, a diluent, a sweetener, a flavoring agent, and other excipients to form a blended composition; iv) filling and packaging the blended composition; wherein the intra-granular composition has a median particle size between about 100 and 400 microns, wherein the coated intra-granular composition has a median particle size of less than 500 microns, and wherein the diluent has a dv50 (i.e., 50thpercentile) particle size between about 30 and 180 microns.

[0126] In some embodiments, the provided method is a method of manufacturing a ready-to-use pharmaceutical composition for liquid oral administration, the method comprising the steps of: i) granulating an active pharmaceutical ingredient and other excipients to form an intra-granular composition; ii) overcoating the intra-granular composition with a selectively soluble polymer to form a coated intra-granular composition; iii) blending the coated intra-granular composition, mannitol, a sweetener, a flavoring agent, and other excipients to form a blended composition; iv) filling and packaging the blended composition; wherein the intra-granular composition has a median particle size between about 100 and 400 microns, and wherein the coated intra-granular composition has a median particle size of less than 500 microns, wherein the mannitol has a dv50 (i.e., 50thpercentile) particle size between about 30 and 180 microns.

[0127] In some embodiments, the provided method is a method of manufacturing a ready-to-use pharmaceutical composition for oral administration of a liquid, the method comprising the steps of: i) granulating maraviroc and other excipients to form an intragranular composition; ii) coating the intragranular composition with a selectively soluble polymer to form a coated intragranular composition; iii) blending the coated intragranular composition, mannitol, sweetener, flavoring agent, and other excipients to form a blended composition; iv) filling and packaging the blended composition; wherein the intragranular composition has a median particle size of between about 100 and 400 microns, wherein the coated intragranular composition has a median particle size of less than 500 microns, and wherein the dv50 (i.e., the 50th percentile) particle size of the mannitol is between about 30 and 180 microns.

[0128] In some embodiments, the provided manufacturing method further comprises the step of suspending the pharmaceutical composition in a liquid vehicle (e.g., water) prior to oral administration.

[0129] In some embodiments, the provided manufacturing method further comprises filling the blended composition into a strip pack. In some embodiments, the provided manufacturing method further comprises packaging the blended composition in a strip pack. The compositions and methods of the present application have shown consistency in providing a filled weight and consistent dosage in each strip pack.

[0130] In some embodiments, the provided manufacturing method forms a coated intragranular composition as described above and herein (e.g., wherein the coated intragranular composition has a median particle size of about 225-350 microns, about 250-325 microns, about 250-300 microns, about 250-290 microns, about 250-280 microns, about 250-270 microns, or about 225-300 microns).

[0131] In some embodiments, the provided manufacturing method comprises coating the intragranular composition with a selectively soluble polymer, wherein the selectively soluble polymer is insoluble at neutral pH but soluble at acidic pH. In some embodiments, the selectively soluble polymer is Eudragit® E PO.

[0132] In some embodiments, the provided manufacturing method comprises the step of granulating maraviroc and other excipients to form an intragranular composition. In some embodiments, the granulation comprises wet granulation. In some embodiments, the granulation comprises dry granulation.

[0133] In some embodiments, the maraviroc is micronized maraviroc (e.g., having a particle size as described above and herein). In some embodiments, the other excipient comprises, for example, microcrystalline cellulose as described above and herein. In some embodiments, the other excipient comprises Avicel PH-105®. In some embodiments, the other excipient comprises, for example, cross-linked polyplasdone as described above and herein. In some embodiments, the other excipient comprises Polyplasdone™ XL-10 cross-linked polyplasdone.

[0134] In some embodiments, the step of granulating the maraviroc and the other excipient to form an intragranular composition comprises: a) loading the maraviroc (e.g., micronized maraviroc) and the other excipient (e.g., microcrystalline cellulose (such as Avicel PH-105®) and cross-linked polyplasdone (such as Polyplasdone™ XL-10 cross-linked polyplasdone)) onto a granulator; b) blending the loaded maraviroc and the other excipient; and c) spray-drying the blended maraviroc and the other excipient. In some embodiments, the step of granulating the maraviroc and the other excipient to form an intragranular composition is performed as described in Example 4 with respect to the unsieved maraviroc granules. In some embodiments, the intragranular composition is an unsieved intragranular composition (e.g., an unsieved maraviroc intragranular composition).

[0135] In some embodiments, for example, prior to the step of coating the intragranular composition with a selectively soluble polymer to form a coated intragranular composition, the provided method further comprises the step of filtering the unsieved intragranular composition (e.g., an unsieved intragranular maraviroc composition) to form a sieved intragranular composition (e.g., a sieved intragranular maraviroc composition). In some embodiments, the filtering is performed as described in Example 4 with respect to the sieved maraviroc granules.

[0136] In some embodiments, the step of coating the intragranular composition with a selectively soluble polymer to form a coated intragranular composition comprises: a) loading the intragranular composition (e.g., sieved intragranular maribavir composition) and the selectively soluble polymer (e.g., Eudragit® E PO (ReadyMix)) onto a granulator; b) blending the loaded intragranular composition (e.g., sieved maribavir intragranular composition) and the selectively soluble polymer (e.g., Eudragit® E PO (ReadyMix)); and c) spray drying the blended intragranular composition (e.g., sieved maribavir intragranular composition) and the selectively soluble polymer (e.g., Eudragit® E PO (ReadyMix)). In some embodiments, the step of coating the intragranular composition with a selectively soluble polymer to form a coated intragranular composition is performed as described in Example 4 with respect to coating maribavir spherules.

[0137] The following enumerated embodiments include aspects of the present disclosure: Enumerated Embodiments 1. A method of treating a cytomegalovirus (CMV) infection or disease in a patient having the CMV infection or disease, the method comprising administering maribavir to the patient, wherein the patient is less than 18 years of age.

[0138] 2. The method of embodiment 1, wherein the patient is at least 12 years of age and less than 18 years of age.

[0139] 3. The method of embodiment 1, wherein the patient is less than 12 years of age.

[0140] 4. The method of embodiment 1, wherein the patient is at least 6 years of age and less than 12 years of age.

[0141] 5. The method of embodiment 1, wherein the patient is less than 6 years of age.

[0142] 6. The method of any of the preceding embodiments, wherein the patient weighs less than 35 kg.

[0143] 7. The method of any of the preceding embodiments, wherein the patient weighs at least 25 kg.

[0144] 8. The method of any of the preceding embodiments, wherein the patient weighs less than 25 kg.

[0145] 9. The method of any of the preceding embodiments, wherein the patient weighs 10-25 kg.

[0146] 10. The method of any of the preceding embodiments, wherein the patient weighs at least 5 kg.

[0147] 11. The method of any of the preceding embodiments, comprising orally administering to the patient about 400 mg of maralibavir twice per day.

[0148] 12. The method of any of the preceding embodiments, comprising orally administering to the patient about 200 mg of maralibavir twice per day.

[0149] 13. A method of treating a cytomegalovirus (CMV) infection or disease in a patient having the CMV infection or disease, the method comprising orally administering to the patient maralibavir, wherein the patient is at least 12 years old and less than 18 years old, and wherein the amount of maralibavir administered is i) 100 mg twice per day for a patient weighing at least 10 kg and less than 14 kg, ii) 200 mg twice per day for a patient weighing at least 14 kg and less than 25 kg, or iii) 400 mg twice per day for a patient weighing at least 25 kg.

[0150] 14. A method of treating a cytomegalovirus (CMV) infection or disease in a patient having the CMV infection or disease, the method comprising orally administering to the patient maralibavir, wherein the patient is at least 6 years old and less than 12 years old, and wherein the amount of maralibavir administered is i) 100 mg twice per day for a patient weighing at least 10 kg and less than 14 kg, ii) 200 mg twice per day for a patient weighing at least 14 kg and less than 25 kg, or iii) 400 mg twice per day for a patient weighing at least 25 kg.

[0151] 15. A method of treating a cytomegalovirus (CMV) infection or disease in a patient having the CMV infection or disease, the method comprising orally administering to the patient maralibavir, wherein the patient is less than 6 years old, and wherein the amount of maralibavir administered is i) 50 mg once per day for a patient weighing at least 5 kg and less than 7 kg, ii) 50 mg twice per day for a patient weighing at least 7 kg and less than 10 kg, iii) for patients weighing at least 10 kg and less than 14 kg, 100 mg twice a day, iv) for patients weighing at least 14 kg and less than 25 kg, 200 mg twice a day, or v) for patients weighing at least 25 kg, 400 mg twice a day.

[0152] 16. The method of any one of the preceding embodiments, wherein maribavir is administered daily.

[0153] 17. The method of any one of the preceding embodiments, wherein maribavir is administered daily for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks.

[0154] 18. The method of any one of the preceding embodiments, wherein maribavir is administered in a therapeutically effective amount.

[0155] 19. The method of any one of the preceding embodiments, wherein the patient has a cytomegalovirus (CMV) deoxyribonucleic acid (DNA) screening value of > 1365 international units per milliliter (IU / mL) in whole blood or > 455 IU / mL in plasma in 2 consecutive assessments at least 1 day apart within 14 days of the first dose of maribavir by quantitative polymerase chain reaction (qPCR).

[0156] 20. The method of any one of the preceding embodiments, wherein the patient has not suffered from a CMV tissue invasive disease involving the central nervous system (CNS) or retina prior to treatment with maribavir.

[0157] 21. The method of any one of the preceding embodiments, further comprising the step of confirming clearance of CMV viremia in the patient.

[0158] 22. The method of embodiment 21, wherein clearance of CMV viremia is defined as a plasma CMV DNA concentration below the lower limit of quantification (e.g., < 137 international units per milliliter [IU / mL] in a sample taken at least 5 days apart after 2 consecutive baselines).

[0159] 23. The method of any one of the preceding embodiments, comprising administering maribavir to the patient with or without food.

[0160] 24. The method of any one of the preceding embodiments, wherein the maribavir is administered as a 200 mg tablet.

[0161] 25. The method of any of the preceding embodiments, wherein the patient is refractory to treatment of CMV infection or disease with one or more other drugs.

[0162] 26. The method of any of the preceding embodiments, wherein the patient is refractory to treatment with one or more of ganciclovir, valganciclovir, cidofovir, or foscarnet sodium.

[0163] 27. The method of any of the preceding embodiments, wherein the patient is refractory and has genotypic resistance.

[0164] 28. The method of any of the preceding embodiments, wherein the patient is refractory and does not have genotypic resistance.

[0165] 29. The method of any of the preceding embodiments, wherein the patient is a transplant recipient.

[0166] 30. The method of any of the preceding embodiments, wherein the patient is a hematopoietic stem cell transplant recipient.

[0167] 31. The method of any of the preceding embodiments, wherein the patient is a solid organ transplant recipient.

[0168] 32. The method of any of the preceding embodiments, wherein the patient is receiving or has received a cytochrome P450 3A4 (CYP3A4) inducer prior to administration of maribavir, and comprising the step of discontinuing administration of the CYP3A4 inducer prior to administration of maribavir.

[0169] 33. The method of embodiment 32, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, a prenylamine, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John’s wort.

[0170] 34. The method of embodiment 32 or 33, wherein the CYP3A4 inducer is a strong CYP3A4 inducer.

[0171] 35. The method of any of embodiments 31-33, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, rifabutin, and St. John’s wort.

[0172] 36. The method of any of the preceding embodiments, wherein the patient is receiving or has received a cytochrome P450 3A4 (CYP3A4) inducer, and comprising the step of increasing the amount of maribavir administered to the patient.

[0173] 37. The method of embodiment 36, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, auranofin, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John’s wort.

[0174] 38. The method of embodiment 36 or 37, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John’s wort.

[0175] 39. The method of any one of embodiments 36-38, wherein the CYP3A4 inducer is selected from the group consisting of carbamazepine, phenytoin, and phenobarbital.

[0176] 40. The method of any one of the preceding embodiments, wherein the patient is receiving or has received an immunosuppressant.

[0177] 41. The method of embodiment 40, further comprising the step of monitoring the level of immunosuppressant (e.g., compared to a reference or standard level) after initiation of administration of maralibavir.

[0178] 42. The method of embodiment 40 or 41, further comprising the step of reducing the amount of the immunosuppressant administered to the patient.

[0179] 43. The method of any one of embodiments 40-42, further comprising the step of monitoring the level of immunosuppressant (e.g., compared to a reference or standard level) after cessation of administration of maralibavir.

[0180] 44. The method of embodiment 43, further comprising the step of increasing the amount of immunosuppressant administered to the patient (e.g., relative to the amount of immunosuppressant administered prior to initiation of administration of maralibavir).

[0181] 45. The method of any one of embodiments 40-44, wherein the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, sirolimus, prednisone, and mycophenolate.

[0182] 46. The method of any one of embodiments 40-45, wherein the immunosuppressant is selected from the group consisting of tacrolimus, cyclosporine, everolimus, and sirolimus.

[0183] 47. The method of any one of the preceding embodiments, wherein the patient is receiving or has received digoxin.

[0184] 48. The method of embodiment 47, further comprising the step of monitoring digoxin levels.

[0185] 49. The method as described in embodiment 47 or 48, the method further comprising the step of reducing the amount of digoxin administered to the patient.

[0186] Example General Preparation of Oral Liquid Formulation Marivavir, microcrystalline cellulose, and crospovidone are granulated in a fluidized bed granulator with purified water to form spherical particles. The particles are dried in a fluidized bed processor. The dried particles are sieved to collect particles within the desired size range. The particles are coated with an aqueous suspension of Eudragit® E PO ReadyMix and dried in a fluidized bed processor. The coated particles are sieved to remove any aggregates that may have formed. The polymer-coated particles are combined with a sweetener (e.g., sucralose), a flavoring agent (e.g., fruit flavor), a diluent (e.g., sugar alcohol, such as mannitol), and optionally a suspending agent (microcrystalline cellulose and sodium carboxymethyl cellulose) to form an oral suspension powder formulation (a pharmaceutical composition for oral liquid administration). The oral suspension powder formulation is suspended in water for oral administration.

[0187] Example 1: A phase 3, open-label, single-arm, repeated-dose study was conducted to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of maribavir in children and adolescents who have undergone hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT) for the treatment of cytomegalovirus (CMV) infection. The primary objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) profile of maribavir for the treatment of CMV infection in children and adolescents following HSCT or SOT, and to determine the optimal dose of maribavir based on pharmacokinetic (PK) models using 200 mg adult tablet formulations or other formulations (i.e., oral suspensions). Participants will be treated with maribavir for 8 weeks. Participants are required to have a doctor's visit during the 12-week follow-up period.

[0188] Experimental Groups and Interventions

[0189] The powder for oral suspension will be provided in strips containing 50 or 200 mg of maribavir. The powder for oral suspension should be stored at an ambient temperature of no more than 25°C and should not be frozen or refrigerated.

[0190] method: This is a Phase 3, multicenter, open-label, single-arm, repeat-dose study to evaluate the safety and tolerability, PK, acceptability and palatability, and antiviral activity of maralibavir in the treatment of CMV infection in male and female children and adolescents (0 years to less than 18 years) after HSCT or SOT. This Phase 3 study is designed to determine the optimal dose of maralibavir using either the oral suspension or 200 mg tablet formulation. An external data monitoring committee will be utilized to review the cumulative safety and tolerability data generated in this study.

[0191] There will be 3 age cohorts, including: • Cohort 1: Subjects >12 years to <18 years • Cohort 2: Subjects >6 years to <12 years • Cohort 3: Subjects 0 years to <6 years Cohorts 1 and 2 will enroll at least 10 HSCT subjects in each cohort, and Cohort 3 will enroll at least 13 HSCT subjects, of which 10 subjects are 2 years to <6 years and 3 subjects are 0 to <2 years.

[0192] It is planned to enroll the 3 age cohorts concurrently; however, the initiation of Cohort 3 will begin when the powder for the oral suspension becomes available. Within Cohorts 1, 2, and 3, staggered enrollment will be implemented to allow for an internal interim analysis of safety and PK data for at least 5 subjects who have completed Week 1 (Day 7 [+2 days]) PK sample collection. The goal of this interim analysis is to confirm the dose selection, allow for dose adjustment, and monitor the safety and tolerability of maralibavir within each cohort.

[0193] In each cohort, subjects will receive doses according to the dosing table and will have serial PK samples collected at Week 1 (Day 7 [+2 days]). The PK samples collected in at least 5 subjects enrolled in each cohort at Week 1 (Day 7 [+2 days]) will be analyzed with rapid turnaround to compare the PK exposure obtained in each subject and the entire cohort to the target PK range, allowing for dose adjustment based on observed PK and monitoring safety and tolerability within each cohort. After confirming PK exposure and reviewing safety data, enrollment of the remainder of the cohort will continue.

[0194] After 33 asymptomatic HSCT subjects in the 3 cohorts (at least 10 asymptomatic HSCT subjects in Cohorts 1 and 2, and 13 asymptomatic HSCT subjects in Cohort 3 [including 3 asymptomatic HSCT subjects 0 to <2 years]) have completed the study, another interim analysis will be performed in order to submit data to regulatory authorities.

[0195] To be eligible for the study, subjects must have documented whole blood or plasma CMV infection and, as determined by local laboratory quantitative polymerase chain reaction (qPCR) or similar quantitative CMV DNA result, a screening value of > 1365 IU / mL in whole blood or > 455 IU / mL in plasma within 14 days of the first dose of study drug with 2 consecutive assessments at least 1 day apart (the second assessment within 5 days prior to the first dose). Results should be available prior to the subject receiving the first dose of maribavir treatment to verify the subject is eligible for the study. Both assessments must use the same source (blood or plasma) and the same laboratory.

[0196] The study will have 3 phases: 1) a screening period up to 2 weeks, 2) an 8-week study treatment period, and 3) a 12-week follow-up period after the treatment period.

[0197] Screening Period Approximately 100 subjects will be screened. Eligibility will be determined during the screening period from Day -14 to Day 1.

[0198] Treatment Period During the 8-week treatment period (Day 1 / Week 1 to Day 56 / Week 8), maribavir will be administered BID following a dosing regimen stratified by age and weight. Assessments during weekly study visits during the treatment period include: CMV DNA quantitative testing; incidence of CMV disease; evaluation of graft function, graft versus host disease (GVHD), underlying disease, and opportunistic infections; and concomitant medications and AE review. Pharmacokinetics, maribavir palatability assessments, physical examinations, vital sign assessments, electrocardiograms (ECGs), immunosuppressive drug level monitoring, clinical laboratory tests (hematology and chemistry), and urinalyses will be performed at selected visits throughout the treatment period. Cytomegalovirus genotyping will be performed at baseline (Visit 2 / Day 1 / Week 1) and 1 additional time point (as applicable) for subjects > 2 years of age. Due to blood draw volume limitations, some assessments will be limited in Cohort 3. For subjects in Cohort 3 who develop CMV CNS infection while on study treatment, optional cerebrospinal fluid sampling will be considered for subjects who undergo a lumbar puncture as part of the diagnostic workup prior to stopping study treatment.

[0199] At Weeks 1, 4, and 8, taste / palatability assessments, such as the hedonicity “facial” scale, will also be completed by the subject (as possible) or their parent or legally authorized representative (LAR).

[0200] If, in the opinion of the Investigator, study treatment needs to be discontinued prior to Week 8, alternative anti-CMV treatment can be administered as deemed necessary after study treatment discontinuation. For subjects who discontinue study treatment prior to Week 8 or withdraw consent during the treatment period, the end-of-treatment assessments described in Week 8 of the assessment schedule will be performed as completely as possible at the study visit or immediately after the last dose of study drug. Subjects who discontinue treatment early but remain in the study will follow a modified assessment schedule for the remaining weekly visits of the study treatment period and then enter the 12-week follow-up period.

[0201] Follow-up Period After completion of the 8-week study treatment period, subjects will enter a 12-week follow-up period. During the follow-up period, study-specific assessments will include central specialty laboratory CMV testing; incidence of CMV disease; graft function, GVHD, and underlying disease assessments; concomitant medications; and AE review monthly for the first 4 weeks and then every 2 visits.

[0202] Subjects who withdraw from the study during the follow-up period will have the study end-of-study assessments and procedures performed at Week 20 (12 weeks into follow-up) as soon as possible.

[0203] Outcome Measures Primary Outcome Measure 1. Maximum observed plasma concentration of maribavir (Cmax) The Cmax of maribavir will be assessed.

[0204] [Time frame: Pre-dose, 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1).] 2. Time to maximum observed concentration of maribavir (Tmax) The Tmax of maribavir will be assessed.

[0205] [Time frame: Pre-dose, 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1).] 3. Minimum plasma concentration of maribavir (Cmin) The Cmin of maribavir will be assessed.

[0206] [Time frame: Pre-dose, 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1); pre-dose on Day 28 (Week 4); pre-dose and 2 to 4 hours post-dose on Day 56 (Week 8).] 4. Area under the plasma concentration-time curve of maribavir over 1 12-hour dosing interval at steady state (AUC0-t) The AUC0-t of maribavir will be assessed.

[0207] [Timeframe: Predose, 0.5, 1.5, 3, 4, 6, and 8 hours postdose on Day 7 (Week 1).] 5. Half-life (t½) of maribavir The t½ of maribavir will be evaluated.

[0208] [Timeframe: Predose, 0.5, 1.5, 3, 4, 6, and 8 hours postdose on Day 7 (Week 1).] 6. Terminal elimination rate constant (λ-z) of maribavir The λ-z of maribavir will be evaluated.

[0209] [Timeframe: Predose, 0.5, 1.5, 3, 4, 6, and 8 hours postdose on Day 7 (Week 1).] 7. Volume of distribution (Vz / F) of maribavir The Vz / F of maribavir will be evaluated.

[0210] [Timeframe: Predose, 0.5, 1.5, 3, 4, 6, and 8 hours postdose on Day 7 (Week 1).] 8. Apparent oral clearance (CL / F) of maribavir The CL / F of maribavir will be evaluated.

[0211] [Timeframe: Predose, 0.5, 1.5, 3, 4, 6, and 8 hours postdose on Day 7 (Week 1).] 9. Number of participants with treatment-emergent adverse events (TEAEs) and serious TEAEs An adverse event (AE) is any unfavorable and undesired medical occurrence occurring in a clinical study participant administered a medicinal product and not necessarily caused by this treatment. A TEAE is defined as any event that occurs or presents after the start of treatment with the study product or medicinal product or any existing event that worsens in intensity or frequency after exposure to the study product or medicinal product. An SAE is the occurrence of any unfavorable medical event (whether or not considered related to the study product and at any dose) that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital abnormality or birth defect, is an important medical event. TEAEs include serious and non-serious AEs.

[0212] [Timeframe: From start of administration of study drug to follow-up (Week 20).] Secondary Outcome Measures 10. Percentage of participants with confirmed CMV viremia clearance at Week 8 Confirmed CMV viremia clearance is defined as a plasma CMV DNA concentration below the lower limit of quantification (LLOQ) in 2 consecutive post-baseline samples at least 5 days apart at the central laboratory, irrespective of the length of study treatment. The percentage of participants reporting confirmed CMV viremia clearance at Week 8 will be reported.

[0213] [Timeframe: Week 8.] 11. Percentage of participants achieving sustained confirmed CMV viremia clearance and symptom control from Week 8 to Week 12, Week 16, and Week 20 Confirmed CMV viremia clearance is defined as a plasma CMV DNA concentration below the lower limit of quantification (LLOQ) in 2 consecutive post-baseline samples at least 5 days apart at the central laboratory, irrespective of the length of study treatment. CMV infection symptom control is defined as resolution or improvement of tissue invasive disease or CMV syndrome in participants who were symptomatic at baseline, or no new symptoms in participants who were asymptomatic at baseline. The percentage of participants achieving sustained confirmed CMV viremia clearance and symptom control from Week 8 to Week 12, Week 16, and Week 20 will be reported.

[0214] [Timeframe: Week 8 to Week 12, Week 16, and Week 20.] 12. Percentage of participants with confirmed CMV viremia recurrence at the time of study treatment and at the time of study treatment discontinuation Confirmed CMV viremia recurrence is defined as a plasma CMV DNA concentration greater than or equal to (>=) the LLOQ at the time of assessment in 2 consecutive plasma samples at least 5 days apart after achieving confirmed viremia clearance. The percentage of participants with confirmed viremia recurrence at the time of study treatment and at the time of study treatment discontinuation will be reported.

[0215] [Timeframe: up to Week 20.] 13. Time to first confirmed viremia clearance Confirmed CMV viremia clearance is defined as a plasma CMV DNA concentration below the LLOQ at the time of assessment at the central laboratory in 2 consecutive post-baseline samples at least 5 days apart. The time to first confirmed viremia clearance at any time during the study will be summarized using the Kaplan-Meier method.

[0216] [Timeframe: up to Week 20.] 14. Percentage of participants with confirmed CMV viremia recurrence treated with an alternative anti-CMV therapy administered during the 12-week follow-up period Confirmed CMV viremia recurrence was defined as plasma CMV DNA concentration >= LLOQ assessed in 2 consecutive plasma samples separated by at least 5 days after achieving confirmed viral clearance. The percentage of participants with confirmed CMV viremia recurrence treated with alternative anti-CMV therapy within the 12-week follow-up period will be reported in participants with confirmed viral clearance.

[0217] [Time Frame: 12 weeks of follow-up (Week 9 to Week 20).] 15. Change from baseline in log10 plasma CMV deoxyribonucleic acid (DNA) load Change from baseline in log10 plasma CMV DNA at the time of study when study treatment was received will be reported by study week.

[0218] [Time Frame: Baseline to Week 20.] 16. Number of participants with CMV maribavir resistance CMV DNA genotyping will be performed for UL97, UL54, UL56, and UL27 genes known to confer resistance to conventional anti-CMV therapy or maribavir. The number of participants with CMV maribavir resistance occurring after baseline through Week 12 will be reported.

[0219] [Time Frame: Through Week 12.] 17. Overview score for maribavir palatability assessment Palatability (taste, feel, smell, ease of swallowing, and aftertaste) will be measured using a 5-point facial hedonic scale combined with a 100-point linear visual analog scale (VAS), ranging from 0: very bad to 100: very good. Descriptive overview scores will be described at Week 1, Week 4, and Week 8.

[0220] [Time Frame: Week 1, Week 4, and Week 8.] Exploratory Endpoints: • To evaluate transplant outcomes (acute rejection, graft loss or failure, GVHD in HSCT subjects) and time to each type of transplant event.

[0221] Eligibility Inclusion Criteria: • Before any research-related procedures are completed, one or both parents or their legally authorized representative (LAR) must sign an informed consent form, and there must be documentation of the participant's (if age appropriate) consent. During the COVID-19 public health emergency, informed consent may be obtained from potential or current trial participants via electronic informed consent functions or electronic in-person consent interviews, if permitted by local laws and regulations, when they are unable to travel to the location.

[0222] • At the time of consent, the participant must be a male or female child or an adolescent under 18 years of age. For participants in Cohort 3 only, the gestational age must be at least 38 weeks and the minimum weight must be 5 kg.

[0223] • Is a recipient of SOT or HSCT, which is still functioning at the time of screening.

[0224] • For documented CMV infection, such as that determined by quantitative polymerase chain reaction (qPCR) or similar quantitative nucleic acid amplification test (qNAAT) results from a local or central specialized laboratory, the CMV deoxyribonucleic acid (DNA) screening value in whole blood >= 1365 IU / mL or in plasma >= 455 IU / mL in two consecutive assessments at least 1 day apart. Both samples must be obtained within 14 days of the first dose of the study drug, and the second sample must be obtained within 5 days before the first dose of the study drug. Both assessments must be conducted using the same laboratory and the same sample type (whole blood or plasma).

[0225] • Include all of the following results as part of the screening laboratory evaluation: ○ Absolute neutrophil count >= 500 cells / mm³ (0.5 × 10⁹ cells / L) ○ Platelet count >= 15,000 / mm^3 (15 × 10^9 / L) ○ Hemoglobin >= 8 g / dL (>= 80 g / L) • Estimate glomerular filtration rate (creatinine-based bedside Schwartz equation) >= 30 mL / min / 1.73 m².

[0226] • Is infertile. If fertile, a negative serum human chorionic gonadotropin (hCG) or beta-human chorionic gonadotropin (beta-hCG) pregnancy test at screening. Sexually active males or non-pregnant, non-breast-feeding females must agree to comply with the applicable contraception requirements of this protocol during the study treatment administration period and for 90 days after the last dose of study treatment.

[0227] • Life expectancy >= 8 weeks.

[0228] • Willing and able to fully comply with the study procedures and restrictions as specified in the protocol. For younger children, a parent / guardian or LAR must meet this criterion.

[0229] Exclusion Criteria: • Has active CMV disease involving the central nervous system (CNS) or retina as assessed by the investigator at screening.

[0230] • Has other types of infections that are not controlled as assessed by the investigator at the time of enrollment.

[0231] • Has a history of clinically relevant alcohol or drug abuse that could interfere with treatment compliance or the use of assessments as determined by the investigator.

[0232] • Is receiving valganciclovir, ganciclovir, cidofovir, foscarnet, leflunomide, letimovir, or artesunate at the start of study treatment, or is expected to require one of these agents during the 8-week treatment period.

[0233] • Is known to be hypersensitive to maribavir or any excipients.

[0234] • Has had severe vomiting, diarrhea, or other severe gastrointestinal (GI) disease within 24 hours prior to the first dose of study treatment, or has had a GI malabsorption disorder that would preclude oral administration of the study drug.

[0235] • Requires mechanical ventilation or vasopressor medications to provide hemodynamic support at baseline (Week 0).

[0236] • Is pregnant (or expecting to become pregnant) or breastfeeding.

[0237] • Has previously completed, stopped, or withdrawn from this study.

[0238] • Has received any investigational agent or device (including CMV-specific T cells) within 30 days prior to starting study treatment. Prior approved agents under investigation for other indications are not excluded.

[0239] • Has received maribavir or a CMV vaccine at any time previously.

[0240] • Has a clinically significant medical or surgical condition deemed by the investigator to interfere with the interpretation of study results, contraindicate administration of study treatment, or compromise the safety or health of the participant.

[0241] • Has severe liver disease (Child-Pugh score >= 10).

[0242] • Has serum aspartate aminotransferase greater than (> 5 times the upper limit of normal (ULN) at screening, or serum alanine aminotransferase > 5 times the ULN at screening, or total bilirubin >= 3.0 times the ULN at screening as analyzed by the local laboratory (except for documented Gilbert’s syndrome).

[0243] • Has a positive human immunodeficiency virus (HIV) result. Participants must have a confirmed negative HIV test result within 3 months of study enrollment, or if not available, tested by the local laboratory within the screening period.

[0244] • Has an active malignancy, except for non-melanoma skin cancer, as determined by the investigator. Participants who experienced relapse or progression of the underlying malignancy for which they underwent HSCT or SOT, as determined by the investigator, will not be enrolled.

[0245] • Is experiencing treatment for acute or chronic hepatitis B or hepatitis C.

[0246] • Requires ongoing treatment with a potent cytochrome P450 3A (CYP3A) inducer or anticipates requiring treatment with such an inducer.

[0247] • Has low body weight, in which the total blood volume (TBV) required during participation in the study will exceed 1% TBV at each study visit or 3% TBV over a 30-day period.

[0248] Statistical methodology: All analyses will be descriptive.

[0249] An internal interim analysis of safety and PK data will be performed in at least 5 subjects with Week 1 (Day 7 [+ 2 days]) PK sample collection in each cohort. The objective of this interim analysis is to confirm dose selection, allow dose adjustment, and monitor the safety and tolerability of maribavir within each cohort.

[0250] Following completion of the study in 33 asymptomatic HSCT subjects in 3 cohorts (at least 10 asymptomatic HSCT subjects in each of Cohorts 1 and 2, and 13 asymptomatic HSCT subjects in Cohort 3 [including 3 asymptomatic HSCT subjects aged 0 to <2 years]) in the 3 cohorts, an additional phase of analysis will be performed in order to submit data to regulatory authorities.

[0251] Safety assessments Safety and tolerability of maribavir treatment for CMV infection in the pediatric population (children and adolescents) following HSCT or SOT will be assessed by evaluating SAEs, AEs (including cases of CMV disease or new CMV infection), AEs leading to maribavir treatment or study discontinuation, AEs leading to death, and AEs of special interest (AESIs). Use of concomitant medications, clinical laboratory tests, vital signs, ECGs, abnormal physical findings, and immunosuppressive drug levels will also be summarized.

[0252] For purposes of safety analyses, two observation periods are defined: • Treatment period: from the start of maribavir until 7 days after the last dose of study treatment • Overall study period: from the start of maribavir administration until the end of the study.

[0253] Safety endpoints for the treatment period and overall study period (as appropriate) will be summarized descriptively. Baseline (Visit 2 / Day 1 / Week 1) assessments will be the last assessments prior to the first dose of maribavir treatment.

[0254] Treatment-emergent AEs (TEAEs) are defined as any event that occurs or presents after the start of treatment with study or medical product, or any pre-existing event that worsens in intensity or frequency following exposure to study or medical product.

[0255] The number, incidence, and percentage of TEAEs for each cohort and the overall population for the treatment period and overall study period will be presented using the Preferred Term (PT) from the Medical Dictionary for Regulatory Activities. A summary of the severity and relationship to maribavir treatment will also be provided. Treatment-emergent SAEs will be summarized separately in a similar manner. A summary of AEs leading to discontinuation of maribavir treatment, withdrawal, AEs leading to death, SAEs, and AESIs will be provided.

[0256] Adverse events of particular interest will be analyzed according to the major system organ classification (SOC) and PT. Summary tables with SOC and PT will be generated presenting the number and percentage of subjects by treatment period and overall study period for AEs, severity, seriousness, and relationship to maribavir treatment. Invasive or opportunistic bacterial, viral, and fungal infections, if any, will be recorded.

[0257] The use of concomitant medications will be summarized descriptively for each cohort and overall for the treatment period and overall study period. In addition, the administration of hematopoietic growth factors, blood, and blood products will also be summarized.

[0258] At each assessment visit, changes from baseline (Visit 2 / Day 1 / Week 1) in vital signs and clinical laboratory tests will be summarized for each cohort and overall using descriptive statistics. Potential clinically important results will also be summarized.

[0259] Dose interruptions of maribavir due to any AE will be summarized. ECG results will be summarized by cohort and overall.

[0260] Pharmacokinetic analysis An internal interim PK analysis will be performed in at least 5 subjects with Week 1 (Day 7 [+2 days]) PK sample collection in each cohort. For the interim PK analysis, noncompartmental analysis (NCA) will be performed on the total plasma concentrations of maribavir to characterize the AUC, Cmax, and Cmin for each subject with continuous PK sampling in Week 1. The target PK exposure for efficacy is a group geometric mean AUC in the range of 142-406 h*pg / mL and a Cmin > 5.43 pg / mL.

[0261] Maribavir concentrations will be summarized by visit and scheduled sampling times. A scatter plot of all reportable maribavir concentrations versus actual sampling times will be generated. A list of subjects with maribavir concentrations below the limit of quantification will be provided. If the data permit, relationships between maribavir PK parameters (such as CL / F, Vz / F, lza, and half-life [tl / 2]) and body weight or age can be explored.

[0262] For subjects with continuous PK blood sampling, PK parameters will be calculated from maribavir concentration-time data using NCA, and all calculations will be based on actual sampling times.

[0263] For all sparse PK sampling periods, no NCA will be performed.

[0264] All maribavir concentrations obtained in this study (both continuous and sparse PK samples) will be combined with the PK data from the adult Phase 2 and Phase 3 studies in separate analyses and reporting and analyzed using population PK analysis methods with nonlinear mixed-effects modeling methods using NONMEM version 7 or higher. If the data permit, post hoc relationships between population model maribavir exposure and the efficacy and safety endpoints of particular interest will be explored.

[0265] Efficacy analyses All efficacy endpoints will be summarized descriptively for each age cohort and the overall population. The denominator for percentages will be based on the number of subjects in each age cohort and the overall population. Kaplan-Meier estimates will be used to summarize time-to-event endpoints; 95% confidence intervals for the 25th, 50th, and 75th time of estimation will be presented.

[0266] Palatability assessment analysis Palatability data will be summarized descriptively for each age cohort and the overall population at Week 1, Week 4, and Week 8 (or end of treatment).

[0267] Example 2: Phase 1, Open-Label, Randomized, Two-Part Study in Healthy Adult Participants to Evaluate the Relative Bioavailability of Maribavir Pediatric Formulation Compared to the Commercial Formulation, as well as the Food Effect and the Impact of Rabeprazole to Reduce Gastric Acidity on the Pharmacokinetics of a Single Dose of Maribavir Pediatric Formulation Study Description Outcome Measures Primary Outcome Measure: The study will have 2 parts, Part 1 and Part 2. Participants will only participate in one part.

[0268] The primary objective of Part 1 of this study is to examine the ability of a single dose of maribavir pediatric formulation to be absorbed in the digestive tract compared to the commercial tablet, and to examine how a high-fat, high-calorie meal affects the absorption, distribution, and elimination of maribavir pediatric formulation given orally as a water suspension.

[0269] The primary objective of Part 2 of this study is to evaluate the effect of multiple doses of rabeprazole on reducing gastric acid’s impact on the absorption, distribution, and elimination of maribavir pediatric formulation given orally as a water suspension.

[0270] Each participant will be at the study clinic from the day before the first treatment until the day after the last treatment.

[0271] Part 1 is a crossover design with three treatments (Treatments A, B, and C), six sequences, and three periods.

[0272] The relative bioavailability of a 200 milligram (mg) pediatric formulation of maralibavir (Treatment B) administered orally as a suspension in water under fasting conditions will be compared to a 200 mg maralibavir commercial tablet (Treatment A) administered orally under fasting conditions. In addition, the effect of food on the pharmacokinetics (PK) of a 200 mg pediatric formulation of maralibavir administered orally as a suspension in water under fasting conditions (Treatment B) and under fed conditions (Treatment C) will be evaluated. In each sequence, participants will receive three treatments (Treatments A, B, and C) according to a schedule.

[0273] • Sequence 1 : Treatment A + Treatment B + Treatment C • Sequence 2: Treatment A + Treatment C + Treatment B • Sequence 3: Treatment B + Treatment A + Treatment C • Sequence 4: Treatment B + Treatment C + Treatment A • Sequence 5: Treatment C + Treatment A + Treatment B • Sequence 6: Treatment C + Treatment B + Treatment A Part 2 is a single fixed sequence design with two treatments (Treatments D and E). Two treatments will be administered to evaluate the effect of multiple doses of rabeprazole to reduce gastric acid on the PK of a single dose of 200 mg pediatric formulation of maralibavir administered orally as a suspension in water

[0274]

[0275] Eligibility Inclusion Criteria 1. Part 1 and Part 2: Maximum observed plasma concentration (Cmax) of maralibavir The Cmax of maralibavir in plasma will be evaluated.

[0276] [Time frame: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose on Day 1 of Part 1 and Days 2 and 5 of Part 2 in each treatment period] 2. Part 1 and Part 2: Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) of maralibavir The AUClast of maralibavir in plasma will be evaluated.

[0277] [Time frame: predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose on Day 1 of Part 1 and Days 2 and 5 of Part 2 in each treatment period] 3. Part 1 and Part 2: Area under the plasma concentration-time curve from time 0 to infinity (AUCo-infinity) of maribavir The AUCo-infinity of maribavir in plasma will be assessed.

[0278] [Time frame: In each treatment period on Day 1 of Part 1 and on Days 2 and 5 of Part 2, prior to dosing, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post-dosing] Secondary outcome measures: 4. Part 1 and Part 2: Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) TEAEs will include TEAES by severity, TEAEs by causality, vital signs, electrocardiogram (ECG) values, and any clinically significant changes in clinical laboratory parameters.

[0279] [Time frame: Part 1 and Part 2: From start of administration of study drug to follow-up (Day 16).

[0280] Exclusion Criteria Minimum age: 18 years Maximum age: 55 years Gender: All Gender-based: No Accepting healthy volunteers: Yes Results Understand, are able to, and willing to comply completely with the study procedures and restrictions, and voluntarily sign (in person or via legally authorized representative) an informed consent form to participate in the study.

[0281] Be aged 18 to 55 years (inclusive) at the time of consent at the Screening Visit.

[0282] Be a male or non-pregnant, non-breastfeeding female, or a female of childbearing potential who agrees to comply with any applicable contraceptive requirements of the protocol.

[0283] Have a body mass index (BMI) between 18.0 and 30.0 kilograms per square meter (kg / m^2) (inclusive) and a body weight of greater than (>) 50 kilograms (kg) (110 pounds [lbs]) at the Screening Visit.

[0284] Be healthy as determined by the Investigator or designee based on screening assessments and medical history.

[0285] Male hemoglobin greater than or equal to (>=) 135.0 grams per liter (g / L) and female >= 120.0 g / L at Screening Visit and Day -1 of the 1st Treatment Period.

[0286] Able to swallow a dose of maralibavir or rabeprazole.

[0287] Pharmacokinetics: History of gastritis, gastrointestinal (GI) disorder, liver disease, or cholecystectomy or presence of gastritis, GI disorder, liver disease, or cholecystectomy, with or without treated or untreated H. pylori, ulcer disease, or other clinical conditions that the Investigator or Designated Person believes could affect absorption, distribution, metabolism, or elimination of the study drug.

[0288] History of any hematologic, liver, respiratory, cardiovascular, renal, neurologic, or psychiatric disease, or current presence of recurrent disease that could affect the action, absorption, or disposition of the study drug or clinical or laboratory assessments.

[0289] Current physical or psychiatric disease, any medical condition that could require treatment or make the participant less likely to complete the study completely, or any history of conditions or related illnesses that present undue risk of the study drug or procedures.

[0290] Known or suspected intolerance or hypersensitivity to maralibavir or rabeprazole (Part 2 only), closely related compounds, or any of the components and excipients of the study drug.

[0291] Major illness as judged by the Investigator or Designated Person within 2 weeks of the first dose of study drug (ID).

[0292] Diarrhea within 4 hours of the first dose of ID.

[0293] Donation of blood or blood products (e.g., plasma or platelets) within 60 days prior to receiving the first dose of ID.

[0294] Within 30 days prior to the first dose of ID: Use of any investigational product (if elimination half-life is less than [<] 6 days, otherwise 5 half-lives) within 30 days prior to the first dose of ID.

[0295] Enrolled in a clinical study (including vaccine studies) that the Investigator or Designated Person believes could affect the conduct of the present Takeda-sponsored study.

[0296] Any substantial change in eating habits as assessed by the Investigator or Designated Person.

[0297] Systolic blood pressure > 140 millimeters of mercury (mmHg) or < 90 mmHg, and / or diastolic blood pressure > 90 mmHg or < 50 mmHg at the Screening Visit.

[0298] Corrected QT interval (QTc) > 450 milliseconds (msec) at the Screening Visit. If the QTc exceeds 450 msec, the ECG should be repeated twice more, and the mean of the three QTc values should be used to determine the participant's eligibility.

[0299] Known history of alcohol or other drug abuse within the past year.

[0300] Male participants who drink more than 21 units of alcohol per week or more than three units of alcohol per day. Female participants who drink more than 14 units of alcohol per week or more than two units per day (one alcoholic unit = one bottle of beer or one bottle of wine [5 ounces [oz] / 150 milliliters [mL]] or one bottle of spirits [1.5 oz / 40 mL] or 0.75 oz of alcohol).

[0301] Positive alcohol or drug abuse screen at the Screening Visit or Day -1 of the Treatment Period 1. Urine samples will be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, and phencyclidine.

[0302] Positive human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody screen at the Screening Visit.

[0303] Use of any form of tobacco (e.g., smoking or chewing) or any form of other nicotine-containing product (e.g., gum, patch). Former users must self-report that they have stopped using tobacco for at least 3 months prior to receiving the first dose.

[0304] Participants who routinely consume more than two units of caffeine per day or experience caffeine withdrawal headaches (one unit of caffeine is contained in the following: one cup of 6-oz [180 mL] coffee, two cans of 12-oz [360 mL] cola, one cup of 12-oz tea, three 1-oz [85 gram [g]] chocolate bars). Caffeine-free coffee, tea, or cola is considered to not contain caffeine.

[0305] Any prescription medication other than hormonal contraceptives and hormone replacement therapy is currently used. Any over-the-counter (OTC) medication (including OTC multivitamins, herbal, or homeopathic preparations) is currently used within 14 days of the first dose. Hormonal contraceptives and hormone replacement therapy are allowed if the female participant has been using the same stable dose for at least 3 months prior to the first dose.

[0306] Antacids, proton pump inhibitors (PPIs), or histamine type 2 (H2) antagonists other than rabeprazole being studied are currently used within 14 days of the first dose.

[0307] Cannot or unwilling to consume 100% of the high-fat, high-calorie meals (including participants with lactose or gluten intolerance).

[0308] Female participants who are pregnant or breastfeeding at the time of the screening visit or on Day -1 of Treatment Period 1.

[0309] Participants who, in the opinion of the investigator or designee, have a diet that is not compatible with the diet during the study within 30 days prior to the first dose and throughout the study.

[0310] History of recent (within 1 month) oral / nasal infections, gastroesophageal reflux, albuterol asthma treatment, or zinc supplementation.

[0311] Participants with xerostomia or xerostomia syndrome or participants with taste disorders.

[0312] Palatability Assessment: A total of 18 participants entered Part 1 of the study and were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA). All 18 participants completed the study.

[0313] A total of 14 participants entered Part 2 of the study. All 14 participants completed the study.

[0314] Example 3: Preparation of Maribavir Formulations The Cmax of plasma maraviroc following a single oral dose of maraviroc oral suspension powder formulation administered as a suspension in water under fasting conditions (Treatment B) was approximately 18% lower than following a single oral 200 mg dose of maraviroc administered as a commercial tablet under fasting conditions (Treatment A), while the AUClast and AUC∞ of plasma maraviroc following both treatments were similar. Results of nonparametric analysis also indicated that there were no statistical differences in the tmax and tlag of plasma maraviroc following Treatment A compared to Treatment B. Pharmacokinetic data are shown in the following table: Table: Pharmacokinetic Assessments

[0315] Table: Pharmacokinetics / Bioavailability Assessment

[0316] Unsieved Maribavir Spherules (65% w / w): All 18 participants in Part 1 evaluated the single oral 200 mg dose of maralibavir oral suspension powder formulation administered as a water suspension under fasting conditions (Treatment B) and the single oral 200 mg dose of maralibavir oral suspension powder formulation administered as a water suspension under fed conditions (Treatment C) as easy to swallow. For Treatment B, most (72%) agreed that the overall taste and texture of the medication was acceptable, the medication did not have a rough or gritty texture (72%), and the medication odor was neither good nor bad (67%). Participants evaluated Treatment B as sweet (61%), bitter (33%), or bitter / sweet (6%) and most evaluated the taste as moderate (44%) or strong (44%). The most common medication taste and intensity combinations were sweet / moderate (39%), bitter / strong (28%), and sweet / strong (17%). For Treatment C, most (83%) agreed that the overall taste and texture of the medication was acceptable, the medication did not have a rough or gritty texture (67%), and the medication odor was neither good nor bad (61%). Participants evaluated Treatment C as bitter (44%), sweet (39%), bitter / sweet (11%), and salty (6%) and most evaluated the taste as moderate (50%) or strong (44%). The most common medication taste and intensity combinations were sweet / moderate (33%), bitter / strong (28%), and bitter / moderate (17%). Except for the sweetness of the taste of the medication, the palatability assessments between the single oral 200 mg dose of maralibavir oral suspension powder formulation administered as a water suspension under fasting conditions (Treatment B) and under fed conditions (Treatment C) were similar. Eleven (61%) participants evaluated Treatment B as sweet compared to seven (39%) participants for Treatment C. The palatability data is shown in the table below: Table: Palatability Assessment

[0317] Preparation of Sieved Maribavir Spherules (65% w / w). Preparation of Coated Maribavir Spherules (36.1% w / w).Turn on the VG-25 granulator and adjust to chopper speed of 1,500 rpm, main impeller speed of 150 rpm, and atomizing air pressure of 1.5 bar. Pre-charged and calibrated the pump and lines with USP grade purified water (500 g). Add micronized Maraviroc (1,300 g), Avicel PH-105® (microcrystalline cellulose, NF, Ph. Eur, JP; 620.0 g), and Polyplasdone™ XL-10 cross-linked povidone (Type B NF, EP, JP; 80.0 g) to the VG-25 granulator in the order described and blend for about 1 minute. Prepare the VG-25 granulator for spraying by spraying purified water USP (200 g) at 25 g / min for about 8 minutes and discard any remaining water. Then discharge the pre-wetted blend into a double polyethylene lined container and record the weight (1,941.6 g).

[0318] Divide the pre-wetted blend into two equal portions, 970.8 g each. Pre-charge and calibrate the pump and lines with USP grade purified water to ensure the pump can deliver at rates of 15 and 40 g / min. Load the first portion of the pre-wetted blend onto the powder feeder and run the powder feeder for 60 seconds to verify it can deliver at a rate between 10-20 g / min and return the collected material to the powder feeder. Run the powder feeder as shown in the table below and monitor the median particle size periodically using an Eyecon particle size analyzer:

[0319] Discharge the wet granules into a polyethylene lined container and record the weight as 1,217.8 g. Then process the second portion using the same parameters described above and weigh (1,204.9 g).

[0320] Dry the wet granules by first pre-heating and loading the two portions of wet granules into the fluid bed with a target product temperature of 57 °C ± 5 °C. After reaching the target product temperature, remove a sample to confirm it is dried to < 2.0% loss on drying “LOD”. If the LOD is not < 2.0%, repeat the drying.

[0321] After meeting the LOD, discharge the granules into one or more double polyethylene lined 5 gallon containers (1,852.2 g, 84.2% yield). Remove a portion of the unsieved Maraviroc granules 65% w / w (20.0 g) for in-process testing. For example, the density was determined to be 0.69 g / mL. In addition, analyze the particle size as shown in the table below:

[0322] Example 4: Evaluation of Maribavir Solubility under Specific ConditionsSieved Maribavir granules 65% w / w (719.7 g) x 4 = 2,878.8 g

[0323] Preparation of 25 mM Phosphate Buffer with 0.2% TEA (pH 3.0): USP Purified Water (3,840.0 g) was dispensed into a vessel with a mixer and blade. While the purified water was agitated with a propeller mixer to form a vortex, Eudragit® E PO ReadyMix (960.0 g) was added and the mixture was mixed for 15 minutes after which the speed was reduced and the contents were mixed for an additional 45 minutes before beginning the coating process. The net weight of the coating suspension was determined to be 4,783.5 g, which is within the range of the theoretical net weight of 4,800.0 g ± 3.0%.

[0324] The adjusted amount of coating suspension to be sprayed was calculated as follows: [Total solids content = 20% w / w; coating weight increase = 80%] [Total solids content = 20% w / w; coating weight increase = 80%] Sieved Maribavir granules 65% w / w (719.7 g) x 4 = 2,878.8 g The pump and lines were primed and calibrated with the coating suspension. In addition, the equipment was warmed up and pre-conditioned for at least 10 minutes. Sieved Maribavir granules 65% w / w (719.7 g) were loaded into the fluid bed and coated as shown below:

[0325] The granules were removed and sieved through a U.S. Standard #35 mesh hand sieve, with any granules retained on the hand sieve screen being discarded as oversized. The remaining granules were coated Maribavir granules 36% w / w (1,165.6 g, 90.0% yield).

[0326] A portion of the coated Maribavir granules 36% w / w (20.0 g) was removed for in-process testing. For example, the density was determined to be 0.74 g / mL. In addition, the particle size was analyzed as shown in the table below:

[0327] Preparation of Mobile Phase: Preparation of Diluent: Potassium phosphate monobasic (3.4 g) was weighed and transferred to an appropriate vessel containing 1,000 mL of USP water. The mixture was dissolved by mixing. Triethylamine (2.0 mL) was added and mixed well. The pH of the solution was adjusted to 3.0 ± 0.05 with phosphoric acid (85%).

[0328] Preparation of Maribavir Working Standard Solution: Combine 25 mM phosphate buffer, pH 3.0, with 300 mL of acetonitrile. Mix the solution thoroughly and filter through a 0.45-μm nylon membrane filter and degas.

[0329] Preparation of Solubilization Medium (50 mM Phosphate Buffer, pH 2.5): Dissolution medium (50 mM phosphate buffer, pH 2.5) was used as diluent. A portion of the dissolution medium was filtered, and the first 5 mL of the filtrate was discarded. The clean filtrate was transferred to an HPLC vial for dissolution medium blank analysis.

[0330] Solubilization Procedure: Transfer the maribavir reference standard (20 mg) to a 200-mL volumetric flask. Add the diluent (150 mL) to the flask and sonicate for about 10 minutes or until dissolved. Allow the solution to reach room temperature, and dilute to the volume mark with diluent. The concentration of maribavir in this standard solution is 0.1 mg / mL.

[0331] Figure 2 Weigh out potassium phosphate monobasic (68 mg) and dissolve in deionized water to 10 L and mix. Adjust the pH to 2.5 ± 0.05 with phosphoric acid solution and degas.

[0332] ​ Assemble the dissolution apparatus (USP apparatus II, paddle), and place the paddle so that the distance between its lower edge and the lower inner surface of the vessel is within 25 ± 2 mm throughout the test. Do this for all six positions. Set the speed to 75 rpm, and the temperature to 37 ± 0.05 °C. Place phosphate buffer pH 2.5 (500 mL) in each of the six vessels.

[0333] Weigh out maribavir (50 mg) (e.g., prepared as described in Example 3) and place in each of six separate beakers, record the weight, and transfer the beads in each vessel, respectively. Lower the paddle assembly to its lowest position, and rotate the paddle at 75 rpm. At 5, 10, 15, 20, 30, and 45 minute time points, withdraw samples, then increase the speed of the paddle to 250 rpm and run for an additional 15 minutes. Filter the samples (discard the first 5 mL) and transfer to HPLC vials. Evaluate the samples by HPLC against the standard solution, and calculate the percent dissolution for each of the four batches of maribavir as shown in ​

[0334] ​While we have described a number of embodiments of the present application, it is apparent that our basic example can be varied in many ways to provide other embodiments utilizing the compounds and methods of the present application. Thus, it will be appreciated that the scope of the present application is defined by the appended claims and not by the specific embodiments that have been presented by way of example.

Claims

1. A pharmaceutical composition comprising malibavir suitable for administration to patients under 6 years of age.

2. A pharmaceutical composition comprising: (i) An intragranular composition comprising maribavir, a diluent, and a disintegrant; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising a diluent, a suspending agent, a sweetener, and a flavoring agent.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises: (i) An in-particle composition comprising maribavir, microcrystalline cellulose and a disintegrant; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising a diluent, a suspending agent, a sweetener, and a flavoring agent.

4. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises: (i) An intragranular composition comprising maribavir, microcrystalline cellulose and crospovidone; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising a diluent, a suspending agent, a sweetener, and a flavoring agent.

5. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises: (i) An intragranular composition comprising maribavir, a diluent, and crospovidone; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising a diluent, a suspending agent, a sweetener, and a flavoring agent.

6. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises: (i) An intragranular composition comprising maribavir, a diluent, and a disintegrant; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising mannitol, a suspending agent, a sweetener, and a flavoring agent.

7. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises: (i) An intragranular composition comprising maribavir, microcrystalline cellulose and crospovidone; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising mannitol, a suspending agent, a sweetener, and a flavoring agent.

8. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises: (i) An intragranular composition comprising maribavir, microcrystalline cellulose and crospovidone; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising mannitol, a suspending agent, sucralose, and a flavoring agent.

9. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises: (i) An intragranular composition comprising maribavir, microcrystalline cellulose and crospovidone; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising mannitol, microcrystalline cellulose and sodium carboxymethyl cellulose, a sweetener and a flavoring agent.

10. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises: (i) An intragranular composition comprising maribavir, microcrystalline cellulose and crospovidone; (ii) the enteric coating of the in-particle composition, the enteric coating comprising a selectively soluble polymer; and (iii) An extragranular composition comprising mannitol, microcrystalline cellulose and sodium carboxymethyl cellulose, sucralose and flavoring agents.

11. The pharmaceutical composition according to any one of claims 2-10, wherein the pharmaceutical composition further comprises a suspending agent.

12. The pharmaceutical composition of claim 11, wherein the suspending agent is selected from the group consisting of microcrystalline cellulose and sodium carboxymethyl cellulose or combinations thereof.

13. The pharmaceutical composition of any one of claims 2-12, wherein the in-particle composition comprises particles containing maribavir, microcrystalline cellulose, and crospovidone.

14. The pharmaceutical composition of any one of claims 2-13, wherein the selectively soluble polymer is insoluble at neutral pH but soluble at acidic pH.

15. The pharmaceutical composition of any one of claims 2-13, wherein the selectively soluble polymer is butyl methacrylate, dimethylaminoethyl methacrylate, or methyl methacrylate copolymer (e.g., Eudragit® EPO).

16. The pharmaceutical composition according to any one of claims 2-15, wherein the sweetener is sucralose.

17. The pharmaceutical composition according to any one of claims 2-16, wherein the diluent is mannitol.

18. The pharmaceutical composition of any one of claims 2-17, wherein the flavoring agent is a fruit-flavored flavoring agent.

19. The pharmaceutical composition of any one of claims 2-18, wherein the coated particle composition comprises particles with a median particle size of 225-350 micrometers.

20. The pharmaceutical composition of any one of claims 2-18, wherein the coated particle composition comprises particles with a median particle size of about 250-325 micrometers, about 250-310 micrometers, about 250-300 micrometers, about 250-290 micrometers, about 250-280 micrometers, about 250-270 micrometers, or about 225-300 micrometers.

21. An oral liquid formulation of maribavir, said oral liquid formulation comprising the pharmaceutical composition as described in any one of claims 2-20.

22. The oral liquid formulation of claim 21, wherein the pharmaceutical composition forms a suspension in water.

23. A method of treating a patient with cytomegalovirus (CMV) infection or disease, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition as described in any one of claims 1-20.

24. A method for treating a patient with cytomegalovirus (CMV) infection or disease, the method comprising administering to the patient a therapeutically effective amount of an oral liquid formulation as described in any one of claims 21-22.

25. The method of any one of claims 23-24, wherein maribavir is administered in a therapeutically effective amount.

26. The method of any one of claims 23-25, wherein, by quantitative polymerase chain reaction (qPCR), in two consecutive assessments at least one day apart within 14 days of the first dose of maribavir, the patient has a CMV deoxyribonucleic acid (DNA) screening value of ≥1365 IU / mL in whole blood or ≥455 IU / mL in plasma, and wherein the second sample is obtained within 5 days prior to the first dose of maribavir.

27. The method of any one of claims 23-26, wherein the patient did not have invasive CMV tissue disease involving the central nervous system (CNS) or retina prior to treatment with maribavir.

28. The method of any one of claims 23-27, further comprising the step of confirming the clearance of CMV viremia in the patient.

29. The method of claim 28, wherein CMV viremia clearance is defined as plasma CMV DNA concentration below the lower limit of quantification (e.g., <137 IU / mL in two consecutive baseline samples at least 5 days apart).

30. The method of any one of claims 23-29, wherein the method comprises administering maribavir to the patient in the presence or absence of food.

31. The method of any one of claims 23-30, wherein the patient is treated with one or more other drugs for CMV infection or disease that is difficult to treat.

32. The method of any one of claims 23-31, wherein the patient is difficult to treat with one or more of ganciclovir, valganciclovir, cidofovir, or sodium foscarnet.

33. The method of any one of claims 23-32, wherein the patient is difficult to treat and has genotypic resistance.

34. The method of any one of claims 23-33, wherein the patient is difficult to treat and does not have genotypic resistance.

35. The method of any one of claims 23-34, wherein the patient is a transplant recipient.

36. The method of any one of claims 23-35, wherein the patient is a hematopoietic stem cell transplant recipient.

37. The method of any one of claims 23-36, wherein the patient is a solid organ transplant recipient.

38. The method of any one of claims 23-37, wherein the patient is less than 6 years old.

39. The method of any of the preceding claims, wherein the patient is receiving or has received an antacid (e.g., rabeprazole).

40. The method of any of the preceding claims, wherein the pharmaceutical composition is administered to a patient who is receiving or has received rabeprazole.

41. The method as described in any of the preceding claims, wherein the patient is given 50 mg of maribavir once daily.

42. The method as described in any of the preceding claims, wherein the patient is given 50 mg of maribavir twice daily.

43. The method as described in any of the preceding claims, wherein the patient is given 100 mg of maribavir twice daily.

44. The method as described in any of the preceding claims, wherein the patient is given 150 mg of maribavir twice daily.

45. The method as described in any of the preceding claims, wherein the patient is given 200 mg of maribavir twice daily.

46. ​​The method as described in any of the preceding claims, wherein the patient is administered 300 mg of maribavir twice daily.

47. The method as described in any of the preceding claims, wherein the patient is administered 400 mg of maribavir twice daily.

48. A composition for oral administration of maribavir, the composition comprising particles with a median particle size of about 225-350 micrometers, the particles comprising an intraparticle composition coated by an enteric coating, and wherein the particles are further mixed in an extraparticle component.

49. The composition of claim 48, wherein the composition comprises particles having a median particle size of about 250-325 micrometers, about 250-310 micrometers, about 250-300 micrometers, about 250-290 micrometers, about 250-280 micrometers, about 250-270 micrometers, or about 225-300 micrometers.

50. A pharmaceutical composition comprising: (a) Malibawe; (b) Pharmaceutically acceptable carriers or excipients; and (c) A component used to mask (e.g., reduce) the perceived bitterness of malivavir.

51. The pharmaceutical composition of claim 50, wherein the perceived bitterness is reduced by 50% compared to maribavir when evaluated according to a flavor characterization method.

52. The pharmaceutical composition of claim 50, wherein the perceived oral bitterness is reduced by 66% compared to maribavir when evaluated according to the flavor characterization method.

53. The pharmaceutical composition of claim 50, wherein the perceived oral bitterness is reduced by 75% compared to maribavir when evaluated according to the flavor characterization method.

54. The pharmaceutical composition of claim 50, wherein the perceived oral bitterness is reduced by 80% compared to maribavir when evaluated according to the flavor characterization method.

55. The pharmaceutical composition of claim 50, wherein the perceived oral bitterness is reduced by 90% compared to maribavir when evaluated according to the flavor characterization method.

56. A method for preparing a pharmaceutical composition for oral liquid administration, the method comprising the steps of: i) Granulating the active pharmaceutical ingredient and other excipients to form an intragranular composition; ii) Coating the in-particle composition with a selectively soluble polymer to form a coated in-particle composition; iii) The coated granule composition, diluent, sweetener, flavoring agent and other excipients are blended to form a blended composition; iv) Filling and packaging the blended composition; The median particle size of the in-particle composition is between about 100 and 400 micrometers, the median particle size of the coated in-particle composition is less than 500 micrometers, and the dv50 particle size of the diluent is between about 30 and 180 micrometers.

57. A method for preparing a pharmaceutical composition for oral liquid administration, the method comprising the steps of: i) Granulating the active pharmaceutical ingredient and other excipients to form an intragranular composition; ii) Coating the in-particle composition with a selectively soluble polymer to form a coated in-particle composition; iii) The coated granule composition, mannitol, sweetener, flavoring agent and other excipients are blended to form a blended composition; iv) Filling and packaging the blended composition; The median particle size of the intraparticle composition is between about 100 and 400 micrometers, the median particle size of the coated intraparticle composition is less than 500 micrometers, and the dv50 particle size of mannitol is between about 30 and 180 micrometers.

58. A method for preparing a pharmaceutical composition for oral liquid administration, the method comprising the steps of: i) Granulate maribavir and other excipients to form an in-granule composition; ii) Coating the in-particle composition with a selectively soluble polymer to form a coated in-particle composition; iii) The coated granule composition, mannitol, sweetener, flavoring agent and other excipients are blended to form a blended composition; iv) Filling and packaging the blended composition; The median particle size of the intraparticle composition is between about 100 and 400 micrometers, the median particle size of the coated intraparticle composition is less than 500 micrometers, and the dv50 particle size of mannitol is between about 30 and 180 micrometers.

59. The method of any one of claims 56-58, further comprising the step of suspending the pharmaceutical composition in a liquid medium (e.g., water) prior to oral administration.

60. The method of any one of claims 56-59, wherein the median particle size of the composition within the coated particles is about 225-350 micrometers.

61. The method of any one of claims 56-59, wherein the median particle size of the composition within the coated particles is about 250-325 micrometers.

62. The method of any one of claims 56-59, wherein the median particle size of the composition within the coated particles is about 250-300 micrometers.

63. The method of any one of claims 56-59, wherein the median particle size of the composition within the coated particles is about 250-290 micrometers.

64. The method of any one of claims 56-59, wherein the median particle size of the composition within the coated particles is about 250-280 micrometers.

65. The method of any one of claims 56-59, wherein the median particle size of the composition within the coated particles is about 250-270 micrometers.

66. The method of any one of claims 56-59, wherein the median particle size of the composition within the coated particles is about 225-300 micrometers.

67. The method of any one of claims 56-66, wherein the selectively soluble polymer is insoluble at a neutral pH but soluble at an acidic pH.

68. The method of claim 67, wherein the selectively soluble polymer is Eudragit® E PO.

69. The method of any one of claims 23-47, wherein the patient is less than 12 years old.

70. The method of claim 69, wherein the patient is at least 6 years old and less than 12 years old.

71. The pharmaceutical composition according to any one of claims 1-20 or 48-55, wherein the pharmaceutical composition is a powder.

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