Bictegravir and lenacapavir pharmaceutical formulations

Abstract

The present invention provides solid oral dosage forms comprising bictegravir or a pharmaceutically acceptable salt thereof, and lenacapavir or a pharmaceutically acceptable salt thereof. The present invention provides tablets containing bictegravir (BIC) and lenacapavir (LEN). These tablets are suitable for use in pharmaceuticals, particularly in the treatment of viral infections such as HIV. These tablets are intended to be pharmaceutically acceptable. In one embodiment, the present disclosure provides tablets comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50 to 100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 to 100 mg of lenacapavir free acid.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Patent Application No. 63 / 519,675, filed on 15 August 2023, and European Patent Application No. 23201068.6, filed on 29 September 2023, the entire contents of each of these applications being incorporated herein by reference.

[0002] (Field of invention) Pharmaceutical formulations suitable for treating viral infections such as HIV are disclosed, particularly tablets containing bictegravir and lenacapavir. [Background technology]

[0003] Human immunodeficiency virus, type 1 (HIV-1) infection is a life-threatening disease of significant public health importance, infecting approximately 35 million people worldwide (Joint United Nations Programme on HIV / AIDS (UNAIDS); World Report: UNAIDS Report on the Global AIDS Epidemic, 2013). Standard care for HIV-1 infection involves the use of combination antiretroviral therapy (ART) to suppress viral replication to below undetectable levels, increase CD4 cell count, and halt disease progression. Successful potent and well-tolerated ART means that although most people living with HIV-1 with a history of virological failure and viral resistance (patients with a HIV-1, PWH) can achieve and maintain virological suppression, they often require complex multi-tablet regimens administered more than once a day with different dosing schedules. Multi-tablet regimens are more difficult for PWH to adhere to consistently over the long term, and inadequate adherence is a common cause of virological failure. Lower pill burden is associated with higher levels of adherence (Nachega, Clin Infect Dis 2014, 58:1297-307; Raboud, AIDS behave 2011, 15(7):1397-409). Furthermore, PWH receiving a single-tablet regimen are less likely to discontinue treatment (i.e., have higher persistence) compared with PWH receiving a multi-tablet regimen (Hines, Patient preference and adherence 2019, 13:1927-39). In two meta-analyses, PWH on single-tablet regimens were more likely to achieve and maintain virological suppression (Clay, Medicine, 2015, 94(42): e1-14, Clay, AIDS research and therapy 2018, 15:17). Convenience (e.g., pill burden, dosing frequency, availability of FDC or single-tablet regimen formulations) is one of the regimen-specific considerations when selecting an initial ARV regimen. Therefore, there remains a great unmet need for simplifying treatment regimens for all PWH, including those who are virologically suppressed on complex regimens due to a prior history of virological failure and viral resistance. [Prior Art Literature] [Non-Patent Literature]

[0004] [Non-Patent Literature 1] Nachega, Clin Infect Dis 2014, 58:1297-307 [Non-Patent Literature 2] Raboud, AIDS behave 2011, 15(7): 1397-1409 [Non-Patent Literature 3] Hines, Patient preference and adherence 2019, 13: 1927-1939 [Non-Patent Literature 4] Clay, Medicine, 2015, 94(42): J.1-14 [Non-Patent Literature 5] Clay, AIDS research and therapy 2018, 15: 17 Summary of the Invention Means for Solving the Problems

[0005] The present invention provides a tablet containing bictegravir (BIC) and lenacapavir (LEN). These tablets are suitable for use in medicine, particularly in the treatment of viral infections such as HIV. These tablets are intended to be pharmaceutically acceptable.

[0006] In one aspect, the present disclosure provides a tablet comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or the pharmaceutically acceptable salt thereof corresponds to about 50 to 100 mg of free bictegravir acid, and the amount of lenacapavir or the pharmaceutically acceptable salt thereof corresponds to about 25 to 100 mg of free lenacapavir acid.

[0007] In another aspect, the present disclosure provides a tablet comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or the pharmaceutically acceptable salt thereof corresponds to about 75 mg of free bictegravir acid, and the amount of lenacapavir or the pharmaceutically acceptable salt thereof corresponds to about 25 mg of free lenacapavir acid.

[0008] In yet another embodiment, the disclosure provides a tablet comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid.

[0009] In yet another embodiment, the disclosure also provides a method for manufacturing tablets and a method for treating a patient. [Brief explanation of the drawing]

[0010] [Figure 1] This is a flowchart showing the preparation of bictegravir tablets.

[0011] [Figure 2] This is a flowchart showing the preparation of lenacapavir tablet formulations.

[0012] [Figure 3] This is a flowchart illustrating the preparation of monolayer tablets containing bictegravir and lenacapavir.

[0013] [Figure 4] This is a flowchart illustrating the preparation of a two-layer tablet containing bictegravir and lenacapavir.

[0014] [Figure 5A] The results of tests conducted on bilayer and monolayer tablet formulations containing bictegravir and lenacapavir to evaluate bictegravir dissolution compared to bictegravir dissolution from combinations of mono-tablets containing the same doses of bictegravir and lenacapavir are shown. Figure 5A shows the results for tablets containing 75 mg of bictegravir and 25 mg of lenacapavir, respectively, and Figure 5B shows the results for tablets containing 75 mg of bictegravir and 50 mg of lenacapavir. [Figure 5B]The results of tests conducted on bilayer and monolayer tablet formulations containing bictegravir and lenacapavir to evaluate bictegravir dissolution compared to bictegravir dissolution from combinations of mono-tablets containing the same doses of bictegravir and lenacapavir are shown. Figure 5A shows the results for tablets containing 75 mg of bictegravir and 25 mg of lenacapavir, respectively, and Figure 5B shows the results for tablets containing 75 mg of bictegravir and 50 mg of lenacapavir.

[0015] [Figure 6A] The results of tests conducted on bilayer and monolayer tablet formulations containing bictegravir and lenacapavir to evaluate lenacapavir dissolution compared to lenacapavir dissolution from combinations of mono-tablets containing the same doses of bictegravir and lenacapavir are shown. Figure 6A shows the results for tablets containing 75 mg of bictegravir and 25 mg of lenacapavir, respectively, and Figure 6B shows the results for tablets containing 75 mg of bictegravir and 50 mg of lenacapavir. [Figure 6B] The results of tests conducted on bilayer and monolayer tablet formulations containing bictegravir and lenacapavir to evaluate lenacapavir dissolution compared to lenacapavir dissolution from combinations of mono-tablets containing the same doses of bictegravir and lenacapavir are shown. Figure 6A shows the results for tablets containing 75 mg of bictegravir and 25 mg of lenacapavir, respectively, and Figure 6B shows the results for tablets containing 75 mg of bictegravir and 50 mg of lenacapavir.

[0016] [Figure 7A] The results of clinical human studies evaluating the PK parameters of monolayer and bilayer tablets containing bictegravir and lenacapavir are shown. Figures 7A and 7B show the plasma concentration of bictegravir as a function of time, and Figures 8A and 8B show the plasma concentration of lenacapavir as a function of time. [Figure 7B]The results of clinical human studies evaluating the PK parameters of monolayer and bilayer tablets containing bictegravir and lenacapavir are shown. Figures 7A and 7B show the plasma concentration of bictegravir as a function of time, and Figures 8A and 8B show the plasma concentration of lenacapavir as a function of time. [Figure 8A] The results of clinical human studies evaluating the PK parameters of monolayer and bilayer tablets containing bictegravir and lenacapavir are shown. Figures 7A and 7B show the plasma concentration of bictegravir as a function of time, and Figures 8A and 8B show the plasma concentration of lenacapavir as a function of time. [Figure 8B] The results of clinical human studies evaluating the PK parameters of monolayer and bilayer tablets containing bictegravir and lenacapavir are shown. Figures 7A and 7B show the plasma concentration of bictegravir as a function of time, and Figures 8A and 8B show the plasma concentration of lenacapavir as a function of time.

[0017] [Figure 9A] Figure 9A shows the results of dissolution tests performed on two-layer tablet formulations containing different fillers in the bictegravir layer, compared to dissolution from single-ingredient tablets containing bictegravir and lenacapavir, respectively. Figure 9A shows the dissolution of bictegravir from the tested tablet formulations, and Figure 9B shows the dissolution of lenacapavir from the tested tablet formulations. [Figure 9B] Figure 9A shows the results of dissolution tests performed on two-layer tablet formulations containing different fillers in the bictegravir layer, compared to dissolution from single-ingredient tablets containing bictegravir and lenacapavir, respectively. Figure 9A shows the dissolution of bictegravir from the tested tablet formulations, and Figure 9B shows the dissolution of lenacapavir from the tested tablet formulations. [Modes for carrying out the invention]

[0018] The tablets disclosed herein contain two active pharmaceutical ingredients (APIs), namely bictegravir (or a pharmaceutically acceptable salt thereof) and lenacapavir (or a pharmaceutically acceptable salt thereof).

[0019] Bictegravir Bictegravir (BIC) is a potent HIV integrase inhibitor with in vitro activity against wild-type HIV-1. It has the following formula (see International Publication No. 2014 / 100323). [ka]

[0020] Its IUPAC name is (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide. Its CAS name is 2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-,(2R,5S,13aR).

[0021] The tablets disclosed herein typically contain bictegravir in the form of a pharmaceutically acceptable salt. Bictegravir or its salts may be present in the tablets in solvated or non-solvated forms, and references to “bictegravir” include both of these forms. In particular, references to bictegravir or its pharmaceutically acceptable salts include pharmaceutically acceptable salts of bictegravir and pharmaceutically acceptable hydrates of bictegravir. In some embodiments, bictegravir is included as its sodium salt having the following formula (bictegravir sodium). [ka]

[0022] When used herein, unless there is a specific reference to a particular pharmaceutically acceptable salt and / or solvate of the bictegravir compound, any dose, whether expressed in milligrams or by weight percent, should be interpreted as referring to the amount of bictegravir free acid, i.e., the amount of . [ka]

[0023] The tablets are provided containing an amount of bictegravir or a pharmaceutically acceptable salt thereof corresponding to approximately 50–100 mg of bictegravir free acid (for example, as approximately 52–105 mg of bictegravir sodium).

[0024] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 65–85 mg of free bictegravir acid (e.g., approximately 68–89 mg of bictegravir sodium).

[0025] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 75–100 mg of free bictegravir acid (e.g., approximately 78–105 mg of bictegravir sodium).

[0026] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 50–75 mg of free bictegravir acid (e.g., approximately 52–78 mg of bictegravir sodium).

[0027] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 60–75 mg of free bictegravir acid (e.g., approximately 63–78 mg of bictegravir sodium).

[0028] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 100 mg of bictegravir free acid (e.g., approximately 105 mg of bictegravir sodium).

[0029] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 60 mg of free bictegravir acid (e.g., as approximately 63 mg of bictegravir sodium).

[0030] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 50 mg of free bictegravir acid (e.g., approximately 52 mg of bictegravir sodium).

[0031] In one embodiment, the amount of bictegravir or a pharmaceutically acceptable salt in the tablets of the present disclosure corresponds to about 75 mg of bictegravir free acid (for example, as about 78 mg of bictegravir sodium).

[0032] Renacapaville Lenacapavir (LEN) is a first-in-class capsid inhibitor with multi-step selective activity against the HIV capsid protein. It has the following formula (see International Publication No. 2018 / 035359). [ka]

[0033] Its IUPAC name is N-[(1S)-1-(3-{4-chloro-3-[(methylsulfonyl)amino]-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl}-6-[3-methyl-3-(methylsulfonyl)buto-1-in-1-yl]pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl]-2-[(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl]acetamide.

[0034] The tablets disclosed herein typically contain lenacapavir in the form of a pharmaceutically acceptable salt. Lenacapavir or its salts may exist in solvated or unsolvated forms in oral dosage forms, and references to “lenacapavir” include both of these forms. In particular, references to lenacapavir or its pharmaceutically acceptable salts include pharmaceutically acceptable salts of lenacapavir and pharmaceutically acceptable hydrates of lenacapavir. In some embodiments, lenacapavir is included as its sodium salt (lenacapavir sodium) having the following formula: [ka]

[0035] When used herein, unless there is a specific reference to a particular pharmaceutically acceptable salt and / or solvate of a compound of lenacapavir (e.g., lenacapavir sodium), any dose, whether expressed in milligrams or weight percent, refers to the amount of free lenacapavir acid, i.e., [ka] This should be interpreted as referring to the quantity of [something].

[0036] The tablets are provided containing an amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponding to approximately 25–100 mg of lenacapavir free acid (for example, as approximately 26–102 mg of lenacapavir sodium).

[0037] The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 25–75 mg of free lenacapvir acid (e.g., approximately 26–77 mg of lenacapvir sodium).

[0038] The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 25–50 mg of free lenacapvir acid (e.g., approximately 26–51 mg of lenacapvir sodium).

[0039] The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 50–75 mg of free lenacapvir acid (e.g., approximately 51–77 mg of lenacapvir sodium).

[0040] The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 40–60 mg of free lenacapvir acid (e.g., as approximately 41–61 mg of lenacapvir sodium).

[0041] The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 75 mg of lenacapvir free acid (e.g., as approximately 77 mg of lenacapvir sodium).

[0042] In one embodiment, the amount of lenacapvir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapvir free acid (e.g., as about 51 mg of lenacapvir sodium). In another embodiment, the amount of lenacapvir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapvir free acid (e.g., as about 26 mg of lenacapvir sodium).

[0043] Dosage form The inventors have formulated bictegravir and lenacapavir into a single tablet that provides the combined therapeutic effect of each individual active agent. In addition to the clinical benefits that can arise from the use of bictegravir and lenacapavir described above, the tablet of this disclosure offers further advantages by being a single, fixed-dose combination tablet. In particular, the tablet provides both bictegravir and lenacapavir in amounts that are comparable to, or better than, a combination of monotherapy tablets containing equal amounts of bictegravir and lenacapavir in terms of pharmacokinetic properties. Furthermore, the tablet of this disclosure reduces the tablet burden on patients and the complexity of treatment regimens, which may lead to improved patient compliance and a reduced likelihood of virological failure.

[0044] A particular advantage of this disclosure is the provision of tablets having specific pharmacokinetic parameters comparable to, or better than, those of, a combination of monotherapy tablets containing equal amounts of bictegravir and lenacapavir. Achieving such pharmacokinetic characteristics may require the use of specific doses of bictegravir and lenacapavir.

[0045] The tablets disclosed herein are intended for pharmaceutically active use in human subjects. Therefore, the tablets must be of an appropriate size and weight for oral administration to humans. In some embodiments, the tablets have a total weight of less than about 1.5 g. In some embodiments, the tablets weigh less than about 1.0 g.

[0046] Dosage A tablet is provided containing bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 50-100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 25-100 mg of lenacapavir free acid.

[0047] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 65–85 mg of bictegravir free acid. The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 75–100 mg of bictegravir free acid. The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 50–75 mg of bictegravir free acid.

[0048] The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 25-75 mg of free lenacapvir acid. The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 25-50 mg of free lenacapvir acid. The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 50-75 mg of free lenacapvir acid. The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to approximately 40-60 mg of free lenacapvir acid.

[0049] The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 75-100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 25-75 mg of lenacapavir free acid. The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 75-100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 25-50 mg of lenacapavir free acid. The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 75-100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 50-75 mg of lenacapavir free acid. The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 75-100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 40-60 mg of lenacapavir free acid.

[0050] The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 50-75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 25-75 mg of lenacapavir free acid. The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 50-75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 25-50 mg of lenacapavir free acid. The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 50-75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 50-75 mg of lenacapavir free acid. The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 50-75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 40-60 mg of lenacapavir free acid.

[0051] The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 65-85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 25-75 mg of lenacapavir free acid. The amount of bictegravir or a pharmaceutically acceptable salt is equivalent to approximately 65-85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may be equivalent to approximately 50-75 mg of lenacapavir free acid.

[0052] In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt corresponds to about 65–85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt corresponds to about 25–50 mg of lenacapavir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt corresponds to about 65–85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt corresponds to about 25 mg or about 50 mg of lenacapavir free acid.

[0053] The amount of bictegravir or a pharmaceutically acceptable salt in a tablet may correspond to about 50, 60, 75, or 100 mg of bictegravir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt corresponds to about 50 mg of bictegravir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt corresponds to about 75 mg of bictegravir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt corresponds to about 100 mg of bictegravir free acid.

[0054] In one embodiment, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of free bictegravir acid.

[0055] The amount of lenacapvir or a pharmaceutically acceptable salt in a tablet may correspond to about 25, 50, 75, or 100 mg of lenacapvir free acid. In some embodiments, the amount of lenacapvir or a pharmaceutically acceptable salt corresponds to about 100 mg of lenacapvir free acid. In some embodiments, the amount of lenacapvir or a pharmaceutically acceptable salt corresponds to about 75 mg of lenacapvir free acid.

[0056] In one embodiment, the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 or about 50 mg of lenacapavir free acid. In one embodiment, the tablet contains an amount of bictegravir or a pharmaceutically acceptable salt thereof equivalent to about 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt thereof equivalent to about 25 mg of lenacapavir free acid. In one embodiment, the tablet contains an amount of bictegravir or a pharmaceutically acceptable salt thereof equivalent to about 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt thereof equivalent to about 50 mg of lenacapavir free acid.

[0057] A tablet is provided containing bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 100 mg of lenacapavir free acid.

[0058] A tablet is provided containing bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of lenacapavir free acid.

[0059] In one embodiment, the tablet comprises bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid. In some embodiments, the tablet is a two-layer tablet.

[0060] In one embodiment, the tablet comprises bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid. In some embodiments, the tablet is a two-layer tablet.

[0061] Single-layer tablets The tablets of this disclosure may be in the form of monolayer tablets. In one embodiment, a tablet is provided comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50 to 100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 to 100 mg of lenacapavir free acid, and the tablet is a monolayer tablet.

[0062] In some embodiments, the tablet is a single-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt therein corresponds to about 65–85 mg of bictegravir free acid. In some embodiments, the tablet is a single-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt therein corresponds to about 75–100 mg of bictegravir free acid. In some embodiments, the tablet is a single-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt therein corresponds to about 50–75 mg of bictegravir free acid.

[0063] In some embodiments, the tablet is a single-layer tablet, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25–75 mg of lenacapavir free acid. In some embodiments, the tablet is a single-layer tablet, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25–50 mg of lenacapavir free acid. In some embodiments, the tablet is a single-layer tablet, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50–75 mg of lenacapavir free acid.

[0064] In a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt may correspond to approximately 65–85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may correspond to approximately 25–75 mg of lenacapavir free acid. In some embodiments, in a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt may correspond to approximately 65–85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt may correspond to approximately 40–60 mg of lenacapavir free acid.

[0065] The amount of bictegravir or a pharmaceutically acceptable salt in a single-layer tablet may correspond to about 50, 60, 75, or 100 mg of bictegravir free acid. The amount of bictegravir or a pharmaceutically acceptable salt in a single-layer tablet may correspond to about 50 mg of bictegravir free acid. The amount of bictegravir or a pharmaceutically acceptable salt in a single-layer tablet may correspond to about 60 mg of bictegravir free acid. The amount of bictegravir or a pharmaceutically acceptable salt in a single-layer tablet may correspond to about 100 mg of bictegravir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt in a single-layer tablet corresponds to about 75 mg of bictegravir free acid.

[0066] The amount of lenacapavir or a pharmaceutically acceptable salt in a single-layer tablet may correspond to about 25, 50, 75, or 100 mg of free lenacapavir acid. The amount of lenacapavir or a pharmaceutically acceptable salt in a single-layer tablet may correspond to about 100 mg of free lenacapavir acid. The amount of lenacapavir or a pharmaceutically acceptable salt in a single-layer tablet may correspond to about 75 mg of free lenacapavir acid. The amount of lenacapavir or a pharmaceutically acceptable salt in a single-layer tablet may correspond to about 50 mg of free lenacapavir acid. In some embodiments, the amount of lenacapavir or a pharmaceutically acceptable salt in a single-layer tablet corresponds to about 25 mg of free lenacapavir acid.

[0067] In one embodiment, a single-layer tablet is provided comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 100 mg of lenacapavir free acid.

[0068] In one embodiment, a single-layer tablet is provided comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of lenacapavir free acid.

[0069] In one embodiment, a single-layer tablet is provided comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid.

[0070] In one embodiment, a single-layer tablet is provided comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid.

[0071] This disclosure provides a monolayer tablet of bictegravir and lenacapavir that offers dissolution and bioavailability of both active ingredients at least comparable to a combination of monotherapy tablets containing equal amounts of bictegravir and lenacapavir.

[0072] Multilayer tablets The tablets of this disclosure may be in the form of multilayer tablets. In some embodiments, the tablets are bilayer tablets. The inventors have found that the dissolution of lenacapavir is affected by the presence of bictegravir when formulated in monolayer tablets at certain doses, and vice versa. The inventors have found that such interactions can be overcome by separating the API using bilayer tablets. Pharmacokinetic properties (AUC) of certain bilayer tablets. inf AUC last , T max and T 1 / 2 A tablet containing, but not limited to, bictegravir and lenacapavir may be improved compared to a single-layer tablet containing the same amounts of bictegravir and lenacapavir, and also compared to a single-agent tablet containing the same amounts of bictegravir and lenacapavir. A tablet is provided containing bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50-100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25-100 mg of lenacapavir free acid, and the tablet is a multilayer tablet. In some embodiments, the tablet is a two-layer tablet.

[0073] In some embodiments, a two-layer tablet comprises (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. In some embodiments, the first layer is substantially free of lenacapavir or a pharmaceutically acceptable salt thereof. In some embodiments, the first layer contains less than about 1% by weight of lenacapavir or a pharmaceutically acceptable salt thereof. In some embodiments, the second layer is substantially free of bictegravir or a pharmaceutically acceptable salt thereof. In some embodiments, the second layer contains less than about 1% by weight of bictegravir or a pharmaceutically acceptable salt thereof. In one embodiment, the first layer is substantially free of lenacapavir or a pharmaceutically acceptable salt thereof. In one embodiment, the second layer does not contain bictegravir or a pharmaceutically acceptable salt thereof. In one embodiment, the first layer does not contain lenacapavir or a pharmaceutically acceptable salt thereof, and the second layer does not contain bictegravir or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, a two-layer tablet comprises (a) a first layer containing lenacapavir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing bictegravir or a pharmaceutically acceptable salt thereof. In some embodiments, the first layer is substantially free of bictegravir or a pharmaceutically acceptable salt thereof. In some embodiments, the first layer contains less than about 1% by weight of bictegravir or a pharmaceutically acceptable salt thereof. In some embodiments, the second layer is substantially free of lenacapavir or a pharmaceutically acceptable salt thereof. In some embodiments, the second layer contains less than about 1% by weight of lenacapavir or a pharmaceutically acceptable salt thereof. In one embodiment, the first layer does not contain bictegravir or a pharmaceutically acceptable salt thereof. In one embodiment, the second layer does not contain lenacapavir or a pharmaceutically acceptable salt thereof. In one embodiment, the first layer does not contain bictegravir or a pharmaceutically acceptable salt thereof, and the second layer does not contain lenacapavir or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 50, 60, 75, or 100 mg of bictegravir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 50 mg of bictegravir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 60 mg of bictegravir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 75 mg of bictegravir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 100 mg of bictegravir free acid.

[0076] In some embodiments, the tablet is a double-layered tablet, and the amount of lenacapavir or a pharmaceutically acceptable salt therein corresponds to about 25–75 mg of lenacapavir free acid. In some embodiments, the tablet is a double-layered tablet, and the amount of lenacapavir or a pharmaceutically acceptable salt therein corresponds to about 25–50 mg of lenacapavir free acid. In some embodiments, the tablet is a double-layered tablet, and the amount of lenacapavir or a pharmaceutically acceptable salt therein corresponds to about 50–75 mg of lenacapavir free acid. In some embodiments, the tablet is a double-layered tablet, and the amount of lenacapavir or a pharmaceutically acceptable salt therein corresponds to about 40–60 mg of lenacapavir free acid.

[0077] In some embodiments, the amount of lenacapavir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 25, 50, 75, or 100 mg of free lenacapavir acid. In some embodiments, the amount of lenacapavir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 100 mg of free lenacapavir acid. In some embodiments, the amount of lenacapavir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 75 mg of free lenacapavir acid. In some embodiments, the amount of lenacapavir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 50 mg of free lenacapavir acid. In some embodiments, the amount of lenacapavir or a pharmaceutically acceptable salt in a two-layer tablet may correspond to about 25 mg of free lenacapavir acid.

[0078] In some embodiments, the tablet is a single-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 65–85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25–75 mg of lenacapavir free acid. In some embodiments, the tablet is a single-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 65–85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25–50 mg of lenacapavir free acid.

[0079] In some embodiments, in a two-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt corresponds to about 65–85 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt corresponds to about 25 mg of lenacapavir free acid. In some embodiments, the amount of lenacapavir or a pharmaceutically acceptable salt corresponds to about 50 mg of lenacapavir free acid.

[0080] In one embodiment, a two-layer tablet is provided, comprising (a) a first layer containing an amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 50 to 100 mg of bictegravir free acid, and (b) a second layer containing an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 25 to 100 mg of lenacapavir free acid. In some embodiments, the tablet is a two-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 65 to 85 mg of bictegravir free acid. In some embodiments, the tablet is a two-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 75 to 100 mg of bictegravir free acid. In some embodiments, the tablet is a two-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 50 to 75 mg of bictegravir free acid. In some embodiments, the tablet is a two-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of free bictegravir acid.

[0081] In some embodiments, a two-layer tablet is provided comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 50 mg of lenacapavir free acid.

[0082] In some embodiments, a two-layer tablet is provided comprising (a) a first layer containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and (b) a second layer containing an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the two-layer tablet comprises (a) a first layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 50 mg of lenacapavir free acid, and (b) a second layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid.

[0084] In some embodiments, the two-layer tablet comprises (a) a first layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 mg of lenacapavir free acid, and (b) a second layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid.

[0085] Elution The tablets disclosed herein are typically immediate-release tablets. In one embodiment, the Disclosure provides a tablet that releases at least about 50% bictegravir or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured using a USP instrument II, in 250 mL of fasted simulated intestinal fluid at pH 6.5 at 37°C and a paddle speed of 75 rpm. In some embodiments, the tablets disclosed herein release at least about 60% bictegravir or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured using a USP instrument II, in 250 mL of fasted simulated intestinal fluid at pH 6.5 at 37°C and a paddle speed of 75 rpm. In some embodiments, tablets are provided that release at least about 70% bictegravir or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured using a USP instrument II, in 250 mL of fasted simulated intestinal fluid at pH 6.5 at 37°C and a paddle speed of 75 rpm.

[0086] In one embodiment, the disclosure provides a tablet that releases at least about 50% of lenacapavir or a pharmaceutically acceptable salt thereof in about 15 minutes, as measured using a USP instrument II, in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0, at 37°C and a paddle speed of 75 rpm. In some embodiments, the tablet releases at least about 70% of lenacapavir or a pharmaceutically acceptable salt thereof in about 15 minutes, as measured using a USP instrument II, in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0, at 37°C and a paddle speed of 75 rpm. In some embodiments, tablets are provided that release at least about 80% of lenacapavir or a pharmaceutically acceptable salt thereof in about 15 minutes, as measured using a USP instrument II, in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0, at 37°C and a paddle speed of 75 rpm.

[0087] In some embodiments, the method for measuring the dissolution of lenacapavir from tablets is performed on a batch of tablets containing an amount of lenacapavir equivalent to about 300 mg of lenacapavir free acid. Thus, in one embodiment, the present disclosure provides tablets that release at least about 50% of lenacapavir or a pharmaceutically acceptable salt thereof in about 15 minutes, measured using a USP instrument II in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0 at 37°C and a paddle speed of 75 rpm, and the dissolution method is performed on a batch of tablets containing an amount of lenacapavir equivalent to about 300 mg of lenacapavir free acid. In some embodiments, tablets are provided that release at least about 70% lenacapavir or a pharmaceutically acceptable salt in about 15 minutes, as measured using a USP instrument II, at 37°C and a paddle speed of 75 rpm in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0, and the dissolution method is performed on a batch of tablets containing an amount of lenacapavir equivalent to about 300 mg of lenacapavir free acid. In some embodiments, tablets are provided that release at least about 80% lenacapavir or a pharmaceutically acceptable salt in about 15 minutes, as measured using a USP instrument II, at 37°C and a paddle speed of 75 rpm in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0, and the dissolution method is performed on a batch of tablets containing an amount of lenacapavir equivalent to 300 mg of lenacapavir free acid.

[0088] Excipients Tablets typically contain one or more excipients. Excipients must be compatible with the other components of the formulation and physiologically harmless to its recipient. Examples of suitable excipients are well known to those skilled in the art of tablet formulations and can be found, for example, in the Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009. As used herein, the term “excipient” is intended to refer, among other things, to basicizing agents, solubilizers, flow enhancers, fillers, binders, lubricants, diluents, preservatives, surfactants, dispersants, and the like. The term also includes pharmaceuticals such as sweeteners, flavoring agents, colorants, and preservatives. Such components generally exist as mixtures within the tablet.

[0089] In some embodiments, the tablets may contain excipients, including flow enhancers, fillers, binders, and polymers. Examples of polymers in some embodiments include hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), and hydroxypropyl methylcellulose acetate succinate (HPMC-AS). In some embodiments, the polymer is copovidone. In some embodiments, the tablets provided herein contain about 5 to 25 mg of copovidone, for example, about 10 to 25 mg of copovidone or 5 to 8 mg of copovidone. In some embodiments, the tablets provided herein contain 1 to 6% w / w of copovidone.

[0090] Examples of solubilizers include, but are not limited to, ionic surfactants (including both ionic and nonionic surfactants), such as sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates (e.g., polysorbate 20 or 80), poloxamers (e.g., poloxamer 188, 207, or 407), and macrogol. The tablets of this disclosure may contain poloxamer, particularly poloxamer 407. In some embodiments, the amount of poloxamer is about 0.5 to 7 mg, for example, about 1 to 3 mg or about 2 to 5 mg. In some embodiments, the amount of poloxamer is about 0.1 to 1.6% w / w, for example, about 0.3 to 0.8% w / w.

[0091] Examples of lubricants, flow enhancers, and flow aids include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide, and talc. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the tablets contain about 1 to 50 mg, for example, about 5 to 10 mg, and in some embodiments, about 5 to 8 mg of magnesium stearate. In some embodiments, the tablets contain about 1 to 2% w / w of magnesium stearate.

[0092] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP, sodium starch glycolate, and croscarmellose sodium. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the tablet contains about 25 to 50 mg, for example, about 30 to 50 mg of croscarmellose sodium. In some embodiments, the tablet contains about 3 to 10% w / w of croscarmellose sodium.

[0093] Examples of binders include, but are not limited to, cross-linked PVP, HPMC, microcrystalline cellulose, sucrose, and starch.

[0094] Examples of fillers (also known as bulking agents or diluents) include, but are not limited to, starch, maltodextrin, polyols (such as lactose), and cellulose. Tablets provided herein may contain microcrystalline cellulose and / or mannitol. In some embodiments, tablets contain microcrystalline cellulose. Tablets provided herein may contain 60 to 250 mg, e.g., about 60 to 100 mg or about 200 to 250 mg of microcrystalline cellulose. Tablets provided herein may contain about 10 to 55% w / w of microcrystalline cellulose, e.g., about 10 to 25% w / w or about 40 to 55% w / w. Tablets provided herein may contain 50 to 200 mg, e.g., about 100 to 200 mg or about 50 to 125 mg of mannitol. The tablets provided herein may contain approximately 10–45% w / w mannitol, for example, approximately 10–25% w / w or approximately 25–45% w / w.

[0095] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof, wherein the first layer contains a filler selected from mannitol, microcrystalline cellulose, or a combination thereof. In such a tablet, the weight ratio of mannitol to microcrystalline cellulose in the first layer may be about 2:1 to about 1:2, such as about 2:1, about 1:1, or about 1:2. The inventors have found that the use of microcrystalline cellulose as the sole filler in the bictegravir layer of a two-layer tablet results in improved processability and manufacturability compared to two-layer tablets using both mannitol and microcrystalline cellulose as fillers in the bictegravir layer. Therefore, in some embodiments of the tablet, the filler in the first layer is microcrystalline cellulose, and the first layer is substantially mannitol-free. In some embodiments, the first layer contains less than 1% w / w of mannitol. In some embodiments, the first layer does not contain mannitol. In such tablets, the first layer may contain about 30-75% w / w of microcrystalline cellulose. In some embodiments, the first layer contains about 50-75% w / w of microcrystalline cellulose. In some embodiments, the first layer contains about 60-70% w / w of microcrystalline cellulose.

[0096] The tablets provided herein may be coated or uncoated. Uncoated tablets may be used, but it is more common to provide coated tablets, in which case conventional non-enteric coatings may be used. In some embodiments, the tablets are coated with a non-functional coating, i.e., a coating that does not affect the release properties of the tablet. In some embodiments, the tablets are coated with a titanium dioxide-free film coating.

[0097] Film coatings are known in the art and may consist of hydrophilic polymer materials, but are not limited to polysaccharide materials, such as hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), poly(vinyl alcohol-co-ethylene glycol), and other water-soluble polymers. The water-soluble materials included in the film coatings of this disclosure may consist of a single polymer material, but may also be formed using a mixture of two or more polymers. The coatings may be white, or they may be colored, for example, yellow or brown. Suitable coatings include, but are not limited to, polymer film coatings containing polyvinyl alcohol, such as “Opadry® II” (containing partially hydrolyzed polyvinyl acetate (PVA), titanium dioxide, macrogol 3350, and talc, and including any coloring agent such as iron oxide, indigo carmine, or yellow iron oxide) or Opadry® TF, a formulation film without TiO2 (containing partially hydrolyzed polyvinyl acetate (PVA), calcium carbonate, microcrystalline cellulose, macrogol 6000, magnesium aluminometasilicate, carnauba wax, and xanthan gum, and including any coloring agent such as iron oxide, indigo carmine, or yellow iron oxide). The amount of coating is generally about 2–6% of the core weight, and in certain embodiments, about 4%. Unless otherwise specified, when the dosage form is coated, references to weight percent of the tablet should be understood to mean the weight percent of the uncoated tablet, i.e., the tablet without the coating.

[0098] The tablets of this disclosure comprise bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50 to 100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 to 100 mg of lenacapavir free acid. The tablets further comprise copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg or 50 mg of lenacapavir free acid. In some embodiments, the tablets comprise bictegravir sodium. In some embodiments, the tablets comprise lenacapavir sodium. In some embodiments, the tablets contain bictegravir sodium and lenacapavir sodium. In some embodiments, the tablets are coated with a film coating.

[0099] The tablets may consist of bictegravir or a pharmaceutically acceptable salt thereof, lenacapavir or a pharmaceutically acceptable salt thereof, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50-100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25-100 mg of lenacapavir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg or 50 mg of lenacapavir free acid. In some embodiments, bictegravir or a pharmaceutically acceptable salt thereof is bictegravir sodium. In some embodiments, lenacapavir or a pharmaceutically acceptable salt thereof is lenacapavir sodium. In some embodiments, the tablets are coated with a film coating.

[0100] The tablets of this disclosure may be monolayer tablets comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50 to 100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 to 100 mg of lenacapavir free acid, and the tablets further comprise copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, in this monolayer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid. The single-layer tablets may consist of bictegravir or a pharmaceutically acceptable salt thereof, lenacapavir or a pharmaceutically acceptable salt thereof, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50-100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25-100 mg of lenacapavir free acid. In some embodiments, in these single-layer tablets, bictegravir or a pharmaceutically acceptable salt thereof is bictegravir sodium. In some embodiments, lenacapavir or a pharmaceutically acceptable salt thereof is lenacapavir sodium. In some embodiments, the single-layer tablets are coated with a film coating.

[0101] The tablets of this disclosure may be two-layer tablets comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50 to 100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 to 100 mg of lenacapavir free acid, and the tablets further comprise copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, in these two-layer tablets, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid. In some embodiments, the amount of bictegravir or a pharmaceutically acceptable salt in this two-layer tablet corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt corresponds to about 50 mg of lenacapavir free acid. The first layer of the two-layer tablet may contain bictegravir or a pharmaceutically acceptable salt, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, the first layer of the two-layer tablet is substantially mannitol-free. In some embodiments, the first layer contains less than 1% w / w mannitol. In some embodiments, the first layer does not contain mannitol. The second layer of the two-layer tablet may contain lenacapavir or a pharmaceutically acceptable salt, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, in this two-layer tablet, bictegravir or a pharmaceutically acceptable salt thereof is bictegravir sodium. In some embodiments, lenacapavir or a pharmaceutically acceptable salt thereof is lenacapavir sodium. In some embodiments, this two-layer tablet is coated with a film coating.

[0102] In some embodiments, the disclosed two-layer tablets are two-layer tablets in which the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of free acid, wherein the first layer of the two-layer tablet contains an amount of bictegravir or a pharmaceutically acceptable salt thereof equivalent to about 75 mg of bictegravir free acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, wherein the first layer of the two-layer tablet is substantially mannitol-free, and the second layer of the two-layer tablet contains an amount of lenacapavir or a pharmaceutically acceptable salt thereof equivalent to about 25 mg of lenacapavir free acid, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, the first layer contains less than 1% w / w of mannitol. In some embodiments, the first layer does not contain mannitol.

[0103] In some embodiments, the disclosed two-layer tablets are two-layer tablets in which the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of free acid, wherein the first layer of the two-layer tablet contains an amount of bictegravir or a pharmaceutically acceptable salt thereof equivalent to about 75 mg of bictegravir free acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, wherein the first layer of the two-layer tablet is substantially mannitol-free, and the second layer of the two-layer tablet contains an amount of lenacapavir or a pharmaceutically acceptable salt thereof equivalent to about 50 mg of lenacapavir free acid, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, the first layer contains less than 1% w / w of mannitol. In some embodiments, the first layer does not contain mannitol.

[0104] The tablets of this disclosure may contain about 1-6% w / w copovidone, about 0-2% w / w poloxamer, about 10-50% w / w mannitol, about 10-60% w / w microcrystalline cellulose, about 6-10% w / w croscarmellose sodium, and about 1-2% w / w magnesium stearate. In some embodiments, tablets containing these excipients contain about 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof and about 5-30% w / w lenacapavir or a pharmaceutically acceptable salt thereof. Weight percentages indicate the proportion of the whole tablet.

[0105] A single-layer tablet is provided containing approximately 1-6% w / w copovidone, approximately 0.1-2% w / w poloxamer, approximately 20-50% w / w mannitol, approximately 10-30% w / w microcrystalline cellulose, approximately 5-15% w / w croscarmellose sodium, and approximately 0.1-10% w / w magnesium stearate. In certain embodiments, the tablet contains approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof and approximately 5-30% w / w lenacapavir or a pharmaceutically acceptable salt thereof. Weight percentages indicate the proportion of the whole tablet.

[0106] A single-layer tablet is provided containing approximately 1-6% w / w copovidone, approximately 0.3-1.6% w / w poloxamer, approximately 25-45% w / w mannitol, approximately 10-25% w / w microcrystalline cellulose, approximately 6-10% w / w croscarmellose sodium, and approximately 1-2% w / w magnesium stearate. In certain embodiments, the tablet contains approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof and approximately 5-30% w / w lenacapavir or a pharmaceutically acceptable salt thereof. Weight percentages indicate the proportion of the entire tablet.

[0107] A monolayer tablet is provided containing an amount of bictegravir or a pharmaceutically acceptable salt equivalent to approximately 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to approximately 25 mg of lenacapavir free acid, the monolayer tablet further comprising approximately 1-2% w / w copovidone, approximately 0.2-0.4% w / w poloxamer, approximately 40-45% w / w mannitol, approximately 20-25% w / w microcrystalline cellulose, approximately 7-9% w / w croscarmellose sodium, and approximately 1-2% w / w magnesium stearate. In this embodiment, the monolayer tablet contains approximately 15-20% w / w of bictegravir or a pharmaceutically acceptable salt and approximately 5-8% w / w of lenacapavir or a pharmaceutically acceptable salt. Weight percentages indicate the proportion of the whole tablet.

[0108] A monolayer tablet is provided containing an amount of bictegravir or a pharmaceutically acceptable salt equivalent to approximately 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to approximately 25 mg of lenacapavir free acid, the monolayer tablet further comprising approximately 1.4% w / w copovidone, approximately 0.4% w / w poloxamer, approximately 43% w / w mannitol, approximately 22% w / w microcrystalline cellulose, approximately 8% w / w croscarmellose sodium, and approximately 1.5% w / w magnesium stearate. In this embodiment, the monolayer tablet contains approximately 18% w / w of bictegravir or a pharmaceutically acceptable salt and approximately 6% w / w of lenacapavir or a pharmaceutically acceptable salt. Weight percentages indicate the proportion of the whole tablet.

[0109] A monolayer tablet is provided containing an amount of bictegravir or a pharmaceutically acceptable salt equivalent to approximately 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to approximately 50 mg of lenacapavir free acid, the monolayer tablet further comprising approximately 2-3% w / w copovidone, approximately 0.6-0.8% w / w poloxamer, approximately 35-40% w / w mannitol, approximately 18-22% w / w microcrystalline cellulose, approximately 7-9% w / w croscarmellose sodium, and approximately 1-2% w / w magnesium stearate. In this embodiment, the monolayer tablet contains approximately 15-20% w / w of bictegravir or a pharmaceutically acceptable salt and approximately 10-14% w / w of lenacapavir or a pharmaceutically acceptable salt. Weight percentages indicate the proportion of the whole tablet.

[0110] A monolayer tablet is provided containing an amount of bictegravir or a pharmaceutically acceptable salt equivalent to approximately 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to approximately 50 mg of lenacapavir free acid, the monolayer tablet further comprising approximately 2.8% w / w copovidone, approximately 0.8% w / w poloxamer, approximately 38% w / w mannitol, approximately 19% w / w microcrystalline cellulose, approximately 8% w / w croscarmellose sodium, and approximately 1.5% w / w magnesium stearate. In this embodiment, the monolayer tablet contains approximately 18% w / w of bictegravir or a pharmaceutically acceptable salt and approximately 12% w / w of lenacapavir or a pharmaceutically acceptable salt. Weight percentages indicate the proportion of the whole tablet.

[0111] Two-layer tablets are provided containing approximately 0.1–5% w / w copovidone, approximately 0.1–2% w / w poloxamer, approximately 5–30% w / w mannitol, approximately 30–60% w / w microcrystalline cellulose, approximately 5–20% w / w croscarmellose sodium, and approximately 0.1–5% w / w magnesium stearate. In these embodiments, the two-layer tablet contains approximately 10–25% w / w bictegravir or a pharmaceutically acceptable salt thereof and approximately 5–20% w / w lenacapavir or a pharmaceutically acceptable salt thereof. Weight percentages indicate the proportion of the whole tablet.

[0112] Also provided are two-layer tablets containing approximately 1-3% w / w copovidone, approximately 0.3-0.8% w / w poloxamer, approximately 10-25% w / w mannitol, approximately 40-60% w / w microcrystalline cellulose, approximately 6-10% w / w croscarmellose sodium, and approximately 1-2% w / w magnesium stearate. In these embodiments, the two-layer tablets contain approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof and approximately 5-20% w / w lenacapavir or a pharmaceutically acceptable salt thereof. In these embodiments, weight percentages represent the proportion of the entire tablet.

[0113] A two-layer tablet is provided containing an amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 25 mg of lenacapavir free acid, the two-layer tablet further comprising about 1-3% w / w copovidone, about 0.3-0.8% w / w poloxamer, about 10-25% w / w mannitol, about 45-55% w / w microcrystalline cellulose, about 6-10% w / w croscarmellose sodium, and about 1-2% w / w magnesium stearate. In these embodiments, the two-layer tablet contains about 15-20% w / w of bictegravir or a pharmaceutically acceptable salt and about 5-10% w / w of lenacapavir or a pharmaceutically acceptable salt. In some embodiments, the two-layer tablet comprises (a) a first layer containing about 15-20% w / w bictegravir or a pharmaceutically acceptable salt thereof, about 40-50% w / w microcrystalline cellulose, about 4-8% w / w croscarmellose sodium, and about 0.1-2% w / w magnesium stearate; and (b) a second layer containing about 5-10% w / w lenacapavir or a pharmaceutically acceptable salt thereof, about 0.1-5% w / w copovidone, about 0.1-2% w / w poloxamer, about 5-20% w / w mannitol, about 1-10% w / w microcrystalline cellulose, about 1-3% w / w croscarmellose sodium, and about 0.1-1% w / w magnesium stearate. In these embodiments, weight percentages represent the proportion of the entire tablet. In some embodiments, the two-layer tablets are coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0114] A two-layer tablet is provided containing an amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 25 mg of lenacapavir free acid, the two-layer tablet further comprising about 1.4% w / w copovidone, about 0.4% w / w poloxamer, about 12.5% ​​w / w mannitol, about 51.7% w / w microcrystalline cellulose, about 8% w / w croscarmellose sodium, and about 1.5% w / w magnesium stearate. In these embodiments, the two-layer tablet contains about 18% w / w of bictegravir or a pharmaceutically acceptable salt and about 6% w / w of lenacapavir or a pharmaceutically acceptable salt. In some embodiments, a two-layer tablet comprises: (a) a first layer containing about 18% w / w bictegravir or a pharmaceutically acceptable salt thereof (e.g., 18.5% w / w bictegravir sodium), about 45% w / w microcrystalline cellulose, about 6% w / w croscarmellose sodium, and about 1% w / w magnesium stearate; and (b) a second layer containing about 6% w / w lenacapavir or a pharmaceutically acceptable salt thereof, about 1.4% w / w copovidone, about 0.4% w / w poloxamer, about 12.5% ​​w / w mannitol, about 6% w / w microcrystalline cellulose, about 2% w / w croscarmellose sodium, and about 0.4% w / w magnesium stearate. In these embodiments, weight percentages represent the proportion of the entire tablet.

[0115] A two-layer tablet is provided containing an amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 75 mg of bictegravir free acid, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 50 mg of lenacapavir free acid, the two-layer tablet further comprising about 1-3% w / w of copovidone, about 0.3-0.8% w / w of poloxamer, about 10-25% w / w of mannitol, about 40-50% w / w of microcrystalline cellulose, about 6-10% w / w of croscarmellose sodium, and about 1-2% w / w of magnesium stearate. In these embodiments, the two-layer tablet contains about 10-20% w / w of bictegravir or a pharmaceutically acceptable salt and about 5-10% w / w of lenacapavir or a pharmaceutically acceptable salt. In some embodiments, the two-layer tablet comprises: (a) a first layer containing about 10–20% w / w bictegravir or a pharmaceutically acceptable salt thereof, about 30–40% w / w microcrystalline cellulose, about 2–6% w / w croscarmellose sodium, and about 0.5–1.5% w / w magnesium stearate; and (b) a second layer containing about 8–13% w / w lenacapavir or a pharmaceutically acceptable salt thereof, about 2–3% w / w copovidone, about 0.1–1% w / w poloxamer, about 15–25% w / w mannitol, about 7–13% w / w microcrystalline cellulose, about 2–4% w / w croscarmellose sodium, and about 0.1–1% w / w magnesium stearate. In these embodiments, weight percentages represent the proportion of the entire tablet.

[0116] A two-layer tablet is provided containing an amount equivalent to approximately 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and an amount equivalent to approximately 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, the two-layer tablet further comprising approximately 2% w / w copovidone, approximately 0.6% w / w poloxamer, approximately 19% w / w mannitol, approximately 45% w / w microcrystalline cellulose, approximately 8% w / w croscarmellose sodium, and approximately 1.5% w / w magnesium stearate. In these embodiments, the two-layer tablet contains approximately 14% w / w bictegravir or a pharmaceutically acceptable salt thereof and approximately 9% w / w lenacapavir or a pharmaceutically acceptable salt thereof. In some embodiments, a two-layer tablet comprises: (a) a first layer containing about 14% w / w bictegravir or a pharmaceutically acceptable salt thereof, about 35% w / w microcrystalline cellulose, about 4% w / w croscarmellose sodium, and about 0.8% w / w magnesium stearate; and (b) a second layer containing about 9% w / w lenacapavir or a pharmaceutically acceptable salt thereof, about 2% w / w copovidone, about 0.6% w / w poloxamer, about 19% w / w mannitol, about 10% w / w microcrystalline cellulose, about 4% w / w croscarmellose sodium, and about 0.7% w / w magnesium stearate. In these embodiments, weight percentages represent the proportion of the entire tablet.

[0117] In some embodiments, the two-layer tablets are coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0118] In some embodiments, the tablets contain about 5 to 50 mg of copovidone, about 0.5 to 10 mg of poloxamer, about 50 to 200 mg of mannitol, about 50 to 250 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 1 to 10 mg of magnesium stearate.

[0119] In some embodiments, the tablet contains bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 to 100 mg of lenacapavir free acid, 5 to 50 mg of copovidone, about 0.5 to 10 mg of poloxamer, about 50 to 200 mg of mannitol, about 50 to 250 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 1 to 10 mg of magnesium stearate.

[0120] In some embodiments, the tablet contains about 5 to 30 mg of copovidone, about 0.5 to 7 mg of poloxamer, about 50 to 200 mg of mannitol, about 55 to 250 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 1 to 10 mg of magnesium stearate.

[0121] In some embodiments, the tablet contains bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 to 100 mg of lenacapavir free acid, 5 to 30 mg of copovidone, about 0.5 to 7 mg of poloxamer, about 50 to 200 mg of mannitol, about 55 to 250 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 1 to 10 mg of magnesium stearate.

[0122] In some embodiments, the tablet contains bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 mg of lenacapavir free acid, 5 to 15 mg of copovidone, about 0.5 to 5 mg of poloxamer, about 50 to 200 mg of mannitol, about 70 to 250 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 1 to 10 mg of magnesium stearate.

[0123] In some embodiments, the tablet contains bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 50 mg of lenacapavir free acid, 5 to 15 mg of copovidone, about 0.5 to 5 mg of poloxamer, about 50 to 200 mg of mannitol, about 70 to 250 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 1 to 10 mg of magnesium stearate.

[0124] In some embodiments, the tablet is a single-layer tablet containing 5-30 mg of copovidone, about 0.5-10 mg of poloxamer, about 100-200 mg of mannitol, about 50-100 mg of microcrystalline cellulose, about 25-50 mg of croscarmellose sodium, and about 5-10 mg of magnesium stearate.

[0125] In some embodiments, the tablet is a single-layer tablet containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, an amount equivalent to about 25-100 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, 5-30 mg of copovidone, about 0.5-10 mg of poloxamer, about 100-200 mg of mannitol, about 50-100 mg of microcrystalline cellulose, about 25-50 mg of croscarmellose sodium, and about 5-10 mg of magnesium stearate.

[0126] In some embodiments, the tablet is a single-layer tablet containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, about 5 to 15 mg of copovidone, about 0.5 to 5 mg of poloxamer, about 150 to 200 mg of mannitol, about 70 to 100 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 5 to 10 mg of magnesium stearate.

[0127] In some embodiments, the tablet is a single-layer tablet containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, about 10-15 mg of copovidone, about 0.5-5 mg of poloxamer, about 150-200 mg of mannitol, about 70-100 mg of microcrystalline cellulose, about 25-50 mg of croscarmellose sodium, and about 5-10 mg of magnesium stearate.

[0128] In some embodiments, the tablet is a single-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid, and the tablet contains about 5–15 mg of copovidone, about 2–5 mg of poloxamer, about 150–175 mg of mannitol, about 75–90 mg of microcrystalline cellulose, about 30–40 mg of croscarmellose sodium, and about 5–8 mg of magnesium stearate. In some embodiments, the tablet weighs about 410–460 mg, for example, about 430–440 mg. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0129] In some embodiments, the tablet is a single-layer tablet containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 50 mg of lenacapavir free acid, about 12 mg of copovidone, about 3 mg of poloxamer, about 165 mg of mannitol, about 83 mg of microcrystalline cellulose, about 35 mg of croscarmellose sodium, and about 7 mg of magnesium stearate. In some embodiments, the tablet weighs about 434 mg. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0130] In some embodiments, the tablets are single-layer tablets containing about 79 mg of bictegravir sodium, about 51 mg of lenacapavir sodium, about 12 mg of copovidone, about 3 mg of poloxamer, about 165 mg of mannitol, about 83 mg of microcrystalline cellulose, about 35 mg of croscarmellose sodium, and about 7 mg of magnesium stearate. In some embodiments, the tablets are coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0131] In some embodiments, the tablet is a single-layer tablet containing approximately 75 mg of bictegravir free acid equivalent to bictegravir or a pharmaceutically acceptable salt thereof, approximately 50 mg of lenacapavir free acid equivalent to lenacapavir or a pharmaceutically acceptable salt thereof, approximately 12.2 mg of copovidone, approximately 3.3 mg of poloxamer, approximately 165.0 mg of mannitol, approximately 82.5 mg of microcrystalline cellulose, approximately 34.7 mg of croscarmellose sodium, and approximately 6.5 mg of magnesium stearate. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating. In some embodiments, the tablet weighs approximately 434 mg excluding the film coating.

[0132] In some embodiments, the tablets are single-layer tablets containing approximately 78.6 mg of bictegravir sodium, approximately 51.1 mg of lenacapavir sodium, approximately 12.2 mg of copovidone, approximately 3.3 mg of poloxamer, approximately 165.0 mg of mannitol, approximately 82.5 mg of microcrystalline cellulose, approximately 34.7 mg of croscarmellose sodium, and approximately 6.5 mg of magnesium stearate. In some embodiments, the tablets are coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0133] In some embodiments, the tablet is a single-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid, and the tablet contains about 5–8 mg of copovidone, about 1–3 mg of poloxamer, about 175–200 mg of mannitol, about 90–100 mg of microcrystalline cellulose, about 30–40 mg of croscarmellose sodium, and about 5–8 mg of magnesium stearate. In some embodiments, the tablet weighs about 410–460 mg, for example, about 430–440 mg. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0134] In some embodiments, the tablet is a single-layer tablet containing approximately 75 mg of bictegravir free acid equivalent to bictegravir or a pharmaceutically acceptable salt thereof, approximately 25 mg of lenacapavir free acid equivalent to lenacapavir or a pharmaceutically acceptable salt thereof, approximately 6 mg of copovidone, approximately 2 mg of poloxamer, approximately 187 mg of mannitol, approximately 94 mg of microcrystalline cellulose, approximately 35 mg of croscarmellose sodium, and approximately 7 mg of magnesium stearate. In some embodiments, the tablet weighs approximately 434 mg. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0135] In some embodiments, the tablets are single-layer tablets containing about 79 mg of bictegravir sodium, about 26 mg of lenacapavir sodium, about 6 mg of copovidone, about 2 mg of poloxamer, about 187 mg of mannitol, about 94 mg of microcrystalline cellulose, about 35 mg of croscarmellose sodium, and about 7 mg of magnesium stearate. In some embodiments, the tablets are coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0136] In some embodiments, the tablet is a single-layer tablet containing approximately 75 mg of bictegravir free acid equivalent to bictegravir or a pharmaceutically acceptable salt thereof, approximately 25 mg of lenacapavir free acid equivalent to lenacapavir or a pharmaceutically acceptable salt thereof, approximately 6.1 mg of copovidone, approximately 1.6 mg of poloxamer, approximately 187.3 mg of mannitol, approximately 93.6 mg of microcrystalline cellulose, approximately 34.7 mg of croscarmellose sodium, and approximately 6.5 mg of magnesium stearate. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating. In some embodiments, the tablet weighs approximately 434 mg excluding the film coating.

[0137] In some embodiments, the tablets are single-layer tablets containing approximately 78.6 mg of bictegravir sodium, approximately 25.6 mg of lenacapavir sodium, approximately 6.1 mg of copovidone, approximately 1.6 mg of poloxamer, approximately 187.3 mg of mannitol, approximately 93.6 mg of microcrystalline cellulose, approximately 34.7 mg of croscarmellose sodium, and approximately 6.5 mg of magnesium stearate. In some embodiments, the tablets are coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0138] In some embodiments, the tablet is a single-layer tablet, and the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 100 mg of lenacapavir free acid, and the tablet contains about 20-25 mg of copovidone, about 5-8 mg of poloxamer, about 115-125 mg of mannitol, about 55-65 mg of microcrystalline cellulose, about 30-40 mg of croscarmellose sodium, and about 5-8 mg of magnesium stearate. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating. In some embodiments, the tablet weighs about 410-460 mg excluding the film coating, for example, about 430-440 mg excluding the film coating.

[0139] In some embodiments, the tablet is a single-layer tablet containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 100 mg of lenacapavir free acid, about 25 mg of copovidone, about 7 mg of poloxamer, about 121 mg of mannitol, about 60 mg of microcrystalline cellulose, about 35 mg of croscarmellose sodium, and about 7 mg of magnesium stearate. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating. In some embodiments, the tablet weighs about 434 mg excluding the film coating.

[0140] In some embodiments, the tablets are single-layer tablets containing about 79 mg of bictegravir sodium, about 102 mg of lenacapavir sodium, about 25 mg of copovidone, about 7 mg of poloxamer, about 121 mg of mannitol, about 60 mg of microcrystalline cellulose, about 35 mg of croscarmellose sodium, and about 7 mg of magnesium stearate. In some embodiments, the tablets are coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0141] In some embodiments, the tablet is a single-layer tablet containing approximately 75 mg of bictegravir free acid equivalent to bictegravir or a pharmaceutically acceptable salt thereof, approximately 100 mg of lenacapavir free acid equivalent to lenacapavir or a pharmaceutically acceptable salt thereof, approximately 24.5 mg of copovidone, approximately 6.6 mg of poloxamer, approximately 120.6 mg of mannitol, approximately 60.3 mg of microcrystalline cellulose, approximately 34.7 mg of croscarmellose sodium, and approximately 6.5 mg of magnesium stearate. In some embodiments, the tablet is coated with a film coating. In some embodiments, the coating is a non-functional coating. In some embodiments, the tablet weighs approximately 434 mg excluding the film coating.

[0142] In some embodiments, the tablets are single-layer tablets containing approximately 78.6 mg of bictegravir sodium, approximately 102.2 mg of lenacapavir sodium, approximately 24.5 mg of copovidone, approximately 6.6 mg of poloxamer, approximately 120.6 mg of mannitol, approximately 60.3 mg of microcrystalline cellulose, approximately 34.7 mg of croscarmellose sodium, and approximately 6.5 mg of magnesium stearate. In some embodiments, the tablets are coated with a film coating. In some embodiments, the coating is a non-functional coating.

[0143] In some embodiments, the tablet is a two-layer tablet containing about 5–15 mg of copovidone, about 0.5–5 mg of poloxamer, 50–125 mg of mannitol, about 200–250 mg of microcrystalline cellulose, about 25–50 mg of croscarmellose sodium, and about 5–10 mg of magnesium stearate.

[0144] In some embodiments, the tablet is a two-layer tablet containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, an amount equivalent to about 25-50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, about 5-15 mg of copovidone, about 0.5-5 mg of poloxamer, 50-125 mg of mannitol, about 200-250 mg of microcrystalline cellulose, about 25-50 mg of croscarmellose sodium, and about 5-10 mg of magnesium stearate.

[0145] In some embodiments, the tablet is a two-layer tablet containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, about 5 to 15 mg of copovidone, about 0.5 to 5 mg of poloxamer, 50 to 125 mg of mannitol, about 200 to 250 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 5 to 10 mg of magnesium stearate.

[0146] In some embodiments, the tablet is a two-layer tablet containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 mg of lenacapavir free acid, about 5 to 15 mg of copovidone, about 0.5 to 5 mg of poloxamer, about 50 to 125 mg of mannitol, about 200 to 250 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 5 to 10 mg of magnesium stearate.

[0147] In some embodiments, the first layer of the two-layer tablet contains an amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 75 mg of bictegravir free acid, and the first layer further contains about 185–200 mg of microcrystalline cellulose, about 20–30 mg of croscarmellose sodium, and about 3–5 mg of magnesium stearate. In some embodiments, the first layer of the two-layer tablet does not contain any fillers other than microcrystalline cellulose. In some embodiments, the first layer of the two-layer tablet does not contain mannitol.

[0148] In some embodiments, the first layer of the two-layer tablet contains an amount of bictegravir or a pharmaceutically acceptable salt thereof equivalent to about 75 mg of bictegravir free acid, and the first layer further contains about 193 mg of microcrystalline cellulose, about 24 mg of croscarmellose sodium, and about 5 mg of magnesium stearate. In some embodiments, the first layer of this two-layer tablet does not contain any fillers other than microcrystalline cellulose. In some embodiments, the first layer of this two-layer tablet does not contain mannitol.

[0149] In some embodiments, the first layer of the two-layer tablet contains about 79 mg of bictegravir sodium, about 193 mg of microcrystalline cellulose, about 24 mg of croscarmellose sodium, and about 5 mg of magnesium stearate. In some embodiments, the first layer of this two-layer tablet does not contain any fillers other than microcrystalline cellulose. In some embodiments, the first layer of this two-layer tablet does not contain mannitol.

[0150] In some embodiments, the first layer of the two-layer tablet contains an amount of bictegravir or a pharmaceutically acceptable salt thereof equivalent to about 75 mg of bictegravir free acid, and the first layer further contains about 193.0 mg of microcrystalline cellulose, about 24.0 mg of croscarmellose sodium, and about 4.5 mg of magnesium stearate. In some embodiments, the first layer of this two-layer tablet does not contain any fillers other than microcrystalline cellulose. In some embodiments, the first layer of this two-layer tablet does not contain mannitol.

[0151] In some embodiments, the first layer of the two-layer tablet contains about 78.5 mg of bictegravir sodium, 193.0 mg of microcrystalline cellulose, about 24.0 mg of croscarmellose sodium, and about 4.5 mg of magnesium stearate. In some embodiments, the first layer of this two-layer tablet does not contain any fillers other than microcrystalline cellulose. In some embodiments, the first layer of this two-layer tablet does not contain mannitol.

[0152] In some embodiments, the first layer of a two-layer tablet contains an amount equivalent to about 25 mg of lenacapavir free acid, or a pharmaceutically acceptable salt thereof, and the second layer further contains about 5-8 mg of copovidone, about 1-3 mg of poloxamer, about 45-60 mg of mannitol, about 20-30 mg of microcrystalline cellulose, about 5-15 mg of croscarmellose sodium, and about 1-3 mg of magnesium stearate.

[0153] In some embodiments, the second layer of a two-layer tablet contains an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, and the second layer further contains about 6 mg of copovidone, about 2 mg of poloxamer, about 53 mg of mannitol, about 27 mg of microcrystalline cellulose, about 10 mg of croscarmellose sodium, and about 2 mg of magnesium stearate.

[0154] In some embodiments, the second layer of the two-layer tablet contains about 26 mg of lenacapavir sodium, about 6 mg of copovidone, about 2 mg of poloxamer, about 53 mg of mannitol, about 27 mg of microcrystalline cellulose, about 10 mg of croscarmellose sodium, and about 2 mg of magnesium stearate.

[0155] In some embodiments, the second layer of a two-layer tablet contains an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, and the second layer further contains about 6.1 mg of copovidone, about 1.7 mg of poloxamer, about 53.2 mg of mannitol, about 26.6 mg of microcrystalline cellulose, about 10.0 mg of croscarmellose sodium, and about 1.9 mg of magnesium stearate.

[0156] In some embodiments, the second layer of the two-layer tablet contains approximately 25.6 mg of lenacapavir sodium, approximately 6.1 mg of copovidone, approximately 1.7 mg of poloxamer, approximately 53.2 mg of mannitol, approximately 26.6 mg of microcrystalline cellulose, approximately 10.0 mg of croscarmellose sodium, and approximately 1.9 mg of magnesium stearate.

[0157] In some embodiments, the second layer of a two-layer tablet contains an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, and the second layer further contains about 10–15 mg of copovidone, about 2–5 mg of poloxamer, about 100–110 mg of mannitol, about 45–60 mg of microcrystalline cellulose, about 15–25 mg of croscarmellose sodium, and about 2–5 mg of magnesium stearate.

[0158] In some embodiments, the second layer of a two-layer tablet contains an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, and the second layer further contains about 12 mg of copovidone, about 3 mg of poloxamer, about 106 mg of mannitol, about 53 mg of microcrystalline cellulose, about 20 mg of croscarmellose sodium, and about 4 mg of magnesium stearate.

[0159] In some embodiments, the second layer of the two-layer tablet contains about 51 mg of lenacapavir sodium, about 12 mg of copovidone, about 3 mg of poloxamer, about 106 mg of mannitol, about 53 mg of microcrystalline cellulose, about 20 mg of croscarmellose sodium, and about 4 mg of magnesium stearate.

[0160] In some embodiments, the second layer of a two-layer tablet contains an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, and the second layer further contains about 12.2 mg of copovidone, about 3.3 mg of poloxamer, about 106.4 mg of mannitol, about 53.2 mg of microcrystalline cellulose, about 20.0 mg of croscarmellose sodium, and about 3.8 mg of magnesium stearate.

[0161] In some embodiments, the second layer of the two-layer tablet contains approximately 51.1 mg of lenacapavir sodium, approximately 12.2 mg of copovidone, approximately 3.3 mg of poloxamer, approximately 106.4 mg of mannitol, approximately 53.2 mg of microcrystalline cellulose, approximately 20.0 mg of croscarmellose sodium, and approximately 3.8 mg of magnesium stearate.

[0162] In some embodiments, the first layer of a two-layer tablet contains an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 25–50 mg of lenacapavir free acid. In some embodiments, the first layer of a two-layer tablet contains about 25.6–51.1 mg of lenacapavir sodium. In some embodiments, the first layer further contains about 5–15 mg of copovidone, about 1–5 mg of poloxamer, about 45–110 mg of mannitol, about 20–55 mg of microcrystalline cellulose, about 5–25 mg of croscarmellose sodium, and about 1–5 mg of magnesium stearate. In some embodiments, the first layer of a two-layer tablet contains an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 50 mg of lenacapavir free acid. In some embodiments, the first layer of a two-layer tablet contains about 51.2 mg of lenacapavir sodium. In some embodiments, the first layer of a two-layer tablet contains an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof. In some embodiments, the first layer of a two-layer tablet contains about 25.6 mg of lenacapavir sodium.

[0163] In some embodiments, the second layer of the two-layer tablet contains an amount of bictegravir or a pharmaceutically acceptable salt equivalent to about 75 mg of bictegravir free acid. In some embodiments, the second layer of the two-layer tablet contains about 78.5 mg of bictegravir sodium. In some embodiments, the second layer further contains about 185–200 mg of microcrystalline cellulose, about 20–30 mg of croscarmellose sodium, and about 3–5 mg of magnesium stearate. In some embodiments, the second layer of the two-layer tablet does not contain any fillers other than microcrystalline cellulose. In some embodiments, the second layer of the two-layer tablet does not contain mannitol.

[0164] In some embodiments, the first layer of a two-layer tablet contains an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, and the second layer of the two-layer tablet contains an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the first layer of a two-layer tablet contains an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, and the second layer of the two-layer tablet contains an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the multilayer tablets further include a film coating.

[0167] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of free bictegravir acid, and the first layer further contains approximately 175–210 mg of microcrystalline cellulose, approximately 15–35 mg of croscarmellose sodium, and approximately 1–10 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 25 mg of free lenacapavir acid, and the second layer further comprises approximately 1–10 mg of copovidone, approximately 1–6 mg of poloxamer, approximately 30–75 mg of mannitol, approximately 15–40 mg of microcrystalline cellulose, approximately 1–20 mg of croscarmellose sodium, and approximately 1–10 mg of magnesium stearate.

[0168] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol. In some embodiments, the tablet weighs about 400–450 mg excluding the film coating, for example, about 420–430 mg excluding the film coating.

[0169] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or its pharmaceutically acceptable salt corresponds to approximately 75 mg of free bictegravir acid, and the third layer further contains approximately 185-200 mg of microcrystalline cellulose, approximately 20-30 mg of croscarmellose sodium, and approximately 1-5 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 25 mg of free lenacapavir acid, and the second layer further comprises approximately 5-8 mg of copovidone, approximately 1-3 mg of poloxamer, approximately 45-60 mg of mannitol, approximately 20-30 mg of microcrystalline cellulose, approximately 5-15 mg of croscarmellose sodium, and approximately 1-3 mg of magnesium stearate.

[0170] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol. In some embodiments, the tablet weighs about 400–450 mg excluding the film coating, for example, about 420–430 mg excluding the film coating.

[0171] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of free bictegravir acid, and the first layer further contains approximately 193 mg of microcrystalline cellulose, approximately 24 mg of croscarmellose sodium, and approximately 5 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 25 mg of free lenacapavir acid, and the second layer further comprises approximately 6 mg of copovidone, approximately 2 mg of poloxamer, approximately 53 mg of mannitol, approximately 27 mg of microcrystalline cellulose, approximately 10 mg of croscarmellose sodium, and approximately 2 mg of magnesium stearate.

[0172] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol.

[0173] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing about 79 mg of bictegravir sodium and (b) a second layer containing about 26 mg of lenacapavir sodium. The first layer further contains approximately 193 mg of microcrystalline cellulose, approximately 24 mg of croscarmellose sodium, and approximately 5 mg of magnesium stearate. The second layer further contains approximately 6 mg of copovidone, approximately 2 mg of poloxamer, approximately 53 mg of mannitol, approximately 27 mg of microcrystalline cellulose, approximately 10 mg of croscarmellose sodium, and approximately 2 mg of magnesium stearate.

[0174] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol.

[0175] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of free bictegravir acid, and the first layer further contains approximately 193.0 mg of microcrystalline cellulose, approximately 24.0 mg of croscarmellose sodium, and approximately 4.5 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 25 mg of free lenacapavir acid, and the second layer further contains approximately 6.1 mg of copovidone, approximately 1.7 mg of poloxamer, approximately 53.2 mg of mannitol, approximately 26.6 mg of microcrystalline cellulose, approximately 10.0 mg of croscarmellose sodium, and approximately 1.9 mg of magnesium stearate.

[0176] In some embodiments, the tablet further includes a film coating.

[0177] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing about 78.5 mg of bictegravir sodium and (b) a second layer containing about 25.6 mg of lenacapavir sodium. The first layer further contains approximately 193.0 mg of microcrystalline cellulose, approximately 24.0 mg of croscarmellose sodium, and approximately 4.5 mg of magnesium stearate. The second layer further contains approximately 6.1 mg of copovidone, approximately 1.7 mg of poloxamer, approximately 53.2 mg of mannitol, approximately 26.6 mg of microcrystalline cellulose, approximately 10.0 mg of croscarmellose sodium, and approximately 1.9 mg of magnesium stearate.

[0178] In some embodiments, the tablet further includes a film coating.

[0179] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of free bictegravir acid, and the first layer further contains approximately 175–210 mg of microcrystalline cellulose, approximately 15–35 mg of croscarmellose sodium, and approximately 1–10 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 50 mg of free lenacapavir acid, and the second layer further comprises approximately 5–25 mg of copovidone, approximately 1–10 mg of poloxamer, approximately 75–125 mg of mannitol, approximately 40–65 mg of microcrystalline cellulose, approximately 10–30 mg of croscarmellose sodium, and approximately 1–10 mg of magnesium stearate.

[0180] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol. In some embodiments, the tablet weighs about 540–560 mg excluding the film coating.

[0181] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of free bictegravir acid, and the first layer further contains approximately 185-200 mg of microcrystalline cellulose, approximately 20-30 mg of croscarmellose sodium, and approximately 3-5 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 50 mg of free lenacapavir acid, and the second layer further comprises approximately 10–15 mg of copovidone, approximately 2–5 mg of poloxamer, approximately 100–110 mg of mannitol, approximately 45–60 mg of microcrystalline cellulose, approximately 15–25 mg of croscarmellose sodium, and approximately 2–5 mg of magnesium stearate.

[0182] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol. In some embodiments, the tablet weighs about 520–580 mg excluding the film coating, for example, about 545–555 mg excluding the film coating.

[0183] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of free bictegravir acid, and the first layer further contains approximately 193 mg of microcrystalline cellulose, approximately 24 mg of croscarmellose sodium, and approximately 5 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 50 mg of free lenacapavir acid, and the second layer further comprises approximately 12 mg of copovidone, approximately 3 mg of poloxamer, approximately 106 mg of mannitol, approximately 53 mg of microcrystalline cellulose, approximately 20 mg of croscarmellose sodium, and approximately 4 mg of magnesium stearate.

[0184] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol.

[0185] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing about 79 mg of bictegravir sodium and (b) a second layer containing about 51 mg of lenacapavir sodium. The first layer further contains approximately 193 mg of microcrystalline cellulose, approximately 24 mg of croscarmellose sodium, and approximately 5 mg of magnesium stearate. The second layer further contains approximately 12 mg of copovidone, approximately 3 mg of poloxamer, approximately 106 mg of mannitol, approximately 53 mg of microcrystalline cellulose, approximately 20 mg of croscarmellose sodium, and approximately 4 mg of magnesium stearate.

[0186] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol.

[0187] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of free bictegravir acid, and the first layer further contains approximately 193.0 mg of microcrystalline cellulose, approximately 24.0 mg of croscarmellose sodium, and approximately 4.5 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 50 mg of free lenacapavir acid, and the second layer further contains approximately 12.2 mg of copovidone, approximately 3.3 mg of poloxamer, approximately 106.4 mg of mannitol, approximately 53.2 mg of microcrystalline cellulose, approximately 20.0 mg of croscarmellose sodium, and approximately 3.8 mg of magnesium stearate.

[0188] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol.

[0189] In some embodiments, the tablet is a two-layer tablet comprising (a) a first layer containing 78.5 mg of bictegravir sodium and (b) a second layer containing 51.1 mg of lenacapavir sodium. The first layer further contains approximately 193.0 mg of microcrystalline cellulose, approximately 24.0 mg of croscarmellose sodium, and approximately 4.5 mg of magnesium stearate. The second layer further contains approximately 12.2 mg of copovidone, approximately 3.3 mg of poloxamer, approximately 106.4 mg of mannitol, approximately 53.2 mg of microcrystalline cellulose, approximately 20.0 mg of croscarmellose sodium, and approximately 3.8 mg of magnesium stearate.

[0190] In some embodiments, the tablet further includes a film coating. In some embodiments, the first layer is substantially free of mannitol.

[0191] In some embodiments, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide. In some embodiments, the film coating comprises Opadry II 85F520107 Yellow. In some embodiments, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and red iron oxide. In some embodiments, the film coating comprises Opadry II 85F86937 Brown. In some embodiments, the film coating comprises polyvinyl alcohol, calcium carbonate, microcrystalline cellulose, polyethylene glycol, magnesium aluminometasilicate, yellow iron oxide, carnauba wax, and xanthan gum. In some embodiments, the film coating comprises Opadry TF 273F120017.

[0192] In some embodiments, the first layer of the two-layer tablet is in contact with the second layer.

[0193] Pharmacokinetics The inventors have found that each active ingredient (e.g., AUC) can be present in an amount at least equivalent to that of a standard comparator (i.e., a single-ingredient tablet containing the same amounts of bictegravir and lenacapavir). inf , C maxWe have found that it is possible to formulate bictegravir (particularly bictegravir sodium) and lenacapavir (particularly lenacapavir sodium) into tablets that can release plasma concentrations (AUC) of one or more of the two active pharmaceutical ingredients that are comparable to the plasma concentrations produced by administration of a combination of monotherapy tablets. inf , C max ) provides.

[0194] Achieving equivalent release of bictegravir and lenacapavir from a fixed-dose combination formulation to that of a single-agent formulation was initially challenging, as the dissolution and subsequent bioavailability of the active agents were found to vary depending on the specific dose contained in the formulation. While not bound by any particular theory, the two active agents are thought to interact with each other in a manner that affects their respective solubility and resulting bioavailability. For example, the dissolution of lenacapavir from a monolayer tablet containing 75 mg of bictegravir and 25 mg of lenacapavir was reduced compared to an equivalent combination of single-agent tablets. Furthermore, the dissolution of bictegravir from a monolayer tablet containing 75 mg of bictegravir and 100 mg of lenacapavir was also reduced compared to an equivalent combination of single-agent tablets. Therefore, a balance should be struck between the doses of bictegravir and lenacapavir to achieve sufficient dissolution of both active agents and to provide bioequivalence with a combination of single-agent tablets.

[0195] As used herein, F (bioavailability) is the proportion of administered drug that reaches systemic circulation.

[0196] In certain embodiments, the tablets of the present disclosure provide at least about 20%, and in some embodiments at least about 30%, of bictegravir bioavailability in fasted dogs pretreated with pentagastrinn.

[0197] In certain specific embodiments, the tablet of the present disclosure provides a bioavailability of lenacapavir of at least about 2%, and in some embodiments at least about 3%, in fasted dogs pre-treated with pentagastrin.

[0198] In some embodiments, the tablet that provides a bioavailability of bictegravir of at least about 20% in fasted dogs pre-treated with pentagastrin is a single-layer tablet comprising bictegravir or a pharmaceutically acceptable salt thereof, and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or the pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or the pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid. In some embodiments, the single-layer tablet provides a bioavailability of lenacapavir of at least about 3% in fasted dogs pre-treated with pentagastrin.

[0199] In some embodiments, the tablet that provides a bioavailability of bictegravir of at least about 20% in fasted dogs pre-treated with pentagastrin is a bilayer tablet comprising (a) a first layer comprising bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer comprising lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or the pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or the pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid. In some embodiments, the single-layer tablet provides a bioavailability of lenacapavir of at least about 2% in fasted dogs pre-treated with pentagastrin.

[0200] F, C max , AUC inf , and AUC lastThese are standard pharmacokinetic parameters that can be estimated manually or by using modeling software well-known in the art, such as the Pharsight WinNonlin package, which uses a non-compartment model. The general basis for calculating these quantities is well known (see, e.g., Rowland & Tozer (2010) Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications ISBN 978-0781750097, or Jambekar & Breen (2012) Basic Pharmacokinetics ISBN 978-0853699804). Typically, parameters are evaluated as the mean (e.g., geometric mean or arithmetic mean) from a group of at least 12 (usually 24-60) healthy adults. Parameters should be measured according to standards and practices acceptable to drug regulatory authorities such as the FDA, EMA, MHLW, or WHO. The values ​​may be based on measurements obtained at appropriate intervals after tablet ingestion, for example every hour, or at increasingly sparse sampling intervals, for example, at 1, 3, 5, 7, 9, 11, 13, 15, 20, and 24 hours after ingestion. They can be evaluated either after a single dose of the drug or at steady state, but are typically evaluated after a single dose. Clinical data were evaluated after a single dose.

[0201] Manufacturing method Methods for producing the compositions and dosage forms described herein (in particular, tablets of this disclosure) are also provided. Tablets may be produced by compressing or molding with one or more excipients as optional. Compressed tablets may be prepared by compressing an active ingredient in a free-flowing form, such as a powder or granules, mixed with excipients as optional, using suitable machinery. In general, methods for tableting are well known in the field of pharmaceuticals. The techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA), which is incorporated herein by reference in whole.

[0202] In some embodiments, the method involves blending bictegravir and lenacapavir (or pharmaceutically acceptable salts thereof) with an excipient and then compressing the mixture.

[0203] In some embodiments of forming monolayer tablets according to this disclosure, bictegravir and lenacapavir (or pharmaceutically acceptable salts thereof) are first mixed with an excipient and granulated, for example, by dry granulation. This step, in some embodiments, includes roller compression and / or grinding. In some embodiments, the co-mixed granules of bictegravir and lenacapavir (or pharmaceutically acceptable salts thereof) are further combined with an extragranular excipient, including but not limited to magnesium stearate, and then compressed.

[0204] In some embodiments, multilayer tablets (e.g., two-layer tablets) are manufactured, and this method comprises (a) compressing bictegravir or a pharmaceutically acceptable salt thereof together with an excipient as a first layer, and (b) compressing lenacapavir or a pharmaceutically acceptable salt thereof together with an excipient to form a second layer. The first and second layers may be compressed separately and then combined. In some embodiments, the first layer is formed by compression, and then the second layer is compressed on top of the first layer.

[0205] In some embodiments, multilayer tablets (e.g., two-layer tablets) are manufactured, and this method comprises (a) compressing lenacapapvir or a pharmaceutically acceptable salt thereof together with an excipient as a first layer, and (b) compressing bictegravir or a pharmaceutically acceptable salt thereof together with an excipient to form a second layer. The first and second layers may be compressed separately and then combined. In some embodiments, the first layer is formed by compression, and then the second layer is compressed on top of the first layer.

[0206] In some embodiments, lenacapavir or a pharmaceutically acceptable salt thereof is spray-dried before further formulation to form a lenacapavir dispersion containing one or more excipients. In some embodiments, the lenacapavir dispersion is obtained by spray-drying a mixture containing lenacapavir or a pharmaceutically acceptable salt thereof and one or more excipients in a suitable solvent. A solvent suitable for spray-drying may be any organic solvent to which lenacapavir or a pharmaceutically acceptable salt thereof is miscible. The solvent should have relatively low toxicity and be removed from the dispersion to a level acceptable according to the guidelines of the International Committee on Harmonization (ICH). Removal of the solvent to this level may require a post-drying step, such as tray drying, following the spray-drying process. Suitable solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol (especially methanol); ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents such as acetonitrile, dichloromethane, toluene, and 1,1,1-trichloroethane. Low-volatility solvents such as dimethylacetamide or dimethyl sulfoxide can also be used.

[0207] The lenacapavir dispersion may optionally be mixed and granulated with an excipient, along with bictegravir or a pharmaceutically acceptable salt thereof. This process may be carried out by roller compression and / or grinding. In some embodiments, this process is carried out by roller compression. The co-mixed bictegravir and lenacapavir granules are further combined with an extragranular excipient and then compressed to form a monolayer tablet. In some embodiments, the excipient is magnesium stearate.

[0208] In some embodiments, two-layer tablets are manufactured. Prior to the manufacture of the tablets, lenacapavir or a pharmaceutically acceptable salt thereof is generally spray-dried with one or more excipients to form a lenacapavir dispersion. The lenacapavir dispersion may be mixed with additional excipients and granulated. This step may be carried out by roller compression and / or grinding. In some embodiments, this step is carried out by grinding. The lenacapavir granules are further combined with an extragranular excipient (magnesium stearate in some embodiments). Separately, when manufacturing two-layer tablets of the present disclosure, bictegravir or a pharmaceutically acceptable salt thereof is blended with an excipient and granulated (roller compression is used in some embodiments). In some embodiments, bictegravir granules are then compressed as the first layer, and then lenacapavir granules are compressed as the second layer to form a two-layer tablet. In some embodiments, lenacapavir granules are then compressed as a first layer, and bictegravir granules are then compressed as a second layer to form a two-layer tablet. The first and second layers may be compressed separately and then combined. In some embodiments, the first layer is formed by compression, and then the second layer is compressed on top of the first layer. In some embodiments, the resulting two-layer tablet is coated with a film coating. In some embodiments, the tablet is coated with a non-functional coating.

[0209] In some embodiments, the method includes a step of coating the tablet core with a film coating, such as the one described above, after compression.

[0210] Treatment method The tablets of this disclosure may be used to treat or prevent HIV (e.g., HIV-1). In some embodiments, the tablets of this disclosure may be used to treat or prevent HIV-1 or HIV-2.

[0211] The tablets of this disclosure may be used to treat HIV (e.g., HIV-1). In some embodiments, the tablets of this disclosure may be used to treat HIV-1 or HIV-2.

[0212] In certain embodiments, the tablets of the Disclosure may be used to prevent HIV (e.g., HIV-1). In some embodiments, the tablets of the Disclosure may be used to prevent HIV-1 or HIV-2.

[0213] Accordingly, a method for treating a subject having HIV is provided, comprising administering a tablet of the present disclosure to the subject. Similarly, a tablet of the present disclosure for use in such a therapeutic method is provided.

[0214] The present invention also provides the use of bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof in the manufacture of tablets of the present disclosure for the treatment of HIV. In some embodiments, the present disclosure provides the use of bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof in the manufacture of tablets of the present disclosure for the prevention of HIV.

[0215] Methods are provided for treating HIV infection in a person who is infected with HIV or at risk of infection, the method comprising administering tablets disclosed herein to the person. Similarly, methods are provided for preventing HIV infection in a person who is infected with HIV or at risk of infection, the method comprising administering tablets disclosed herein to the person. For example, methods are provided for preventing HIV infection from occurring when an individual is exposed to the virus, and / or for preventing the establishment of persistent infection with the virus, and / or for preventing the appearance of symptoms of the disease, and / or for preventing the virus from reaching detectable levels in the blood, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Thus, methods are provided for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2). In some embodiments, the human patient is virologically suppressed, meaning that the HIV RNA level (viral load) in the patient's serum is reduced to less than 50 copies / mL or below the detection limit. In some embodiments, the human patient is virologically suppressed and has experienced treatment, which means the patient has previously taken one or more forms of HIV medication.

[0216] The tablets disclosed herein are provided for use in the treatment of HIV infection in a person who is infected with HIV or at risk of becoming infected. Similarly, the tablets disclosed herein are provided for use in the prevention of HIV infection in a person who is infected with HIV or at risk of becoming infected. The tablets disclosed herein are also provided for use in methods to prevent HIV infection from occurring when an individual is exposed to the virus, and / or to prevent the establishment of permanent infection with the virus, and / or to prevent the appearance of symptoms of the disease, and / or to prevent the virus from reaching detectable levels in the blood, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Thus, the tablets are provided for use in methods to reduce the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2). In some embodiments, the human patient is virologically suppressed. In some embodiments, the human patient is virologically suppressed and has experienced treatment, meaning that the patient has previously taken one or more forms of HIV medication.

[0217] Methods for using the tablets disclosed herein in treatment are provided. In particular, methods for treating the replication of the HIV virus in humans (e.g., men who have sexual intercourse with men or transgender women who have sexual intercourse with men), treating AIDS, or delaying the onset of AIDS or ARC symptoms, are provided, which include administering the tablets disclosed herein to humans.

[0218] Tablets disclosed herein for use in therapeutic methods are provided. In particular, tablets disclosed herein for use in methods of treating the replication of the HIV virus in humans (for example, men who have sexual intercourse with men or transgender women who have sexual intercourse with men), treating AIDS, or delaying the onset of AIDS or ARC symptoms.

[0219] Human patients with HIV infection may be virologically suppressed, meaning that the level of HIV RNA (viral load) in the patient's serum has decreased to less than 50 copies / mL or below the detection limit. In one embodiment, the human patient has undergone treatment, meaning that the patient has previously taken one or more forms of HIV medication. The tablets disclosed herein are provided for use, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), to prevent HIV infection from occurring if an individual is exposed to the virus, and / or to prevent the establishment of persistent infection with the virus, and / or to prevent the onset of symptoms of the disease, and / or to prevent the virus from reaching a detectable level in the blood. Thus, in certain embodiments, methods are provided for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2). For example, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes the administration of the tablets disclosed herein. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes the administration of tablets disclosed herein in combination with safer sexual practices. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administration to individuals at risk of acquiring HIV. Examples of individuals at high risk of acquiring HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

[0220] In another embodiment, the use of the tablets disclosed herein for the manufacture of a medicament for the treatment of HIV infection in a person who has or is at risk of having HIV infection is disclosed. Similarly, in another embodiment, the use of the tablets disclosed herein for the manufacture of a medicament for the prevention of HIV infection in a person who has or is at risk of having HIV infection is disclosed.

[0221] In another embodiment, a manufactured article is disclosed comprising tablets disclosed herein and packaging material including a label indicating that the tablets may be used to treat HIV infection. Similarly, in another embodiment, a manufactured article is disclosed comprising tablets disclosed herein and packaging material including a label indicating that the tablets may be used to prevent HIV infection.

[0222] The methods disclosed herein involve administering the tablets disclosed herein, typically to humans, and generally involve repeated administration, typically once daily. The treatment may be prophylactic or therapeutic.

[0223] The tablets disclosed herein may be administered, for example, as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP) before and / or after an event that exposes an individual to HIV or an event that increases the risk of the individual acquiring HIV by other means. Examples of events that may increase the risk of an individual acquiring HIV include, but are not limited to, unprotected anal sex with an HIV-positive partner or a partner whose HIV status is unknown, anal sex with more than three sexual partners, anal sex in exchange for money, gifts, shelter or medicine, sexual intercourse with a male partner who has been diagnosed with a sexually transmitted infection, and consistent unprotected sexual intercourse with a partner who is known to be HIV-positive.

[0224] In some embodiments, for example, when administered as PrEP, the tablets disclosed herein are administered 2 to 72 hours, 2 to 48 hours, 2 to 24 hours, or 2 to 12 hours before an event that increases the risk of an individual acquiring HIV (e.g., sexual activity or other exposure to the HIV virus). In some embodiments, the tablets disclosed herein are administered within 72 hours, 60 hours, 48 ​​hours, 24 hours, 12 hours, 9 hours, 6 hours, 4 hours, 3 hours, 2 hours, or 1 hour before an event that increases the risk of an individual acquiring HIV (e.g., sexual activity or other exposure to the HIV virus). In some embodiments, when the tablets disclosed herein are administered before an event that increases the risk of an individual acquiring HIV, they are administered daily before the event. In some embodiments, when the tablets disclosed herein are administered before an event that increases the risk of an individual acquiring HIV, they are administered one to three times before the event.

[0225] In one embodiment, for example, when administered as part of a PrEP regimen or as a PEP, the tablets disclosed herein are administered 2–48 hours, 2–36 hours, 2–24 hours, or 2–12 hours after an event that increases the risk of an individual acquiring HIV (e.g., after sexual intercourse or other exposure to the HIV virus). In one embodiment, for example, when administered as a PEP, the tablets disclosed herein are administered for 7, 14, 21, 28, 30, or 45 days after an event that increases the risk of an individual acquiring HIV (e.g., after sexual intercourse or other exposure to the HIV virus). In one embodiment, for example, when administered as a PEP, the tablets disclosed herein are administered for 30 days after an event that increases the risk of an individual acquiring HIV (e.g., after sexual intercourse or other exposure to the HIV virus). In some embodiments, the tablets disclosed herein are administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 18, 24, 36, or less than 48 hours after an event that increases the risk of an individual acquiring HIV (e.g., after sexual intercourse or other exposure to the HIV virus). In other embodiments, the tablets disclosed herein are administered for 1, 2, 3, or 5 days after an event that increases the risk of an individual acquiring HIV (e.g., after sexual intercourse or other exposure to the HIV virus). In some embodiments, when the tablets disclosed herein are administered after an event that increases the risk of an individual acquiring HIV, they are administered daily after the event. In some embodiments, when the tablets disclosed herein are administered after an event that increases the risk of an individual acquiring HIV, they are administered one to three times after the event. In some embodiments, when the tablets disclosed herein are administered after an event that increases the risk of an individual acquiring HIV, they are administered once after the event.

[0226] In some embodiments, when administered as, for example, PrEP, the tablets disclosed herein are administered before (e.g., before sexual intercourse) and after an event that increases the risk of an individual acquiring HIV. For example, in some embodiments, when administered as, for example, PrEP, the tablets disclosed herein are administered 2 to 72 hours, 2 to 48 hours, 2 to 24 hours, or 2 to 12 hours before an event that increases the risk of an individual acquiring HIV (e.g., sexual intercourse), and 2 to 48 hours, 2 to 36 hours, 2 to 24 hours, or 2 to 12 hours after the event. For example, in some embodiments, one or more (e.g., one, two, or three) tablets disclosed herein are administered 1 to 3 days before an event that increases the risk of an individual acquiring HIV (e.g., sexual intercourse) and once daily for a period of 1 to 5 days after the event. In some embodiments, one or more (e.g., one, two, or three) tablets disclosed herein are administered 2 to 24 hours before an event that increases the risk of an individual acquiring HIV (e.g., sexual intercourse) and one or more times (e.g., one, two, or three times) 2 to 48 hours after the event. In some embodiments, tablets disclosed herein are administered once, twice, three, four, or five times per week, and one or more times (e.g., one, two, or three times) 2 to 48 hours after an event that increases the risk of an individual acquiring HIV (e.g., sexual intercourse). In one embodiment, tablets disclosed herein are administered twice per week (one composition (i.e., one tablet) per day) and once after an event that increases the risk of an individual acquiring HIV (one composition) (e.g., one tablet within 24 hours of exposure, such as after sexual intercourse).

[0227] In some embodiments, the tablets are administered once daily. In some embodiments, the administration is followed by a loading dose of lenacapavir or a pharmaceutically acceptable salt equivalent to about 1200 mg of lenacapavir free acid. This loading dose may be administered over several days. In some embodiments, this loading dose is administered over two days. In one embodiment, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid is administered on day 1, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid is administered on day 2.

[0228] In some embodiments, this loading dose is administered over eight days. In one embodiment, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid is administered on day 1, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid is administered on day 2, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 300 mg of lenacapavir free acid is administered on day 8.

[0229] A single-layer tablet containing 75 mg of bictegravir and 50 mg of lenacapavir. In one embodiment, the disclosure provides a single-layer tablet comprising an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof.

[0230] The single-layer tablets may further contain copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0231] This single-layer tablet may have the following composition: approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof, approximately 10-20% w / w lenacapavir or a pharmaceutically acceptable salt thereof, approximately 1-5% w / w copovidone, approximately 0.1-2% w / w poloxamer, approximately 30-50% w / w mannitol, approximately 10-30% w / w microcrystalline cellulose, approximately 5-15% w / w croscarmellose sodium, and approximately 0.1-10% w / w magnesium stearate.

[0232] More specifically, this single-layer tablet may have the following composition: approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof, approximately 10-20% w / w lenacapavir or a pharmaceutically acceptable salt thereof, approximately 1-3% w / w copovidone, approximately 0.3-0.8% w / w poloxamer, approximately 35-45% w / w mannitol, approximately 15-25% w / w microcrystalline cellulose, approximately 6-10% w / w croscarmellose sodium, and approximately 1-2% w / w magnesium stearate.

[0233] More specifically, this single-layer tablet may have the following composition: approximately 15-20% w / w bictegravir or a pharmaceutically acceptable salt thereof, approximately 10-14% w / w lenacapavir or a pharmaceutically acceptable salt thereof, approximately 2-3% w / w copovidone, approximately 0.6-0.8% w / w poloxamer, approximately 35-40% w / w mannitol, approximately 18-22% w / w microcrystalline cellulose, approximately 7-9% w / w croscarmellose sodium, and approximately 1-2% w / w magnesium stearate.

[0234] More specifically, this single-layer tablet may have the following composition: approximately 18% w / w bictegravir or a pharmaceutically acceptable salt thereof, approximately 12% w / w lenacapavir or a pharmaceutically acceptable salt thereof, approximately 2.8% w / w copovidone, approximately 0.8% w / w poloxamer, approximately 38% w / w mannitol, approximately 19% w / w microcrystalline cellulose, approximately 8% w / w croscarmellose sodium, and approximately 1.5% w / w magnesium stearate.

[0235] The single-layer tablet may comprise about 5 to 15 mg of copovidone, about 0.5 to 5 mg of poloxamer, about 150 to 200 mg of mannitol, about 70 to 100 mg of microcrystalline cellulose, about 25 to 50 mg of croscarmellose sodium, and about 5 to 10 mg of magnesium stearate.

[0236] More specifically, the single-layer tablet may comprise about 10 to 15 mg of copovidone, about 2 to 5 mg of poloxamer, about 150 to 175 mg of mannitol, about 75 to 90 mg of microcrystalline cellulose, about 30 to 40 mg of croscarmellose sodium, and about 5 to 8 mg of magnesium stearate.

[0237] Even more specifically, the single-layer tablet may comprise about 12 mg of copovidone, about 3 mg of poloxamer, about 165 mg of mannitol, about 83 mg of microcrystalline cellulose, about 35 mg of croscarmellose sodium, and about 7 mg of magnesium stearate.

[0238] Any of the single-layer tablets disclosed above in this section may be coated or uncoated. In some embodiments, the tablet is coated. The coating is a film coating. In some embodiments, the coating is a non-functional film coating. In some embodiments, the tablet is coated with a titanium dioxide-free film coating.

[0239] Any of the single-layer tablets disclosed above in this section may have a weight of about 410 to 1460 mg excluding the film coating, for example, about 430 to 440 mg excluding the film coating.

[0240] This single-layer tablet may contain bictegravir free acid or a pharmaceutically acceptable salt of bictegravir. In one embodiment, the single-layer tablet contains a pharmaceutically acceptable salt of bictegravir. In one embodiment, the pharmaceutically acceptable salt of bictegravir is bictegravir sodium, i.e., the single-layer tablet contains about 79 mg of bictegravir sodium.

[0241] The single-layer tablet may contain lenacapavir free acid or a pharmaceutically acceptable salt of lenacapavir. In one embodiment, the single-layer tablet contains a pharmaceutically acceptable salt of lenacapavir. In some embodiments, the pharmaceutically acceptable salt of lenacapavir is lenacapavir sodium, i.e., the single-layer tablet contains approximately 51 mg of lenacapavir sodium.

[0242] In one embodiment, lenacapavir or a pharmaceutically acceptable salt thereof in the above-mentioned single-layer tablet is present in a spray-dried dispersion.

[0243] This single-layer tablet can release at least about 50% of bictegravir or a pharmaceutically acceptable salt in about 30 minutes, as measured using a USP instrument II, in 250 mL of fasted-state simulated intestinal fluid at pH 6.5 at 37°C and a paddle speed of 75 rpm. Furthermore, this single-layer tablet can release at least about 50% of lenacapavir or a pharmaceutically acceptable salt in about 15 minutes, as measured using a USP instrument II, in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0 at 37°C and a paddle speed of 75 rpm. In one embodiment, this single-layer tablet can release at least about 70% of lenacapavir or a pharmaceutically acceptable salt in about 15 minutes. In one embodiment, this single-layer tablet can release at least about 80% of lenacapavir or a pharmaceutically acceptable salt in about 15 minutes.

[0244] This monolayer tablet is provided for use in the therapeutic or prophylactic treatment of HIV infection in subjects. For example, the monolayer tablet may be used to treat HIV infection. Alternatively, the monolayer tablet may be used to prevent HIV infection. The monolayer tablet may be used in pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) to prevent HIV infection.

[0245] In some embodiments, the subject to be treated is virologically suppressed. The subject may or may not have received treatment. In some embodiments, the subject has received treatment. The above-described monolayer tablets are provided for use in the treatment of HIV infection in virologically suppressed, treatment-receiving patients.

[0246] Generally, this single-layer tablet may be administered once daily. In some embodiments, administration follows a loading dose of lenacapavir or a pharmaceutically acceptable salt equivalent to about 1200 mg of lenacapavir free acid. This loading dose may be administered over several days, and in some embodiments, over two days. For example, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid may be administered on day 1, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid may be administered on day 2.

[0247] In some embodiments, this loading dose is administered over eight days. In one embodiment, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid is administered on day 1, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid is administered on day 2, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 300 mg of lenacapavir free acid is administered on day 8.

[0248] A two-layer tablet containing 75 mg of bictegravir and 25 mg of lenacapavir. In one embodiment, the disclosure provides a two-layer tablet containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof. In some embodiments, the two-layer tablet comprises (a) a first layer containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and (b) a second layer containing an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof. In some embodiments, the first layer is substantially free of lenacapavir or a pharmaceutically acceptable salt thereof, and the second layer is substantially free of bictegravir or a pharmaceutically acceptable salt thereof.

[0249] This two-layer tablet may further contain copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0250] The first layer of a two-layer tablet may contain bictegravir or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The first layer may contain mannitol, for example, in a weight ratio of mannitol to microcrystalline cellulose of about 2:1 to about 1:2, for example, about 2:1, about 1:1, or about 1:2. In some embodiments, the first layer of the two-layer tablet is substantially mannitol-free (i.e., contains less than 1% w / w mannitol, and in some embodiments, mannitol-free). In some embodiments, microcrystalline cellulose is the sole filler in the first layer. The second layer of the two-layer tablet may contain lenacapavir or a pharmaceutically acceptable salt thereof, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0251] In some embodiments, the two-layer tablet comprises a first layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, and a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 mg of lenacapavir free acid, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, the first layer of the two-layer tablet is substantially mannitol-free (i.e., contains less than about 1% w / w of mannitol, and in some embodiments, mannitol-free).

[0252] This two-layer tablet may have the following composition: approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof, approximately 5-20% w / w lenacapavir or a pharmaceutically acceptable salt thereof, approximately 0.1-5% w / w copovidone, approximately 0.1-2% w / w poloxamer, approximately 5-30% w / w mannitol, approximately 30-60% w / w microcrystalline cellulose, approximately 5-20% w / w croscarmellose sodium, and approximately 0.1-5% w / w magnesium stearate.

[0253] More specifically, this two-layer tablet may have the following composition: approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof, approximately 5-20% w / w lenacapavir or a pharmaceutically acceptable salt thereof, approximately 1-3% w / w copovidone, approximately 0.3-0.8% w / w poloxamer, approximately 10-25% w / w mannitol, approximately 40-60% w / w microcrystalline cellulose, approximately 6-10% w / w croscarmellose sodium, and approximately 1-2% w / w magnesium stearate.

[0254] More specifically, this two-layer tablet may have the following composition: approximately 15-20% w / w bictegravir or a pharmaceutically acceptable salt thereof, approximately 5-10% w / w lenacapavir or a pharmaceutically acceptable salt thereof, approximately 1-3% w / w copovidone, approximately 0.3-0.8% w / w poloxamer, approximately 10-25% w / w mannitol, approximately 45-55% w / w microcrystalline cellulose, approximately 6-10% w / w croscarmellose sodium, and approximately 1-2% w / w magnesium stearate. For example, the first layer may contain approximately 10-25% w / w bictegravir or The first layer contains a pharmaceutically acceptable salt thereof, about 40-50% w / w of microcrystalline cellulose, about 1-10% w / w of croscarmellose sodium, and about 0.1-3% w / w of magnesium stearate. The second layer contains about 5-20% w / w of lenacapavir or a pharmaceutically acceptable salt thereof, about 0.1-5% w / w of copovidone, about 0.1-2% w / w of poloxamer, about 5-20% w / w of mannitol, about 1-10% w / w of microcrystalline cellulose, about 1-10% w / w of croscarmellose sodium, and about 0.1-1% w / w of magnesium stearate. In these embodiments, weight percentages represent the proportion of the entire tablet.

[0255] More specifically, this two-layer tablet may have the following composition: approximately 18% w / w bictegravir or a pharmaceutically acceptable salt thereof, approximately 6% w / w lenacapavir or a pharmaceutically acceptable salt thereof, approximately 1.4% w / w copovidone, approximately 0.4% w / w poloxamer, approximately 12.5% ​​w / w mannitol, approximately 51.7% w / w microcrystalline cellulose, approximately 8% w / w croscarmellose sodium, and approximately 1.5% w / w magnesium stearate. In some embodiments, the first layer comprises about 18% w / w bictegravir or a pharmaceutically acceptable salt thereof, about 45% w / w microcrystalline cellulose, about 6% w / w croscarmellose sodium, and about 1% w / w magnesium stearate, and the second layer comprises about 6% w / w lenacapavir or a pharmaceutically acceptable salt thereof, about 1.4% w / w copovidone, about 0.4% w / w poloxamer, about 12.5% ​​w / w mannitol, about 6% w / w microcrystalline cellulose, and about 0.4% w / w magnesium stearate. In these embodiments, weight percentages represent the proportion of the entire tablet.

[0256] These two-layer tablets may contain approximately 5-15 mg of copovidone, approximately 0.5-5 mg of poloxamer, approximately 50-125 mg of mannitol, approximately 200-250 mg of microcrystalline cellulose, approximately 30-50 mg of croscarmellose sodium, and approximately 5-10 mg of magnesium stearate.

[0257] For example, the first layer of the above two-layer tablet may further contain approximately 185-200 mg of microcrystalline cellulose, approximately 20-30 mg of croscarmellose sodium, and approximately 3-5 mg of magnesium stearate.

[0258] More specifically, the first layer of the two-layer tablet may further comprise about 193 mg of microcrystalline cellulose, about 24 mg of croscarmellose sodium, and about 5 mg of magnesium stearate. Even more specifically, the first layer may further comprise about 193.0 mg of microcrystalline cellulose, about 24.0 mg of croscarmellose sodium, and about 4.5 mg of magnesium stearate. The first layer may also contain mannitol. In some embodiments, the first layer of the two-layer tablet does not contain any fillers other than microcrystalline cellulose.

[0259] The second layer of the above two-layer tablet may further comprise about 5 to 8 mg of copovidone, about 1 to 3 mg of poloxamer, about 45 to 60 mg of mannitol, about 20 to 30 mg of microcrystalline cellulose, about 5 to 15 mg of croscarmellose sodium, and about 1 to 3 mg of magnesium stearate.

[0260] More specifically, the second layer of the above two-layer tablet may further comprise about 6 mg of copovidone, about 2 mg of poloxamer, about 53 mg of mannitol, about 27 mg of microcrystalline cellulose, about 10 mg of croscarmellose sodium, and about 2 mg of magnesium stearate.

[0261] Even more specifically, the second layer of the above two-layer tablet may further comprise about 6.1 mg of copovidone, about 1.7 mg of poloxamer, about 53.2 mg of mannitol, about 26.6 mg of microcrystalline cellulose, about 10.0 mg of croscarmellose sodium, and about 1.9 mg of magnesium stearate.

[0262] In some embodiments, a two-layer tablet may have the following composition: a first layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, about 175-210 mg of microcrystalline cellulose, about 15-35 mg of croscarmellose sodium, and about 1-10 mg of magnesium stearate; and a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 mg of lenacapavir free acid, about 1-10 mg of copovidone, about 1-6 mg of poloxamer, about 30-75 mg of mannitol, about 15-40 mg of microcrystalline cellulose, about 1-20 mg of croscarmellose sodium, and about 1-10 mg of magnesium stearate.

[0263] More specifically, the above two-layer tablet may have the following composition: a first layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, about 185-200 mg of microcrystalline cellulose, about 20-30 mg of croscarmellose sodium, and about 3-5 mg of magnesium stearate; and a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 mg of lenacapavir free acid, about 5-8 mg of copovidone, about 1-3 mg of poloxamer, about 45-60 mg of mannitol, about 20-30 mg of microcrystalline cellulose, about 5-15 mg of croscarmellose sodium, and about 1-3 mg of magnesium stearate.

[0264] More specifically, the above two-layer tablet may have the following composition: a first layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, about 193 mg of microcrystalline cellulose, about 24 mg of croscarmellose sodium, and about 5 mg of magnesium stearate; and a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 mg of lenacapavir free acid, about 6 mg of copovidone, about 2 mg of poloxamer, about 53 mg of mannitol, about 27 mg of microcrystalline cellulose, about 10 mg of croscarmellose sodium, and about 2 mg of magnesium stearate.

[0265] More specifically, the above two-layer tablet may have the following composition: a first layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, about 193.0 mg of microcrystalline cellulose, about 24.0 mg of croscarmellose sodium, and about 4.5 mg of magnesium stearate; and a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 25 mg of lenacapavir free acid, about 6.1 mg of copovidone, about 1.7 mg of poloxamer, about 53.2 mg of mannitol, about 26.6 mg of microcrystalline cellulose, about 10.0 mg of croscarmellose sodium, and about 1.9 mg of magnesium stearate.

[0266] None of the two-layer tablets disclosed in this section may be coated or uncoated. In some embodiments, the two layers are coated. In some embodiments, the coating is a film coating. In some embodiments, the coating is a non-functional film coating.

[0267] Any of the two-layer tablets disclosed in this section may weigh approximately 400–450 mg excluding the film coating, for example, approximately 420–430 mg excluding the film coating.

[0268] The two-layer tablet may contain bictegravir free acid or a pharmaceutically acceptable salt of bictegravir. In some embodiments, the two-layer tablet contains a pharmaceutically acceptable salt of bictegravir. In some embodiments, the pharmaceutically acceptable salt of bictegravir is bictegravir sodium, i.e., the two-layer tablet contains about 79 mg of bictegravir sodium.

[0269] The two-layer tablet may contain lenacapavir free acid or a pharmaceutically acceptable salt of lenacapavir. In some embodiments, the two-layer tablet contains a pharmaceutically acceptable salt of lenacapavir. In some embodiments, the pharmaceutically acceptable salt of lenacapavir is lenacapavir sodium, i.e., the two-layer tablet contains approximately 26 mg of lenacapavir sodium.

[0270] In some embodiments, lenacapavir or a pharmaceutically acceptable salt thereof in the above-described two-layer tablet is present in a spray-dried dispersion.

[0271] The above two-layer tablets may release at least about 50% of bictegravir or a pharmaceutically acceptable salt in about 30 minutes, as measured using a USP instrument II, in 250 mL of fasted-state simulated intestinal fluid at pH 6.5 at 37°C and a paddle speed of 75 rpm. In some embodiments, the above two-layer tablets may release at least about 60% of bictegravir or a pharmaceutically acceptable salt in about 30 minutes. In addition, the above two-layer tablets may release at least about 50% of lenacapavir or a pharmaceutically acceptable salt in about 15 minutes, as measured using a USP instrument II, in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0 at 37°C and a paddle speed of 75 rpm. In some embodiments, the above two-layer tablets may release at least about 70% of lenacapavir or a pharmaceutically acceptable salt in about 15 minutes. In some embodiments, the two-layer tablet described above may release at least about 80% of lenacapavir or a pharmaceutically acceptable salt thereof in about 15 minutes.

[0272] A two-layer tablet containing 75 mg of bictegravir and 50 mg of lenacapavir. In one embodiment, the disclosure provides a two-layer tablet containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof. In some embodiments, the two-layer tablet comprises (a) a first layer containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and (b) a second layer containing an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof. In some embodiments, the first layer is substantially free of lenacapavir or a pharmaceutically acceptable salt thereof, and the second layer is substantially free of bictegravir or a pharmaceutically acceptable salt thereof.

[0273] This two-layer tablet may further contain copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0274] The first layer of a two-layer tablet may contain bictegravir or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The first layer may contain mannitol, for example, in a weight ratio of mannitol to microcrystalline cellulose of about 2:1 to about 1:2, for example, about 2:1, about 1:1, or about 1:2. In some embodiments, the first layer of the two-layer tablet is substantially mannitol-free (i.e., contains less than about 11% w / w mannitol, and in some embodiments, mannitol-free). In some embodiments, microcrystalline cellulose is the sole filler in the first layer. The second layer of the two-layer tablet may contain lenacapavir or a pharmaceutically acceptable salt thereof, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0275] In some embodiments, a two-layer tablet comprises a first layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, and a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 50 mg of lenacapavir free acid, copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0276] The two-layer tablets are provided for use in the therapeutic or prophylactic treatment of HIV infection in a subject. For example, the two-layer tablets may be used to treat HIV infection, or they may be used to prevent HIV infection. Single-layer tablets may be used in pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) to prevent HIV infection.

[0277] In some embodiments, the subject to be treated is virologically suppressed. The subject may or may not have received treatment. In some embodiments, the subject has received treatment. In some embodiments, the above-described two-layer tablet is provided for use in the treatment of HIV infection in virologically suppressed patients. In some embodiments, the above-described two-layer tablet is provided for use in the treatment of HIV infection in virologically suppressed, treatment-receiving patients.

[0278] Generally, the two-layer tablets may be administered once daily. In some embodiments, administration is followed by a loading dose of lenacapavir or a pharmaceutically acceptable salt equivalent to about 1200 mg of lenacapavir free acid. This loading dose may be administered over several days. In some embodiments, this loading dose is administered over two days. For example, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid may be administered on day 1, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid may be administered on day 2.

[0279] In some embodiments, this loading dose is administered over eight days. In one embodiment, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid is administered on day 1, an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 600 mg of lenacapavir free acid is administered on day 2, and an amount of lenacapavir or a pharmaceutically acceptable salt equivalent to about 300 mg of lenacapavir free acid is administered on day 8.

[0280] definition For example, the term “substantially absent” with respect to the presence of a given component in a composition means that the given component is present in less than 5% by weight of the composition (e.g., less than 1% by weight of the composition). The word “substantially” does not exclude “completely.” For example, a composition that “substantially absent” Y does not have to completely absent Y. Where necessary, the word “substantially” may be omitted from the definitions in this disclosure.

[0281] The term "comprise" and its variations, such as "comprises" and "comprising," should be interpreted in an open and inclusive sense, meaning "including, but not limited to."

[0282] The term "~" in relation to two values ​​includes those two values. For example, the range "10mg~20mg" includes, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20mg.

[0283] Where used herein, the term “about” is understood by those skilled in the art to reflect the variability of the numerical value it modifies. Values ​​expressed herein are understood to include a range of variation. To reflect this variability, any numerical value used herein incorporates this variability. Thus, numerical values ​​used herein encompass the stated values ​​as well as values ​​modified with “about.” In some embodiments, the term “about” in relation to a numerical value x is optional, for example, x + 10%, x + 5%, or x + It means 1%.

[0284] "%w / w" refers to the weight of a component as a percentage of the total weight of the dosage form in which the component is present. For example, a composition containing "5%w / w X" refers to a composition in which the weight of component X accounts for 5% of the total weight of the composition.

[0285] Throughout this specification, any reference to “one embodiment” or “embodiment” means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment provided herein. Therefore, occurrences of the phrase “in one embodiment” or “in an embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments.

[0286] The term "pharmaceutically acceptable" in relation to a substance generally refers to a substance that is considered safe, free from excessive toxicity, irritation, or allergic reactions, and suitable for use in proportion to a reasonable benefit-to-risk ratio.

[0287] "Pharmacologically acceptable salts" refer to salts of compounds that are pharmaceutically acceptable and have (or can be converted into) a form having the desired pharmacological activity of the parent compound. Examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, and trimethylacetic acid; salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinations with organic bases such as diethanolamine, triethanolamine, and N-methylglucamine. This definition also includes ammonium and substituted or quaternized ammonium salts. Representative, non-restrictive lists of pharmaceutically acceptable salts can be found in SMBerge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Table 38-5, both of which are incorporated herein by reference.

[0288] As used herein, the term “salts” includes cocrystals. The term “cocrystal” refers to a crystalline compound containing two or more molecular components, for example, in which proton transfer between the molecular components is partial or incomplete. Thus, as used herein, the term “pharmaceutically acceptable salt” encompasses salts and cocrystals as defined herein.

[0289] The term "solvate" refers to a molecular complex containing a compound and one or more pharmaceutically acceptable solvent molecules. Examples of solvent molecules include water and C. 1~6 Alcohols, such as ethanol, are examples. When the solvate is water, the term "hydrate" can be used.

[0290] "To treat" a disease and "treatment" of a disease include (1) and (2) below. (1) inhibiting the disease, that is, preventing or reducing the onset of the disease or its clinical symptoms, and (2) To alleviate the disease, that is, to cause regression of the disease or its clinical symptoms.

[0291] The term "effective dose" refers to the amount of a compound that, when administered to a subject to treat a disease, is sufficient to achieve such treatment of the disease and is effective in eliciting a desired biological or medical response. The effective dose varies depending on the compound, the disease and its severity, as well as the age and weight of the subject being treated. The effective dose may include a range of amounts.

[0292] Disease "prevention" and "prevention" mean preventing or reducing the risk of developing a disease, that is, preventing the development of clinical symptoms of a disease in a person who may be exposed to or susceptible to the disease but has not yet experienced or shown symptoms of the disease.

[0293] The term "virologically suppressed" as used in reference to human patients with HIV infection means that antiretroviral therapy (ART) has reduced the patient's serum HIV RNA level (viral load) to less than 50 copies / mL or below the detection limit. Viral suppression does not mean that the person is cured. If ART is discontinued, the person's HIV viral load is likely to return to a detectable level.

[0294] The term "treatment experience," as used in reference to human patients with HIV infection, means that the patient has previously taken one or more forms of HIV medication. Embodiments of the present invention The present invention provides embodiments numbered as follows: 1. A tablet comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to approximately 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to approximately 50 mg of lenacapavir free acid. 2. A tablet according to Embodiment 1, comprising approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof and approximately 5-25% w / w lenacapavir or a pharmaceutically acceptable salt thereof. 3. The tablet according to Embodiment 1 or Embodiment 2, wherein bictegravir or a pharmaceutically acceptable salt thereof is bictegravir sodium. 4. A tablet according to any one of Embodiments 1 to 3, comprising approximately 79 mg of bictegravir sodium. 5. A tablet according to any one of Embodiments 1 to 4, wherein the pharmaceutically acceptable salt thereof is lenacapavir sodium. 6. A tablet according to any one of Embodiments 1 to 5, comprising approximately 51 mg of lenacapavir sodium. 7. A tablet according to any one of Embodiments 1 to 6, comprising copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. 8. A tablet according to Embodiment 7, comprising approximately 5-15 mg of copovidone, approximately 0.5-10 mg of poloxamer, approximately 50-200 mg of mannitol, approximately 50-250 mg of microcrystalline cellulose, approximately 25-50 mg of croscarmellose sodium, and approximately 1-10 mg of magnesium stearate, and optionally comprising approximately 10-15 mg of copovidone, approximately 2-5 mg of poloxamer, approximately 150-175 mg of mannitol, approximately 75-90 mg of microcrystalline cellulose, approximately 30-40 mg of croscarmellose sodium, and approximately 5-8 mg of magnesium stearate. 9. The tablet according to any one of Embodiments 1 to 8, wherein the tablet is coated with a film coating, preferably a non-functional film coating. 10. The tablet according to Embodiment 9, which is coated with a film coating that does not contain titanium dioxide. 11. A tablet according to Embodiment 9 or Embodiment 10, having a weight of approximately 430-440 mg excluding the film coating. 12. A tablet according to any one of Embodiments 1 to 11 for use in the therapeutic or prophylactic treatment of HIV infection in a subject. 13. A tablet for use according to Embodiment 12, wherein the subject is virologically suppressed. 14. A tablet for use as described in Embodiment 13, for subjects experiencing treatment. 15. A tablet for use according to any one of embodiments 12 to 14, administered once daily after a loading dose of lenacapavir or a pharmaceutically acceptable salt equivalent to approximately 1200 mg of lenacapavir free acid. [Examples]

[0295] This disclosure is illustrated by the following non-limiting embodiments. Example 1 - BIC 75mg tablets for comparison

[0296] A comparative tablet containing 75 mg of bictegravir with the following composition was prepared. [Table 1] a This is equivalent to 75 mg of bictegravir free acid. b Opadry II Yellow 85F92259 contains 40.0% w / w polyvinyl alcohol (USP / Ph.Eur), 23.3% w / w titanium dioxide (USP / Ph.Eur), 20.2% w / w polyethylene glycol / macrogol 3350 (USP / Ph.Eur), 14.8% w / w talc (USP / Ph.Eur), and 1.7% w / w iron oxide yellow (NF). c This represents a theoretical weight increase of 4% (in the range of 3-5%). d The BIC tablets are film-coated using purified water and removed during the coating process.

[0297] Bictegravir (BIC) tablets were manufactured through a series of unit operations, as summarized in the manufacturing process flow chart in Figure 1. First, bictegravir was blended with granular excipients (microcrystalline cellulose, lactose monohydrate, and crospovidone). The mixture was blended with a portion of a lubricant (sodium stearyl fumarate), rolled, compressed, and ground. The resulting granules were then blended with the remaining lubricant (sodium stearyl fumarate). The final blend was compressed into tablet cores. The tablet cores were film-coated yellow and packaged. Example 2 - Comparative LEN 25 mg and 50 mg tablets

[0298] Comparative tablets containing 25 mg and 50 mg of lenacapavir with the following composition were manufactured. [Table 2] a This is equivalent to 25 mg of free lenacapavir acid. b This is equivalent to 50 mg of free lenacapavir acid. cOpadry II Green 85F110187 contains 40.00% w / w polyvinyl alcohol (USP / PhEur), 20.86% w / w titanium dioxide (USP / PhEur), 20.20% w / w macrogol / PEG 3350 (NF / PhEur), 14.80% w / w talc (USP / PhEur), 3.32% w / w yellow iron oxide (NF), and 0.82% w / w black iron oxide (NF). d This represents a theoretical weight increase of 4% (in the range of 3-5%). e The LEN tablets are film-coated using purified water and removed during the coating process.

[0299] As summarized in the manufacturing process flow diagram in Figure 2, lenacapavir (LEN) tablets were manufactured through a series of unit operations. First, lenacapavir sodium and excipients in solution were spray-dried and then secondary-dried to form a lenacapavir spray-dried dispersion. The lenacapavir spray-dried dispersion was blended with granular excipients and then ground / dispersed. The mixture was blended with a portion of the lubricant, roller-compressed, and ground. The resulting granules were then blended with the remaining lubricant. The final blend was compressed into tablet cores. The tablet cores were film-coated green and packaged. Example 3 - Monolayer BIC / LEN tablets (75 / 25mg, 75 / 50mg, 75 / 75mg, and 75 / 100mg)

[0300] For comparison with combinations of tablets containing single drugs, monolayer tablets containing bictegravir and lenacapavir were prepared. The compositions of the bictegravir / lenacapavir 75 / 25 mg, 75 / 50 mg, 75 / 75 mg, and 75 / 100 mg monolayer fixed-dose combination tablets evaluated were as follows: [Table 3] a This is equivalent to 75 mg of bictegravir free acid. b This is equivalent to 25 mg of free lenacapavir acid. c This is equivalent to 50 mg of free lenacapavir acid. d This is equivalent to 75 mg of free lenacapavir acid. e This is equivalent to 100 mg of free lenacapavir acid. f Use Opadry II Brown 85F86937. Opadry II Brown 85F86937 contains 40.0% w / w polyvinyl alcohol (USP / Ph.Eur), 20.2% w / w polyethylene glycol / macrogol 3350 (USP / Ph.Eur), 19.0% w / w titanium dioxide (USP / Ph.Eur), 14.8% w / w talc (USP / Ph.Eur), and 6.0% w / w red iron oxide (NF). g Use Opadry II Yellow 85F520107. Opadry II Yellow 85F520107 contains 40.0% w / w polyvinyl alcohol (USP / Ph.Eur), 22.6% w / w titanium dioxide (USP / Ph.Eur), 20.2% w / w polyethylene glycol / macrogol 3350 (USP / Ph.Eur), 14.8% w / w talc (USP / Ph.Eur), and 2.4% w / w iron oxide yellow (NF). h This represents a theoretical weight increase of 4% (within the range of 2-6%). i BIC / LEN tablets are film-coated using purified water and removed during the coating process.

[0301] As summarized in the manufacturing process flow diagram of Figure 3, bictegravir / lenacapavir (BIC / LEN) monolayer tablets were manufactured through a series of unit operations. First, lenacapavir sodium and excipients in solution were spray-dried and then secondary-dried to form a lenacapavir spray-dried dispersion. The bictegravir sodium and lenacapavir spray-dried dispersion was mixed with granular excipients and then ground / dispersed. The mixture was blended with a portion of the lubricant, roller-compressed, and ground. The resulting granules were then blended with the remaining lubricant. The final blend was compressed into tablet cores. The tablet cores were film-coated in brown or yellow and packaged. Example 4 - Two-layer BIC / LEN tablets (75 / 25 mg and 75 / 50 mg)

[0302] For comparison with single-drug tablet combinations, two-layer tablets containing a first layer of bictegravir and a second layer of lenacapavir were prepared. The compositions of the evaluated bictegravir / lenacapavir 75 / 25 mg and 75 / 50 mg two-layer fixed-dose tablet formulations were as follows: [Table 4] a This is equivalent to 75 mg of bictegravir free acid. b This is equivalent to 25 mg of free lenacapavir acid. c This is equivalent to 50 mg of free lenacapavir acid. d Opadry II Yellow 85F520107 contains 40.0% w / w polyvinyl alcohol (USP / Ph.Eur), 22.6% w / w titanium dioxide (USP / Ph.Eur), 20.2% w / w polyethylene glycol / macrogol 3350 (USP / Ph.Eur), 14.8% w / w talc (USP / Ph.Eur), and 2.4% w / w iron oxide yellow (NF). e This shows a theoretical weight increase of 4% (in the range of 2-6%). fBIC / LEN tablets are film-coated using purified water and removed during the coating process.

[0303] As summarized in the manufacturing process flow diagram in Figure 4, bictegravir / lenacapavir (BIC / LEN) bilayer tablets were manufactured through a series of unit operations.

[0304] First, the lenacapavir sodium and excipients in solution were spray-dried, followed by secondary drying to form a lenacapavir spray-dried dispersion. The lenacapavir spray-dried dispersion was blended with the granular excipients and then ground / dispersed. The mixture was blended with a portion of the lubricant, roll-compressed, and ground. The resulting granules were then blended with the remaining lubricant to obtain the final LEN blend for compression.

[0305] Bictegravir sodium was blended with the granular excipient and then ground / dispersed. The mixture was blended with a portion of the lubricant, roll-compressed, and ground. The resulting granules were then blended with the remaining lubricant to obtain the final BIC blend for compression.

[0306] The final blend of BIC and LEN was compressed into a two-layer tablet to obtain a BIC / LEN tablet core, which was then coated with a yellow film and packaged. Example 5 - BIC non-sink elution (FaSSIF)

[0307] The elution of bictegravir in a biomedical medium was determined as a function of time. A single tablet was placed in 250 mL of 3.75 mM fasting-simulated intestinal fluid (FaSSIF) (3 mM taurocholic acid, 0.75 mM lecithin, 0.10 M NaCl) at pH 6.5 preheated to 37°C and stirred at 75 rpm. Samples (10 mL) were collected at predetermined time points of 0, 5, 10, 15, 20, 30, 45, 60, and 120 minutes. The collected medium was immediately replaced with 10 mL of fresh medium. Each sample was filtered through a 0.22 μm PES filter (Millex-GP Fast Flow & Low Binding Millipore Express), and the first approximately 8 mL of filtrate was discarded. The remaining filtrate was transferred to an amber vial for direct analysis using an appropriate ULC-UV method.

[0308] The dissolution of bictegravir from 75 / 25 mg BIC / LEN monolayer (M1) and bilayer (B1) tablets was compared with the dissolution of bictegravir from a combination of 75 mg BIC (C1) and 25 mg LEN (C2) mono-tablets. The results are shown in Figure 5A, indicating that the dissolution of bictegravir from the bilayer and monolayer tablets was faster than that from the comparator mono-tablets.

[0309] The dissolution of bictegravir from 75 / 50 mg BIC / LEN monolayer (M2) and bilayer (B2) tablets was compared with the dissolution of bictegravir from a combination of 75 mg BIC (C1) and 50 mg LEN (C3) mono-tablets. The results are shown in Figure 5B, indicating that the dissolution of bictegravir from the monolayer tablets was similar to that of the mono-tablets. The dissolution of bictegravir from the bilayer tablets was faster than that from the mono-tablets. Example 6 - LEN non-sink elution (Cremophor)

[0310] The elution of lenacapavir in the associated medium was determined as a function of time. Multiple tablets (the number of tablets was determined so that 300 mg of lenacapavir was added to the system) were placed in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0, preheated to 37°C, and stirred at 75 rpm. Samples (10 mL) were taken at predetermined time points of 0, 10, 15, 20, 25, 30, 45, 60, and 120–125 minutes. Each sample was filtered through a 0.22 μm PES filter (Millex-GP Fast Flow & Low Binding Millipore Express), and the first approximately 8 mL of filtrate was discarded. The remaining filtrate was transferred to an amber vial for direct analysis using an appropriate ULC-UV method.

[0311] The dissolution of lenacapavir from 75 / 25 mg BIC / LEN monolayer (M1) tablets and bilayer (B1) tablets was compared with the dissolution of lenacapavir from a combination of 75 mg BIC (C1) and 25 mg LEN (C2) mono-tablets. The results are shown in Figure 6A, indicating that the dissolution of lenacapavir from monolayer tablets was significantly reduced compared to that of the comparator mono-tablets, while the dissolution of lenacapavir from bilayer tablets was similar to that of the comparator mono-tablets.

[0312] The dissolution of lenacapavir from 75 / 50 mg BIC / LEN monolayer (M2) tablets and bilayer (B2) tablets was compared with the dissolution of lenacapavir from a combination of 75 mg BIC (C1) and 50 mg LEN (C3) mono-tablets. The results are shown in Figure 6B, demonstrating that the dissolution of lenacapavir from the bilayer and monolayer tablets was similar to that of the comparator mono-tablets.

[0313] These results indicate that LEN release from 75 / 25 mg BIC / LEN monolayer tablets is significantly reduced compared to the combination of 75 mg BIC and 25 mg LEN monolayer tablets. However, increasing the amount of lenacapavir from 25 mg to 50 mg in the BIC / LEN monolayer tablet containing 75 mg bictegravir provides LEN release comparable to that observed with the comparative 75 mg BIC monolayer tablet and 50 mg LEN monolayer tablet. Example 7 - Preclinical PK in dogs

[0314] The PK properties of bictegravir and lenacapavir in the monolayer and bilayer tablets of this disclosure were compared with those resulting from combinations of tablets containing the single agent, using the following method.

[0315] Each treatment group consisted of six male, non-naive purebred beagle dogs. At the time of administration, the animals weighed between 6 and 13 kg. The animals were fasted overnight before dose administration and for 4 hours after administration. Each subject was pre-treated with pentagastrinn (6 μg / kg), and 30 minutes later, a tablet containing 75 mg of bictegravir and 25 mg or 50 mg of lenacapavir was administered. Each subject was given 5 mL of water to aid swallowing, followed by an additional 25 mL of water, for a total of 30 mL of water administered with each dose.

[0316] Continuous venous blood samples (approximately 1 mL each) were collected from each animal at 0, 0.25, 0.50, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0, 48.0, 72.0, 96.0, and 120.0 hours after administration. Blood samples were collected in Vacutainer® tubes containing K2EDTA as an anticoagulant and immediately placed on moist ice until centrifugation for plasma. The concentrations of the test compounds in plasma were measured using LC / MS / MS. A 20 μL aliquot of each plasma sample was added to a clean 96-well plate, and 120 μL of 50 nM GS-833737 and 100 ng / mL carbamazeprine in acetonitrile (ACN) was added. After protein precipitation, 100 μL of the supernatant was transferred to a clean 96-well plate and diluted with 100 μL of water. 0.5–1.5 μL aliquots of the above solution were injected into an Applied Biosystems API-6500 LC / MS / MS system. A Waters Acquity UPLC system with a sample organizer was used for sample injection, elution, and separation. An API-6500 triple quadrupole mass spectrometer was used in multiple reaction monitoring mode (Sciex, Framingham, MA).

[0317] For the analysis of bictegravir concentration, the system utilized a Waters HSS T3 UPLC column (50 × 2.1 mm, 2.5 μm). Liquid chromatography was performed using two mobile phases: mobile phase A contained 100 / 0.1 v / v% water / formic acid, and mobile phase B contained 100 / 0.1 v / v% acetonitrile / formic acid.

[0318] For the analysis of lenacapavir concentration, the system utilized a Waters BEH C8 UPLC column (50 × 2.1 mm, 1.7 μm). Liquid chromatography was performed using two mobile phases: mobile phase A contained 50 / 25 / 25 / 0.1 v / v% water / acetonitrile / methanol / formic acid, and mobile phase B contained 50 / 50 / 0.1 v / v% acetonitrile / methanol / formic acid.

[0319] Non-compartmental pharmacokinetic analysis was performed on plasma concentration-time data. F(%) refers to oral bioavailability. AUC last This refers to the area under the curve from time zero to the last quantifiable concentration, and is a measure of total plasma exposure to the indicated compound. max This refers to the peak plasma concentration of the compound after administration.

[0320] The PK properties of bictegravir in dogs from the evaluated tablets are shown in the table below. [Table 5]

[0321] The PK properties of lenacapavir in dogs from the evaluated tablets are shown in the table below. [Table 6] Example 8 - Clinical PK in Human Subjects

[0322] The pharmacokinetic (PK) properties of bictegravir and lenacapavir in the monolayer tablets of this disclosure were compared in human subjects with those arising from combinations of tablets containing the individual drugs, using the following method.

[0323] This study was conducted as a phase 1, open-label, multicenter, single-dose, multi-cohort, parallel study in healthy participants to evaluate the relative bioavailability of a fixed-dose BIC / LEN combination tablet. Following completion of screening and evaluation, eligible participants received the study drug on day 1, as described below.

[0324] Cohort 1: Single dose of 1×C1 (BIC 75mg tablet) and 1×C2 (LEN 25mg tablet) administered orally simultaneously to a fasted patient.

[0325] Cohort 2: Single dose of 1xM1 administered orally to a fasted state (BIC / LEN 75 / 25 mg single-layer tablet).

[0326] Cohort 5: Single dose of 1xM2 administered orally to a fasted state (BIC / LEN 75 / 50 mg single-layer tablet).

[0327] Cohort 6: Single dose of 1 x M4 administered orally to a fasted state (BIC / LEN 75 / 100 mg single-layer tablet).

[0328] Cohort 7: Single dose of 1x B1 administered orally to a fasted state (BIC / LEN 75 / 25 mg single-layer tablet).

[0329] All study procedures were administered orally at approximately the same time each morning at the study site, along with 240 mL of water. The study drug was administered in the morning after an overnight fast (no food or drink other than water for at least 10 hours). Participants were restricted from eating until after blood collection, which took place 4 hours after administration. Furthermore, participants were restricted from drinking water 1 hour before and 2 hours after administration, except for the 240 mL of water given with the study procedure(s). After blood collection 4 hours after administration, participants were provided with a meal (a standardized lunch).

[0330] Eligible participants were confined to the testing facility from day -1 until the completion of the evaluation on day 8.

[0331] For each cohort, plasma concentrations and the relevant PK parameters of BIC and LEN were enumerated and summarized using descriptive statistics (where applicable). Two-sided 90% confidence intervals (CIs) were calculated for the ratio of geometric least-squares means (GLSMs) between the test treatment being compared and the reference treatment.

[0332] The PK properties of bictegravir from the evaluated tablets are shown in the table below, as well as in Figures 7A and 7B. [Table 7] * Pharmacokinetic parameters are presented as mean values ​​(%CV). However, T max and T 1 / 2This is presented as the median (interquartile 1, interquartile 3) and is shown with three significant figures. a. For each participant in Cohort 2, the area extrapolated from the last available time point to infinity is the total AUC. inf Because it was over 20%, AUC inf It was excluded.

[0333] The PK properties of lenacapavir from the evaluated tablets are shown in the table below and in Figures 8A and 8B. [Table 8] * Pharmacokinetic parameters are presented as mean values ​​(%CV). However, T max This is presented as the median (interquartile 1, interquartile 3) and is shown with three significant figures. a. For the 11, 16, 2, 9, and 3 participants in cohorts 1, 2, 5, 6, and 7, respectively, the area extrapolated from the last available time point to infinity is the total AUC. inf Because it was over 20%, AUC inf It was excluded. b. For 1, 4, and 2 participants in cohorts 1, 2, and 6, respectively, the Rsq-adjusted value of the regression line was >0.8, therefore, T 1 / 2 It was excluded.

[0334] The results showed that the C15% of bicetegravir from 75 / 100 mg BIC / LEN monolayer tablets (M4) max AUC inf and AUC last However, this shows a decrease compared to the combination of 75mg BIC monotherapy tablet + 25mg LEN monotherapy tablet (C1+C2).

[0335] Furthermore, the results showed the AUC of lenacapavir from 75 / 25 mg BIC / LEN monolayer tablets (M1). 0last However, this shows a decrease compared to simultaneous administration of 75 mg BIC + 25 mg LEN (C1 + C2). In contrast, the AUC of lenacapavir from 75 / 50 mg BIC / LEN monolayer tablets (M2) is shown. lastThis was superior to administration of 25 mg LEN as monotherapy (C2) (approximately 2 to 2.4 times higher). Example 9 - Summary of Preclinical and Clinical Data

[0336] A summary of the preclinical and clinical data discussed in the above examples is provided in the table below. [Table 9] a Dose normalization and linearity are assumed for comparison. Example 10 - Evaluation of the effect of fillers on the manufacturability of BIC layer formulations

[0337] The effect of filler selection in the 75 mg bictegravir layer of a bilayer BIC / LEN tablet formulation was evaluated. Bilayer tablets containing 75 / 25 mg BIC / LEN and 75 / 50 mg BIC / LEN were manufactured, and the bictegravir layer composition was varied as summarized in the table below. The lenacapavir layer composition was manufactured to have the same composition as C2 (75 / 25 mg BIC / LEN tablet) and C3 (75 / 50 mg BIC / LEN tablet). [Table 10] a Filler b Disintegrant c lubricant d IG=intragranular; EG=extragranular e Opadry II Yellow 85F520107 contains 40.0% w / w polyvinyl alcohol (USP / Ph.Eur), 22.6% w / w titanium dioxide (USP / Ph.Eur), 20.2% w / w polyethylene glycol / macrogol 3350 (USP / Ph.Eur), 14.8% w / w talc (USP / Ph.Eur), and 2.4% w / w iron oxide yellow (NF). f BIC / LEN tablets are film-coated using purified water and removed during the coating process.

[0338] First, the lenacapavir sodium and excipients in solution were spray-dried, followed by secondary drying to form a lenacapavir spray-dried dispersion. The lenacapavir spray-dried dispersion was blended with the granular excipients and then ground / dispersed. The mixture was blended with a portion of the lubricant, roll-compressed, and ground. The resulting granules were then blended with the remaining lubricant to obtain the final LEN blend for compression.

[0339] Bictegravir sodium was blended with the granular excipient and then ground / dispersed. The mixture was blended with a portion of the lubricant, roll-compressed, and ground. The resulting granules were then blended with the remaining lubricant to obtain the final BIC blend for compression.

[0340] The final blend of BIC and LEN was compressed into a two-layer tablet to obtain a BIC / LEN tablet core. Manufacturing parameters

[0341] The obtained BIC layer was evaluated across several manufacturing parameters, and the results are shown in the table below. [Table 11] The LEN layer formulation is the same as the LEN single agent (SA) formulation (C1 contains 25 mg of LEN, and C2 contains 50 mg of LEN). b Sticking / filming evaluations were performed for individual BIC blends before compression. These evaluations were conducted at a minimum of 1300 taps on a Korsch XL-100. 1.5% EG Mg St required only 500 taps on the Korsch XL-100. 2:1 and 1:1 mannitol:MCC were evaluated only using a compaction simulator (CS). Stable filming did not accumulate or deteriorate throughout the experiment. cThe final BIC / LEN tablets (i.e., after combining the BIC and LEN layers) were evaluated for their elimination capacity. d Delamination was evaluated on the final BIC / LEN tablet (i.e., after combining the BIC and LEN layers). Delamination was evaluated by hardness testing. This was performed using a CS modeling XL-400, with n=3 tablets / force. The minimum delamination was 1 / 3 tablet / force across the target roller compression range. e Blend characteristics were evaluated for each BIC blend before compression. These characteristics included compressibility profile, tensile strength, flowability, permeability, density, and particle size distribution.

[0342] The results indicate that the use of 100% intragranular MCC and 100% intragranular MCC + 0.5% extragranular Mg St provided BIC layers (K4 and K5) that were stable against filming, required less extrusion, and had acceptable blend characteristics. In contrast, the use of mannitol:MCC filler mixtures (K1, K2, and K3) resulted in significant sticking or filming in the tested formulations. BIC non-sync elution (FaSSIF)

[0343] The elution of bictegravir from 75 / 25 mg BIC / LEN and 75 / 50 mg BIC / LEN bilayer tablets with different BIC layer formulations (K1 / K1' and K4 / K4') was determined as a function of time using the method of Example 5. The results were compared with the elution of bictegravir from the combination of 75 mg BIC + 25 mg LEN (C1 + C2) and 75 mg BIC + 50 mg LEN (C1 + C3) comparison tablets. The results are shown in Figure 9A, indicating that the elution of bictegravir from the 75 / 25 mg BIC / LEN bilayer tablet was higher than that of the comparison 75 mg BIC + 25 mg LEN co-administration, and the elution of bictegravir from the 75 / 50 mg BIC / LEN bilayer tablet was also higher than that of the comparison 75 mg BIC + 50 mg LEN co-administration. LEN non-sync elution (Cremophor)

[0344] The dissolution of lenacapavir from 75 / 25 mg BIC / LEN and 75 / 50 mg BIC / LEN bilayer tablets with different BIC layer formulations (K1 / K1' and K4 / K4') was determined as a function of time using the method of Example 6. The results were compared with the dissolution of lenacapavir from comparative tablet combinations of 75 mg BIC + 25 mg LEN (C1 + C2) and 75 mg BIC + 50 mg LEN (C1 + C3). The results are shown in Figure 9B, indicating that the dissolution of lenacapavir from the 75 / 25 mg BIC / LEN bilayer tablets was equivalent to that of the comparative 75 mg BIC + 25 mg LEN co-administration, and the dissolution of lenacapavir from the 75 / 50 mg BIC / LEN bilayer tablets was equivalent to that of the comparative 75 mg BIC + 50 mg LEN co-administration. Preclinical PK in dogs

[0345] The pharmacokinetic properties of bictegravir and lenacapavir derived from 75 / 25 mg BIC / LEN and 75 / 50 mg BIC / LEN bilayer tablets with different BIC layer formulations (K1 / K1' and K4 / K4') were evaluated using the method described in Example 7. The results are shown in the table below. [Table 12]

[0346] The PK properties of lenacapavir in dogs from the evaluated tablets are shown in the table below. [Table 13] Example 11 - A study to compare bictegravir / renacapavir with current therapies in people with HIV-1 who have successfully received treatment with complex regimens.

[0347] This is a phase 2 / 3 randomized, open-label, multicenter, actively controlled trial to evaluate the safety and efficacy of bictegravir / renacapavir compared to a stable baseline regimen in individuals with virologically suppressed HIV-1 on a stable combination therapy regimen. The trial includes five treatment groups.

[0348] Arm 1 (Experiment: Phase 2: Bictegravir (BIC) 75 mg + Renacapavir (LEN) 25 mg): Participants will switch from their stable baseline regimen (SBR) to the BIC 75 mg + LEN 25 mg regimen. Participants will receive a daily dose of BIC 75 mg + LEN 25 mg, starting on day 1 and continuing until the end of their randomized treatment (ERT) visit, in addition to a two-day loading regimen of LEN 600 mg (days 1 and 2). Participants will be treated for at least 24 weeks during the randomization period.

[0349] After the randomization period, participants have the option to participate in an extension period to receive a fixed-dose combination (FDC) of BIC / LEN at a selected dose.

[0350] Arm 2 (Experiment: Phase 2: Bictegravir (BIC) 75 mg + Renacapavir (LEN) 50 mg): Participants will switch from their SBR to the BIC 75 mg + LEN 50 mg regimen. Participants will receive a daily dose of BIC 75 mg + LEN 50 mg, starting on day 1 until ERT visit, in addition to a 2-day loading regimen of LEN 600 mg (days 1 and 2). Participants will be treated for at least 24 weeks during the randomization period.

[0351] After the randomization period, participants have the option to participate in an extension period to receive BIC / LEN FDC at a selected dose.

[0352] Arm 3 (Active Comparator: Phase 2: Stable Baseline Regimen (SBR)): Participants will continue their SBR as prescribed until their ERT visit, and will be treated for at least 24 weeks during the randomization period.

[0353] After the randomization period, participants have the option to participate in an extension period to receive BIC / LEN FDC at a selected dose.

[0354] SBR includes combinations of antiretroviral (ARV) regimens. ARV regimens may include the following, except that participants take a single tablet regimen or a complete parenteral regimen (Cabenuva):

[0355] Nucleoside (nucleotide) reverse transcriptase inhibitors: a. Abacavir b. Emtricitabine c. Lamivudine d. Tenofovir alafenamide e. Tenofovir disoproxil fumarate f. Zidovudine

[0356] Non-nucleoside reverse transcriptase inhibitors: a. Delavirdine b. Efavirenz c. Nevirapine d. Rilpivirine e. doraviline

[0357] Integrase inhibitors: a. Bictegravir b. Cabotegravir c. Dolutegravir d. Elvitegravir e. raltegravir

[0358] Protease inhibitors; a. Atazanavir b. Darunavir c. Fosamprenavir d. Indinavir e. lopinavir f. Nelfinavir g. Saquinavir h. tipranavir

[0359] Chemokine co-receptor 5 (CCR5) antagonist: a. Maraviroc

[0360] Fusion inhibitors: a. Enfvirtide

[0361] gp120 adhesion inhibitors: a. HosteSavir

[0362] Anti-CD4 monoclonal antibody: a. Ibalizumab-uiyk

[0363] Arm 4 (Experiment: Phase 3: BIC / LEN fixed-dose combination (FDC)): Participants will switch to the BIC / LEN FDC regimen (daily dose selection at week 24 from Phase 2). Participants will receive a daily dose of BIC / LEN FDC starting on day 1 until ERT visit, in addition to a 2-day loading regimen of LEN 600 mg (days 1 and 2), and will be treated for at least 48 weeks during the randomization period.

[0364] After the randomization period, participants have the option to participate in an extension period to receive BIC / LEN FDC at a selected dose.

[0365] Arm 5 (Active Comparator: Phase 3: Stable Baseline Regimen (SBR)): Participants will continue their SBR as prescribed until their ERT visit, and will be treated for at least 48 weeks during the randomization period.

[0366] After the randomization period, participants have the option to participate in an extension period to receive BIC / LEN FDC at a selected dose.

[0367] SBR includes combinations of antiretroviral (ARV) regimens. ARV regimens may include the following, except that participants take a single tablet regimen or a complete parenteral regimen (Cabenuva):

[0368] Nucleoside (nucleotide) reverse transcriptase inhibitors: a. Abacavir b. Emtricitabine c. Lamivudine d. Tenofovir alafenamide e. Tenofovir disoproxil fumarate f. Zidovudine

[0369] Non-nucleoside reverse transcriptase inhibitors: a. Delavirdine b. Efavirenz c. Nevirapine d. Rilpivirine e. doraviline

[0370] Integrase inhibitors: a. Bictegravir b. Cabotegravir c. Dolutegravir d. Elvitegravir e. raltegravir

[0371] Protease inhibitors; a. Atazanavir b. Darunavir c. Fosamprenavir d. Indinavir e. lopinavir f. Nelfinavir g. Saquinavir h. tipranavir

[0372] Chemokine coreceptor 5 (CCR5) antagonist: a. Maraviroc

[0373] Fusion inhibitors: a. Enfvirtide

[0374] gp120 adhesion inhibitors: a. HosteSavir

[0375] Anti-CD4 monoclonal antibody: a. Ibalizumab-uiyk endpoint

[0376] The primary evaluation criteria are as follows:

[0377] Phase 2: Percentage of participants with 50 or more copies / mL of HIV-1 RNA at week 24, determined by a snapshot algorithm defined by the US FDA [Time frame: Week 24]

[0378] Phase 3: Percentage of participants with 50 or more copies / mL of HIV-1 RNA at week 48, determined by a snapshot algorithm defined by the US FDA [Time frame: Week 48]

[0379] The secondary evaluation items are as follows:

[0380] Phase 2: Percentage of participants with less than 50 copies / mL of HIV-1 RNA at week 24, determined by a snapshot algorithm defined by the US FDA [Time frame: Week 24]

[0381] Phase 2: Change from baseline in CD4 cell count at week 24 [Time frame: baseline, week 24]

[0382] Phase 2: Percentage of participants who experienced adverse events (AEs) during treatment by 24 weeks [Time frame: from the first dose to 24 weeks]

[0383] Phase 2: Pharmacokinetic (PK) parameters: C of bictegravir (BIC) and lenacapavir (LEN) in a stable state. max [Time frame: From day 1 to week 24](C max(This is defined as the maximum observed concentration of the drug.)

[0384] Phase 2: PK Parameters: AUC of BIC and LEN in the steady state tau [Time frame: from day 1 to week 24] (AUC tau (This is defined as the area under the concentration-time curve over the dosing interval.)

[0385] Phase 2: PK parameters: C of BIC and LEN in steady state tau [Time frame: From day 1 to week 24](C tau (This is defined as the drug concentration observed at the end of the dosing interval.)

[0386] Phase 3: Percentage of participants with less than 50 copies / mL of HIV-1 RNA at week 48, determined by a snapshot algorithm defined by the US FDA [Time frame: Week 48]

[0387] Phase 3: Change from baseline in CD4 cell count at week 48 [Time frame: baseline, week 48]

[0388] Phase 3: Percentage of participants who experienced adverse events (AEs) under treatment by 48 weeks [Time frame: from the first dose to 48 weeks] Eligibility Criteria

[0389] Key inclusion criteria:

[0390] Recorded plasma human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) levels were less than 50 copies / mL during treatment with the baseline regimen for at least 6 months prior to the screening visit.

[0391] Plasma HIV-1 RNA levels are less than 50 copies / mL at the time of screening.

[0392] Due to previous virus resistance or intolerance, or contraindications to existing single-tablet regimens (STRs), patients are currently receiving compound antiretroviral (ARV) regimens. The criteria for defining compound regimens in this study are as follows: a. A regimen comprising a boosted protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NRTI) plus at least one other third drug (i.e., a drug from a class other than NRTI) (e.g., bictegravir / emtricitabine / tenofovir alafenamide (co-formulation; Biktarvy® (BVY) + darunavir / cobicistat, BVY + etravirine), or b. Regimen requiring more than 2 tablets / day, or regimens requiring more than once a day, c. Regimen including parenteral agents (excluding complete long-acting injection regimens such as intramuscular cabotegravir + rilpivirine) and oral agents.

[0393] • No resistance to bictegravir (BIC) has been recorded, or resistance is not suspected.

[0394] In patients not receiving renal replacement therapy, the glomerular filtration rate estimated according to the Cockcroft-Gault formula for creatinine clearance (CLcr) is 15 mL / min or greater.

[0395] Key inclusion criteria:

[0396] Previous use or exposure to lenacapavir (LEN)

[0397] active tuberculosis infection

[0398] Chronic hepatitis B virus (HBV) infection

[0399] As those skilled in the art will understand, numerous modifications and variations of this disclosure are possible in light of these teachings, and all such are assumed herein.

[0400] For example, in addition to the embodiments described herein, this disclosure claims to represent disclosures arising from combinations of features cited herein and features of cited prior art documents that complement the features of this disclosure. Similarly, any described material, feature, or article may be used in combination with any other material, feature, or article, and it will be understood that such combinations are within the scope of this disclosure.

[0401] All publications, patents, and patent applications are incorporated herein by reference in their entirety, as if each individual were incorporated by reference. This disclosure is described with reference to various particular preferred embodiments and techniques. However, it should be understood that many variations and modifications are possible, while remaining within the spirit and scope of this disclosure.

Claims

1. A tablet comprising bictegravir or a pharmaceutically acceptable salt thereof and lenacapavir or a pharmaceutically acceptable salt thereof, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50 to 100 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 to 100 mg of lenacapavir free acid.

2. The tablet according to claim 1, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 50 to 75 mg of free bictegravir acid.

3. The tablet according to claim 1 or 2, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of free bictegravir acid.

4. The tablet according to any one of claims 1 to 3, wherein the bictegravir or a pharmaceutically acceptable salt thereof is bictegravir sodium.

5. The tablet according to any one of claims 1 to 4, wherein the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 to 75 mg of free lenacapavir acid.

6. The tablet according to claim 5, wherein the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 to 50 mg of free lenacapavir acid.

7. The tablet according to any one of claims 1 to 4, wherein the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 100 mg of lenacapavir free acid.

8. The tablet according to any one of claims 1 to 6, wherein the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of free lenacapavir acid.

9. The tablet according to any one of claims 1 to 6, wherein the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of free lenacapavir acid.

10. The tablet according to any one of claims 1 to 9, wherein the lenacapavir or a pharmaceutically acceptable salt thereof is lenacapavir sodium.

11. The tablet according to any one of claims 1 to 10, wherein the bictegravir or a pharmaceutically acceptable salt thereof is bictegravir sodium, and the lenacapavir or a pharmaceutically acceptable salt thereof is lenacapavir sodium.

12. The tablet according to any one of claims 1 to 11, wherein the tablet does not contain any active pharmaceutical ingredient other than (a) bictegravir or a pharmaceutically acceptable salt thereof, and (b) lenacapavir or a pharmaceutically acceptable salt thereof.

13. The tablet according to any one of claims 1 to 12, wherein the tablet is a single-layer tablet.

14. The tablet according to any one of claims 1 to 12, wherein the tablet is a multilayer tablet.

15. The tablet according to any one of claims 1 to 12 and claim 14, wherein the tablet is a two-layer tablet.

16. The tablet according to claim 14 or 15, comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof.

17. The tablet according to claim 16, wherein (a) the first layer is substantially free of lenacapavir or a pharmaceutically acceptable salt thereof, or (b) the second layer is substantially free of bictegravir or a pharmaceutically acceptable salt thereof.

18. The tablet according to any one of claims 1 to 6 and 9 to 17, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid.

19. The tablet according to any one of claims 1 to 6, 8, and 10 to 17, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid.

20. The tablet according to any one of claims 1 to 7 and 10 to 17, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 100 mg of lenacapavir free acid.

21. The tablet according to any one of claims 1 to 6, 9 to 13, and 18, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid.

22. The tablet according to any one of claims 1 to 6, 8, 10 to 13, and 19, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid.

23. The tablet according to any one of claims 1 to 7, 10 to 13, and 20, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 100 mg of lenacapavir free acid.

24. The tablet according to any one of claims 1 to 6, 9 to 12, and 14 to 18, wherein the tablet is a two-layer tablet comprising (a) a first layer containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and (b) a second layer containing an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof.

25. The tablet according to any one of claims 1 to 6, 8, 10 to 12, 14 to 17, and 19, is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 75 mg of bictegravir free acid, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof in an amount equivalent to about 50 mg of lenacapavir free acid.

26. The tablet according to any one of claims 18 to 25, wherein the bictegravir or a pharmaceutically acceptable salt thereof is bictegravir sodium, and the lenacapavir or a pharmaceutically acceptable salt thereof is lenacapavir sodium.

27. A tablet according to any one of claims 1 to 26, further comprising at least one excipient selected from copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

28. A tablet according to claim 27, comprising copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

29. A tablet according to claim 28, comprising approximately 5 to 50 mg of copovidone, approximately 0.5 to 10 mg of poloxamer, approximately 50 to 200 mg of mannitol, approximately 50 to 250 mg of microcrystalline cellulose, approximately 25 to 50 mg of croscarmellose sodium, and approximately 1 to 10 mg of magnesium stearate.

30. The tablet according to claim 29, wherein the tablet is a single-layer tablet and contains about 5 to 30 mg of copovidone, about 100 to 200 mg of mannitol, about 50 to 100 mg of microcrystalline cellulose, and about 5 to 10 mg of magnesium stearate.

31. The tablet according to claim 29, wherein the tablet is a two-layer tablet and contains about 5 to 15 mg of copovidone, about 0.5 to 5 mg of poloxamer, about 50 to 125 mg of mannitol, about 200 to 250 mg of microcrystalline cellulose, and about 5 to 10 mg of magnesium stearate.

32. The tablet according to any one of claims 16, 17, 24, and 25, wherein the first layer comprises a filler selected from mannitol, microcrystalline cellulose, and combinations thereof.

33. The tablet according to claim 32, wherein the weight ratio of mannitol to microcrystalline cellulose in the first layer is about 2:1 to about 1:

2.

34. The tablet according to claim 32, wherein the weight ratio of mannitol to microcrystalline cellulose in the first layer is approximately 2:

1.

35. The tablet according to claim 32, wherein the weight ratio of mannitol to microcrystalline cellulose in the first layer is approximately 1:

1.

36. The tablet according to claim 32, wherein the weight ratio of mannitol to microcrystalline cellulose in the first layer is approximately 1:

2.

37. The tablet according to claim 32, wherein the filler is microcrystalline cellulose and the first layer is substantially free of mannitol.

38. The tablet according to claim 37, wherein the first layer contains approximately 30-75% w / w of microcrystalline cellulose.

39. The tablet according to claim 38, wherein the first layer contains approximately 50-75% w / w of microcrystalline cellulose.

40. The tablet according to claim 39, wherein the first layer contains approximately 60-70% w / w of microcrystalline cellulose.

41. The tablet according to any one of claims 1 to 40, wherein the tablet is coated with a film coating.

42. The tablet according to claim 41, wherein the film coating comprises Opdary II or Opdary TF.

43. A tablet according to any one of claims 1 to 42, comprising approximately 10-25% w / w bictegravir or a pharmaceutically acceptable salt thereof and approximately 5-25% w / w lenacapavir or a pharmaceutically acceptable salt thereof.

44. The tablet according to any one of claims 1 to 6, 8, 9 to 13, 18, 21, 26 to 30, and 41 to 43, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid, and the tablet further comprises copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

45. The tablet according to any one of claims 1 to 6, 9 to 13, 18, 21, 26 to 30, and 41 to 44, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid, and the tablet comprises about 5 to 8 mg of copovidone, about 1 to 3 mg of poloxamer, about 175 to 200 mg of mannitol, about 90 to 100 mg of microcrystalline cellulose, about 30 to 40 mg of croscarmellose sodium, and about 5 to 8 mg of magnesium stearate.

46. The tablet according to claim 45, wherein the tablet, excluding the film coating, weighs approximately 410 to 460 mg, for example, approximately 430 to 440 mg.

47. The tablet according to any one of claims 1 to 6, 8, 10 to 13, 19, 22, 26 to 30 and 41 to 43, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid, and the tablet further comprises copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

48. The tablet according to any one of claims 1 to 6, 8, 10 to 13, 19, 22, 26 to 30, 41 to 43, and 47, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid, and the tablet comprises about 10 to 15 mg of copovidone, about 2 to 5 mg of poloxamer, about 150 to 175 mg of mannitol, about 75 to 90 mg of microcrystalline cellulose, about 30 to 40 mg of croscarmellose sodium, and about 5 to 8 mg of magnesium stearate.

49. The tablet according to claim 48, wherein the tablet has a weight of approximately 410 to 460 mg, for example, approximately 430 to 440 mg.

50. The tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of free bictegravir acid, and the first layer further comprises microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of free lenacapavir acid, and the second layer further comprises copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, according to any one of claims 1 to 6, 9 to 12, 14 to 18, 24, 26 to 29, 31, 32, 37, 38, and 41 to 43.

51. The tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of free bictegravir acid, and the first layer further comprises about 185 to 200 mg of microcrystalline cellulose, about 20 to 30 mg of croscarmellose sodium, and about 3 to 5 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of free lenacapavir acid, and the second layer further comprises about 5-8 mg of copovidone, about 1-3 mg of poloxamer, about 45-60 mg of mannitol, about 20-30 mg of microcrystalline cellulose, about 5-15 mg of croscarmellose sodium, and about 1-3 mg of magnesium stearate. The tablet according to any one of claims 1 to 6, 9 to 12, 14 to 18, 24, 26 to 29, 31, 32, 37, 38, 41 to 43, and 50, wherein the tablet optionally weighs about 400 to 450 mg.

52. The tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of free bictegravir acid, and the first layer further comprises microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of free lenacapavir acid, and the second layer further comprises copovidone, poloxamer, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, according to any one of claims 1 to 6, 8, 10 to 12, 14 to 17, 19, 25 to 29, 31, 32, 37, 38, and 41 to 43.

53. The tablet is a two-layer tablet comprising (a) a first layer containing bictegravir or a pharmaceutically acceptable salt thereof, and (b) a second layer containing lenacapavir or a pharmaceutically acceptable salt thereof. The amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of free bictegravir acid, and the first layer further comprises about 185 to 200 mg of microcrystalline cellulose, about 20 to 30 mg of croscarmellose sodium, and about 3 to 5 mg of magnesium stearate. The amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of free lenacapavir acid, and the second layer further comprises about 10 to 15 mg of copovidone, about 2 to 5 mg of poloxamer, about 100 to 110 mg of mannitol, about 45 to 60 mg of microcrystalline cellulose, about 15 to 25 mg of croscarmellose sodium, and about 2 to 5 mg of magnesium stearate, according to any one of claims 1 to 6, 8, 10 to 12, 14 to 17, 19, 25 to 29, 31, 32, 37, 38, 41 to 43, and 52.

54. The tablet according to claim 52 or 53, wherein the tablet has a weight of approximately 520 to 580 mg, for example, approximately 545 to 555 mg.

55. The tablet according to any one of claims 44 to 54, wherein the bictegravir or a pharmaceutically acceptable salt thereof is bictegravir sodium.

56. The tablet according to any one of claims 44 to 55, wherein the lenacapavir or a pharmaceutically acceptable salt thereof is lenacapavir sodium.

57. The tablet according to any one of claims 1 to 56, wherein the lenacapavir or a pharmaceutically acceptable salt thereof is present in a spray-dried dispersion.

58. The tablet according to any one of claims 1 to 57, wherein the tablet releases at least about 50% of the bictegravir or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured using a USP instrument II in 250 mL of fasted simulated intestinal fluid at pH 6.5 at 37°C and a paddle speed of 75 rpm.

59. The tablet according to claim 58, wherein the tablet releases at least about 60% of the bictegravir or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured using a USP instrument II in 250 mL of fasted simulated intestinal fluid at pH 6.5 at 37°C and a paddle speed of 75 rpm.

60. The tablet according to claim 59, wherein the tablet releases at least about 70% of the bictegravir or a pharmaceutically acceptable salt thereof in about 30 minutes, as measured using a USP instrument II in 250 mL of fasted simulated intestinal fluid at pH 6.5 at 37°C and a paddle speed of 75 rpm.

61. The tablet according to any one of claims 1 to 60, wherein the tablet releases at least about 50% of the lenacapavir or a pharmaceutically acceptable salt thereof in about 15 minutes, as measured using a USP instrument II in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0 at 37°C and a paddle speed of 75 rpm.

62. The tablet according to claim 60, wherein the tablet releases at least about 70% of the lenacapavir or a pharmaceutically acceptable salt thereof in about 15 minutes, as measured using a USP instrument II in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0 at 37°C and a paddle speed of 75 rpm.

63. The tablet according to claim 61, wherein the tablet releases at least about 80% of the lenacapavir or a pharmaceutically acceptable salt thereof in about 15 minutes, as measured using a USP instrument II in 900 mL of 2% w / w Cremophor EL in 30 mM potassium phosphate at pH 6.0 at 37°C and a paddle speed of 75 rpm.

64. A method for manufacturing a tablet according to any one of claims 1 to 63.

65. A tablet according to any one of claims 1 to 63, for use in the therapeutic or prophylactic treatment of HIV infection in a subject.

66. A method for the therapeutic treatment of HIV infection, comprising administering a tablet according to any one of claims 1 to 63 to a subject who requires such treatment.

67. A method for preventing HIV infection, comprising administering a tablet according to any one of claims 1 to 63 to a subject who requires such administration.

68. A tablet for use according to claim 65, or the method according to claim 66 or 67, wherein the prophylactic treatment is pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV in a subject.

69. The prophylactic treatment is post-exposure prophylaxis (PEP) to reduce the risk of sexually acquired HIV in the subject, the tablet for use according to claim 65, or the method according to claim 66 or 67.

70. A tablet for use according to any one of claims 65, 68, or 69, wherein the subject is virologically suppressed, or the method according to any one of claims 65 to 68.

71. The subject is experiencing treatment, the method or tablet for use according to claim 70.

72. The method according to any one of claims 66 to 67, or a tablet for use according to any one of claims 65 or 68 to 71, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid.

73. The method according to any one of claims 66 to 67, or a tablet for use according to any one of claims 65 or 68 to 71, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid.

74. The method according to any one of claims 66 to 67, or a tablet for use according to any one of claims 65 or 68 to 71, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 100 mg of lenacapavir free acid.

75. The tablet is a single-layer tablet, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 25 mg of lenacapavir free acid, according to the method of any one of claims 66 to 67, or a tablet for use according to any one of claims 65 or 68 to 71.

76. The method according to any one of claims 66 to 67, or a tablet for use according to any one of claims 65 or 68 to 71, wherein the tablet is a single-layer tablet, the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 50 mg of lenacapavir free acid.

77. The tablet is a single-layer tablet, wherein the amount of bictegravir or a pharmaceutically acceptable salt thereof corresponds to about 75 mg of bictegravir free acid, and the amount of lenacapavir or a pharmaceutically acceptable salt thereof corresponds to about 100 mg of lenacapavir free acid, according to the method of any one of claims 66 to 67, or a tablet for use according to any one of claims 65 or 68 to 71.

78. The tablet is a two-layer tablet comprising (a) a first layer containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and (b) a second layer containing an amount equivalent to about 25 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, according to the method of any one of claims 66 to 67, or a tablet for use according to any one of claims 65 or 68 to 71.

79. The tablet is a two-layer tablet comprising (a) a first layer containing an amount equivalent to about 75 mg of bictegravir free acid or a pharmaceutically acceptable salt thereof, and (b) a second layer containing an amount equivalent to about 50 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof, according to the method of any one of claims 66 to 67, or a tablet for use according to any one of claims 65 or 68 to 71.

80. The tablet is administered once daily, as described in claim 64 or any one of claims 67-78, or as described in claim 66-67 or any one of claims 65, 68, 71-79.

81. The tablet according to claim 80 or a tablet for use thereof, wherein the tablet is administered once daily after a loading dose of lenacapavir or a pharmaceutically acceptable salt thereof, equivalent to about 1200 mg of lenacapavir free acid.

82. The loading dose is administered over two days, the method according to claim 81 or a tablet for use.

83. A tablet for use according to claim 82, wherein an amount equivalent to approximately 600 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof is administered on day 1, and an amount equivalent to approximately 600 mg of lenacapavir free acid or a pharmaceutically acceptable salt thereof is administered on day 2.

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