Dosing regimen

Abstract

A method for preventing or treating HIV in a human comprising administering to the human once every 15 to 24 weeks a pharmaceutical composition comprising cabotegravir is invented.

Description

Technical Field

[0001] This invention relates to the treatment or prevention of human immunodeficiency virus (HIV). In particular, this invention relates to dosing regimens for long-acting treatment or prevention of HIV. Background Technology

[0002] People living with HIV often undergo complex treatment regimens involving taking multiple pills at fixed intervals each day. Patient non-adherence is a known problem accompanying these complex HIV treatment regimens and can lead to the emergence of multidrug-resistant strains of HIV.

[0003] The use of long-acting parenteral medications has been established in clinical practice for decades, particularly in the areas of contraception, antipsychotics, and opioid addiction. Recently, long-acting parenteral medications have been proposed as a method to overcome non-adherence issues in HIV treatment regimens. Long-acting injectable formulations, some of which have been approved and marketed, such as CABENUVA® and APRETUDE®, have demonstrated prolonged exposure (≥30 days) after injection, enabling dosing at monthly and bi-monthly intervals.

[0004] However, patients and individuals at risk of HIV infection will benefit from lower dosing frequencies. This will help overcome patient adherence issues and reduce the burden on healthcare providers administering long-acting products.

[0005] Previous attempts to develop high-concentration cabozantvir formulations suitable for dosing regimens with long intervals between administrations have been challenging for several reasons. The formulation needs to be suitable for long-acting injections and stable during storage, while also providing similar pharmacokinetic and safety profiles to currently approved regimens, i.e., achieving at least equivalent efficacy to currently approved cabozantvir regimens. Furthermore, any dosing regimen needs to have minimal injection site reactions (ISRs), namely pain, erythema, and swelling.

[0006] Formulations and / or doses containing high concentrations of cabotevir do not always possess the properties required for longer-acting administration in humans. For example, commercially available cabotevir 200 mg / mL formulations have shown a lack of physical stability when concentrations are increased to 400 mg / mL. Furthermore, in a Phase 1 trial, commercially available cabotevir 200 mg / mL formulations were administered subcutaneously to humans in combination with rHuPH20 (a recombinant human hyaluronidase that enhances subcutaneous drug absorption and dispersion) at doses up to 3200 mg / 16 mL. While the results obtained from this regimen suggested potentially increased bioavailability, all study participants experienced ISRs, including one participant who experienced a drug-related adverse event (AE) of injection site erythema with necrosis, leading to discontinuation of the method.

[0007] The goal is to achieve a cabotevir dosing regimen with longer intervals between administrations, which offers favorable safety and pharmacokinetic characteristics while maintaining patient experience and minimizing injection site reactions. Summary of the Invention

[0008] According to a first aspect of the invention, a method for preventing HIV in humans is provided, comprising administering a pharmaceutical composition containing cabotevir to the person once every 15 to 24 weeks.

[0009] According to a second aspect of the invention, a method for treating HIV in a person in need is provided, comprising administering a pharmaceutical composition comprising cabotevir to the person once every 15 to 24 weeks.

[0010] According to a third aspect of the invention, a pharmaceutical composition for treating HIV is provided, wherein the pharmaceutical composition comprises cabotevir and the treatment comprises administering the pharmaceutical composition to a person once every 15 to 24 weeks.

[0011] According to a fourth aspect of the invention, a pharmaceutical composition for HIV prevention is provided, wherein the pharmaceutical composition comprises cabotevir and the prevention comprises administering the pharmaceutical composition to a person once every 15 to 24 weeks.

[0012] According to a fifth aspect of the invention, the use of a pharmaceutical composition in the preparation of a medicament for treating HIV infection is provided, wherein the pharmaceutical composition comprises cabotevir.

[0013] According to a sixth aspect of the invention, the use of a pharmaceutical composition in the preparation of a medicament for the prevention of HIV infection is provided, wherein the pharmaceutical composition comprises cabotevir.

[0014] The treatment and prevention methods of the present invention, as well as the pharmaceutical compositions for treatment and prevention, are advantageous in many respects. The inventors have discovered that the dosing regimens of the pharmaceutical compositions comprising cabotevir of the present invention have favorable safety and pharmacokinetic characteristics, allowing them to be administered at longer intervals than currently approved regimens while still maintaining a favorable patient experience, namely low or tolerable injection site reactions (ISRs). Longer dosing intervals will help improve patient compliance and reduce the dosing burden on healthcare providers. Attached Figure Description

[0015] Figure 1The simulation of median plasma concentration / time curves for individuals designated as male at birth has been shown. These individuals received an intramuscular loading dose of 3200 mg cabobotevir (CAB) twice (533 mg / mL cabobotevir formulation in 3 mL – as described herein in Group 5, Example 9), followed by a first maintenance dose of 1600 mg cabobotevir one month later, and then 1600 mg cabobotevir every 4 months (533 mg / mL cabobotevir formulation in 3 mL, as described herein in Group 5, Example 9). This has been superimposed on a graph of median plasma concentrations over time for individuals designated as male at birth who have been administered the approved cabobotevir 200 mg / mL formulation Q2M (every 2 months) (APRETUDE® – labeled CAB 200 in the graph). The black line in the middle of the shaded gray area represents the simulated median of the dosing regimen (designated CAB-ULA in the graph). The black line in the middle of the shaded gray area is above the black dashed line (median plasma concentration of CAB200). The lower boundary of the gray band (the 10th percentile of the simulated CAB-ULA) is above the lowest dashed line (the 10th percentile of the simulated CAB200). Therefore, this indicates that the regimen maintains a higher CAB plasma concentration than the approved Q2M regimen of CAB200 IM gluteal injection.

[0016] Figure 2 The simulation of the median plasma concentration / time curve for individuals designated as female at birth is shown. These individuals received a loading dose of 3200 mg cabobetavir intramuscularly (533 mg / mL cabobetavir formulation in 3 mL twice – as described herein in Group 5, Example 9) and a first maintenance dose of 1600 mg cabobetavir one month later, followed by 1600 mg cabobetavir (533 mg / mL cabobetavir formulation in 3 mL, as described herein in Group 5, Example 9) every 4 months. This has been superimposed on the median plasma concentration over time curve for individuals designated as female at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M (every 2 months) (APRETUDE® – labeled CAB 200 in the graph). The black line in the middle of the shaded gray area is the simulated median of the dosing regimen (designated CAB-ULA in the graph). The black line in the middle of the shaded gray area is above the black dashed line (the median of CAB200). The lower boundary of the gray band (the 10th percentile of the simulated CAB-ULA) is above the lowest dashed line (the 10th percentile of the simulated CAB200). Therefore, this indicates that the regimen maintains a higher CAB plasma concentration than the approved Q2M regimen of CAB200 IM gluteal injection.

[0017] Figure 3This is a simulation of the median plasma concentration / time curve for individuals designated as male at birth who received an intramuscular loading dose of 2132 mg cabobetavir (533 mg / mL cabobetavir formulation in 4 mL) and a first maintenance dose of 799.5 mg cabobetavir one month later, followed by 799.5 mg cabobetavir (533 mg / mL cabobetavir formulation in 1.5 mL) every 4 months. This has been superimposed on a graph of median plasma concentrations over time for individuals designated as male at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line represents the median plasma concentration of the approved regimen (APRETUDE®). The gray shaded areas show the 10th to 90th percentile plasma concentrations of the simulated regimen. The black solid line represents the median of the simulated dosing regimen.

[0018] Figure 4 This is a simulation of the median plasma concentration / time curve for individuals designated female at birth who received a loading dose of 2132 mg cabobetavir (533 mg / mL cabobetavir formulation in 4 mL) and a first maintenance dose of 799.5 mg cabobetavir one month later, followed by 799.5 mg cabobetavir (533 mg / mL cabobetavir formulation in 1.5 mL) every 4 months. This has been superimposed on a graph of median plasma concentrations over time for individuals designated female at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line represents the median plasma concentration for the approved regimen (APRETUDE®). The gray shaded areas represent the 10th to 90th percentile plasma concentrations of the simulated regimen. The black solid line represents the median of the simulated dosing regimen.

[0019] Figure 5 The simulation shows a median plasma concentration / time graph for individuals designated as male at birth who had received an intramuscular loading dose of cabobetavir (400 mg / mL cabobetavir formulation in 3 mL twice), followed by a first maintenance dose of 1200 mg cabobetavir one month later, and then 1200 mg cabobetavir (400 mg / mL cabobetavir formulation in 3 mL) every 4 months (see Group 3, Example 9 of this document). This has been superimposed on a graph of median plasma concentrations over time for individuals designated as male at birth who had been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line in the middle of the gray shaded area represents the median plasma concentration of the approved regimen (APRETUDE®). The gray shaded area represents the interval of the approved regimen. The black solid line is the median of the simulated dosing regimen, and the black dashed lines above and below it are the upper and lower boundaries of the predicted intervals for the simulated dosing regimen.

[0020] Figure 6The simulation shows a median plasma concentration / time graph for individuals designated female at birth who had received an intramuscular loading dose of cabobetavir (400 mg / mL cabobetavir formulation in 3 mL twice), followed by a first maintenance dose of 1200 mg cabobetavir one month later, and then 1200 mg cabobetavir (400 mg / mL cabobetavir formulation in 3 mL) every 4 months (see Group 3, Example 9 of this document). This has been superimposed on a graph of median plasma concentration over time for individuals designated female at birth who had been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line in the middle of the gray shaded area represents the median plasma concentration of the approved regimen (APRETUDE®). The gray shaded area represents the interval of the approved regimen. The black solid line is the median of the simulated dosing regimen, and the black dashed lines above and below it are the upper and lower boundaries of the predicted interval for the simulated dosing regimen.

[0021] Figure 7 Showing with Figure 1 The same simulation is shown, but overlaid on the dashed line showing 1.05 μg / mL, instead of the simulation of the approved regimen. The lower boundary of the gray band (the 10th percentile of the simulation for the dosing regimen shown), marked CAB-ULA in the figure, is above the horizontal dashed line, which represents the efficacy benchmark in individuals designated as male at birth.

[0022] Figure 8 Showing with Figure 2 The same simulation is shown, but overlaid on the dashed line showing 1.39 μg / mL, instead of the simulation of the approved regimen. The lower boundary of the gray band (the 10th percentile of the simulation for the dosing regimen shown), marked CAB-ULA in the figure, is above the horizontal dashed line, which represents the efficacy baseline for individuals designated as female at birth.

[0023] Figure 9 This is a simulation of the median plasma concentration / time curve for individuals designated as male at birth who received a loading intramuscular dose of 2132 mg of cabobetavir (533 mg / mL in 4 mL) and a first maintenance dose of 1066 mg of cabobetavir one month later, followed by 1066 mg of cabobetavir (533 mg / mL in 2 mL) every 4 months. This has been superimposed on a graph of median plasma concentrations over time for individuals designated as male at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The dashed black line represents the median plasma concentration of the approved regimen (APRETUDE®). The solid black line represents the median of the simulated dosing regimen (labeled Cab-ULA), and the surrounding gray shaded area represents the predicted interval from the 10th to the 90th percentile of the simulated dosing regimen.

[0024] Figure 10 This is a simulation of the median plasma concentration / time curve for individuals designated female at birth who received a loading intramuscular dose of 2132 mg of cabobetavir (533 mg / mL in 4 mL) and a first maintenance dose of 1066 mg of cabobetavir one month later, followed by 1066 mg of cabobetavir (533 mg / mL in 2 mL) every 4 months. This has been superimposed on a graph of median plasma concentrations over time for individuals designated female at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The dashed black line represents the median plasma concentration of the approved regimen (APRETUDE®). The solid black line represents the median of the simulated dosing regimen (labeled Cab-ULA), and the surrounding gray shaded area represents the predicted interval from the 10th to the 90th percentile of the simulated dosing regimen.

[0025] Figure 11 and 12 The simulations shown are from a second set of simulations based on the CAB ULA PopPK model, where individuals designated as male at birth ( Figure 11 ) and those designated as female at birth ( Figure 12 In this study, a maintenance regimen of 1600 mg CAB ULA (3 mL of 533 mg / mL cabotevir) was administered intramuscularly in the gluteal region (loading dose) followed by a 1600 mg CAB ULA (3 mL of 533 mg / mL cabotevir) regimen. The dashed lines at 22.5 μg / mL and 0.45 μg / mL represent the safety and therapeutic efficacy thresholds, respectively. The middle curve represents the median concentration, and the upper and lower curves represent the 90% prediction interval. Detailed Implementation

[0026] definition

[0027] As used herein, the term "pharmaceutical composition" means a composition suitable for pharmaceutical use.

[0028] As used herein, the terms “prevention” or “preventing” refer to the avoidance of the disease in subjects who do not have the disease.

[0029] As used herein, the term “treatment” or “treating” means to relieve a specified condition, eliminate or reduce the symptoms of the condition, slow or eliminate the progression, invasion or spread of the condition, and reduce or delay the recurrence of the condition in a subject with a prior illness.

[0030] As used herein, the term "aqueous solution" means any solution containing water or in which the solvent is water. Additionally, "aqueous solution" is used to describe solutions exhibiting properties common to water or aqueous solutions, but is not limited to characteristics such as appearance, odor, color, taste, viscosity, pH, absorbance, or physical state at a particular temperature.

[0031] As used in this article, the term "freeze-drying," also known as freeze-drying or cryodesiccation, is a dehydration process that involves freezing a product without damaging the physical structure of the substance.

[0032] As used herein, the terms “lyophilized” and “freeze-dried” are used interchangeably and refer to the condition and / or state of a sample, formulation, or product obtained by lyophilization.

[0033] As may be used interchangeably herein, the terms “lyophilized pharmaceutical composition” and “lyophilized composition” refer to a pharmaceutical composition in a lyophilized form as taught herein, such as a lyophilized powder.

[0034] As used herein, “reconstruction” refers to the process of restoring a dried, lyophilized, dehydrated, or concentrated substance to its original or liquid state by adding a solvent to the lyophilized substance, rehydrating it, and then stirring the mixture of solvent and lyophilized substance. The reconstructed substance can be a product, formulation, sample, raw material, or part of any biological material, but is certainly not limited to substances falling under the common definition of these terms. Reconstruction can be visually assessed with the naked eye. A lyophilized substance is considered reconstructed when a homogeneous suspension is observed. In particular, a suspension with a turbid appearance is considered appropriately reconstructed.

[0035] As used herein, the term “self-administration” means administration by someone other than a healthcare professional, such as a patient administering the drug composition to themselves or someone else, rather than to the patient’s healthcare professional.

[0036] As used in this article, the terms “subject” or “patient” refer to a person.

[0037] As used in this article, the term "diameter" refers to the volume equivalent diameter of a sphere.

[0038] As used in this article, the term "Cmax" refers to the maximum observed plasma concentration.

[0039] As used in this article, the term “Ctau” refers to glutathione concentration, which is the concentration reached immediately before the next dose is administered.

[0040] As used in this article, the term "tmax" refers to the time at which the maximum plasma concentration (tmax) of a substance is observed after administration.

[0041] As used herein, the term "area under the curve" or "AUC" refers to the area under the concentration-time curve (of a substance in plasma). AUC can be a measure of the integral of the instantaneous concentration over the time interval and has a unit mass... Time / volume. AUC is typically calculated using the trapezoidal rule (e.g., linear, linear logarithmic). AUC is usually given for time intervals from zero to infinity (AUC(0-inf)) and indicates other time intervals (e.g., AUC(t1, t2), where t1 and t2 are the start and end times of the interval).

[0042] As used herein, the term “about” generally means ±5%, ±10%, ±15%, or ±20% of the value of a number used with it. In one embodiment, the term “about” means ±10% of the value of a number used with it.

[0043] Description of implementation methods

[0044] In a first aspect, the present invention provides a method for preventing HIV in a person, comprising administering a pharmaceutical composition containing cabotevir to the person once every 15 to 24 weeks.

[0045] In a second aspect, the present invention provides a method for treating HIV in a person in need, comprising administering a pharmaceutical composition comprising cabotevir to the person once every 15 to 24 weeks.

[0046] The embodiments discussed below are also applicable to the first and second aspects.

[0047] Cabotevir (3S,11aR)-N-((2,4-difluorophenyl)methyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro(1,3)oxazolo(3,2-a)pyrido(1,2-d)pyrazin-8-carboxamide is described in Example Z-9 of US 8,129,385, which is incorporated herein by reference. Cabotevir is an integrase strand transfer inhibitor (INSTI) that exhibits sub-nanomolar potency and antiviral activity against a broad range of HIV-1 strains. Oral administration of cabotevir has demonstrated an acceptable safety and tolerability profile, a long half-life, and few drug-drug interactions. Cabotevir in both oral and parenteral formulations has been proven effective in the treatment and prevention of HIV; see, for example, Margolis DA, Brinson CC, Eron JJ et al., 744 and Rilpivirine as Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA, Margolis DA, Podzamczer D, Stellbrink HJ et al., Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 48 Results, 21 st International AIDSConference; July 18-22, 2016; Durban, South Africa, Abstract THAB0206LB.Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016, and Markowitz M, Frank I, Grant R, et al., ÉCLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men. Abstract presented at 23 rd CROI; February 22–25, 2016; Boston, MA. Cabotegravir has been approved by the FDA for long-acting prevention of HIV infection, administered every two months; and in combination with rilpivirine for long-acting treatment of HIV infection, administered monthly or every two months.

[0048] Cabotevir is represented by compound A: (Compound A).

[0049] In one embodiment of the invention, cabotevir is present in the pharmaceutical composition as a free acid.

[0050] The dosage of cabotevir (which is the amount of cabotevir used in the compositions of the present invention) can be selected such that: the plasma concentration of cabotevir in humans is maintained above the trough plasma concentration (Ctau); or the plasma concentration of cabotevir in humans is maintained equal to or higher than the Ctau of the approved 200 mg / mL cabotevir regimen (i.e., in the APRETUDE® dosing regimen).

[0051] Glutamic plasma level (Ctau) refers to glutathione concentration, which is the concentration reached immediately before the next dose is administered. The Ctau value represents the lowest plasma level. Ctau can be measured in any suitable manner.

[0052] The inventors have discovered that, in order to maintain an effective dosing regimen for the treatment or prevention of HIV, the dose of cabozantvir (which is the amount of cabozantvir in the pharmaceutical composition used in this invention) should maintain Ctau at a level higher than the 10th percentile of Ctau observed in Phase 3 studies 201738 (HPTN 083) (for those designated as male at birth) (1.05 μg / mL) and 201739 (HPTN 084) (for those designated as female at birth) (1.39 μg / mL). The 10th percentile of Ctau observed in the mentioned Phase 3 studies is a sex-specific PrEP benchmark, which is achieved in at least 90% of participants, or the dose of cabozantvir needs to maintain both the median and 10th percentile of Ctau higher than those from the approved 200 mg / mL intramuscular cabozantvir regimen (APRETUDE®) for those designated as male at birth and those designated as female at birth.

[0053] In one embodiment, the dose of cabobetavir administered is selected such that Ctau is higher than that observed in the approved 200 mg / mL cabobetavir intramuscular injection regimen in individuals designated as male at birth and individuals designated as female at birth. In one embodiment, the dose of cabobetavir administered is selected such that Ctau is higher than that observed in the APRETUDE® dosing regimen. In one embodiment, the dose of cabobetavir administered is selected such that Ctau is higher than that observed in the 10th percentile of the APRETUDE® dosing regimen.

[0054] In one embodiment, the dose of cabozantvir administered is selected such that Ctau is at least 1 μg / mL, meaning that cabozantvir provides at least about 1 μg / mL of Ctau. In another embodiment, cabozantvir provides at least 1.05 μg / mL of Ctau. In another embodiment, the person is designated female at birth and cabozantvir provides at least about 1.35 μg / mL of Ctau. In another embodiment, the person is designated female at birth and cabozantvir provides at least about 1.39 μg / mL of Ctau. In another embodiment, the person is designated female at birth and cabozantvir provides at least 1.39 μg / mL of Ctau. In one embodiment, the person is designated male at birth and cabozantvir provides at least about 1.05 μg / mL of Ctau. In another embodiment, the person is designated male at birth and cabozantvir provides at least 1.05 μg / mL of Ctau. In one implementation, the person is designated female at birth and cabotevir is provided at least about 1.39 μg / mL of Ctau; or the person is designated male at birth and cabotevir is provided at least about 1.05 μg / mL of Ctau.

[0055] In one implementation, the aforementioned Ctau level was achieved in at least 90% of individuals administering the dosing regimen.

[0056] Cabotevir plasma levels in humans can remain above these Ctau levels because at lower levels the drug may no longer be effective, increasing the risk of HIV transmission and potentially being suboptimal for treating HIV infection. Maintaining higher cabotevir plasma levels helps prevent the development of HIV mutations while preserving a safety margin.

[0057] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after administering the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter.

[0058] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 15 to 24 weeks after administering the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter.

[0059] In one embodiment, a person is screened for HIV infection before receiving a loading dose. In another embodiment, the method is used for HIV prevention, and a person is screened for HIV infection before receiving a loading dose.

[0060] In one embodiment, the loading dose is a single dose of the pharmaceutical composition received at the start of treatment or prevention. In one embodiment, a first maintenance dose is administered to the person 2 to 6 weeks after the loading dose has been administered. In another embodiment, a first maintenance dose is administered to the person 15 to 24 weeks after the loading dose. In one embodiment, a maintenance dose is then administered to the person every 15 to 24 weeks thereafter.

[0061] In one embodiment, the pharmaceutical compositions used for the loading dose and maintenance dose are the same pharmaceutical composition, but they may contain different concentrations or amounts of cabobetavir. In one embodiment of the invention, the pharmaceutical compositions used for the loading dose and maintenance dose contain the same concentration of cabobetavir. In one embodiment of the invention, the pharmaceutical compositions used for the loading dose and maintenance dose contain the same concentration of cabobetavir, wherein the loading dose of cabobetavir is higher than the maintenance dose of cabobetavir. In one embodiment, the loading dose and maintenance dose are the same dose (e.g., the loading dose and maintenance dose are the same volume and each contains the same pharmaceutical composition having the same concentration and the same amount of cabobetavir). In one embodiment, the loading dose and maintenance dose are different doses (e.g., the loading dose and maintenance dose are different volumes of the same pharmaceutical composition having the same concentration of cabobetavir, or the loading dose and maintenance dose are different volumes of different pharmaceutical compositions having different concentrations of cabobetavir). In one implementation, the loading dose of cabotevir is higher than the maintenance dose of cabotevir (e.g., the loading dose and maintenance dose each contain the same concentration of cabotevir, wherein the volume of the loading dose is greater than the volume of the maintenance dose, or the loading dose and maintenance dose contain different concentrations of cabotevir, wherein the volume of the loading dose is greater than the volume of the maintenance dose).

[0062] In another embodiment, the pharmaceutical composition for the loading dose is a different pharmaceutical composition from the pharmaceutical composition for the maintenance dose (e.g., the pharmaceutical composition for the loading dose has a different excipient than the pharmaceutical composition for the maintenance dose).

[0063] In yet another embodiment, the loading dose comprises two different pharmaceutical compositions.

[0064] Administration method

[0065] The pharmaceutical composition described in this invention is suitable for injection. In one embodiment, the pharmaceutical composition is administered intramuscularly or subcutaneously. In one embodiment, the pharmaceutical composition is administered subcutaneously. In one embodiment, the pharmaceutical composition is administered intramuscularly. In one embodiment, the pharmaceutical composition is administered to the gluteal muscles. In a specific embodiment, the pharmaceutical composition is administered to the ventrogluteal or dorsogluteal site. In one embodiment, the pharmaceutical composition is administered to the gluteus medius, gluteus maximus, or both. In one embodiment, the pharmaceutical composition is administered to the gluteus medius. In one embodiment, the pharmaceutical composition is administered to the gluteus maximus.

[0066] Loading dose

[0067] In one embodiment, the loading dose of the pharmaceutical composition comprises at least 600 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises at least 1200 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises at least 1400 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises at least 1500 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 1600 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 1800 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2000 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2200 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2400 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2600 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2800 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 3000 mg of cabobetavir. In one embodiment, the loading dose comprises about 600 mg to about 4000 mg of cabobetavir. In one embodiment, the loading dose comprises about 1200 mg to about 4000 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2000 mg to about 3500 mg of cabobetavir. In an alternative embodiment, the loading dose of the pharmaceutical composition comprises 3000 mg to about 3500 mg of cabobetavir. In an alternative embodiment, the loading dose of the pharmaceutical composition comprises 3100 mg to about 3300 mg of cabobetavir. In an alternative embodiment, the loading dose of the pharmaceutical composition comprises 3150 mg to about 3250 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 600 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 1600 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2000 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2132 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2200 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2400 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 3200 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises 600 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises 1600 mg of cabobetavir.In one embodiment, the loading dose of the pharmaceutical composition comprises 2200 mg of cabotevir. In one embodiment, the loading dose of the pharmaceutical composition comprises 2400 mg of cabotevir. In one embodiment, the loading dose of the pharmaceutical composition comprises 3200 mg of cabotevir.

[0068] The loading dose can be administered in a single injection or in two separate injections. In embodiments where the loading dose is administered in two separate injections, these injections are administered sequentially. In embodiments where the loading dose is administered in two separate injections, the two separate injections are administered at the same or different sites. In embodiments where the loading dose is administered in two separate injections, the two separate injections are administered sequentially at the same site. In another embodiment where the loading dose is administered in two separate injections, the two separate injections are administered sequentially at sites at least 2 cm apart (e.g., one injection in the left gluteus maximus and one injection in the right gluteus maximus, or one injection in the left gluteus medius and another injection in the right gluteus medius). In one embodiment, each of the two separate injections contains the same amount of cabotabine. In one embodiment, each of the two separate injections contains different amounts of cabotabine (e.g., one injection contains about 600 mg of cabotabine, and the other injection contains about 1600 mg of cabotabine).

[0069] In embodiments where the loading dose is administered via two separate injections, each injection contains the same or different pharmaceutical compositions.

[0070] In one embodiment, the loading dose of the pharmaceutical composition comprises 600 mg of cabotevir, wherein the loading dose is administered as a single 2 mL injection.

[0071] In one embodiment, the loading dose of the pharmaceutical composition comprises 1600 mg cabotevir, wherein the loading dose is administered as a single 3 mL injection.

[0072] In one embodiment, the loading dose of the pharmaceutical composition comprises 2200 mg of cabotevir, wherein the loading dose is administered by two separate injections, one of which contains about 600 mg of cabotevir and the other of which contains about 1600 mg of cabotevir.

[0073] In one embodiment, the loading dose of the pharmaceutical composition comprises 2400 mg of cabotevir, wherein the loading dose is administered by two separate injections, each containing approximately 1200 mg of cabotevir.

[0074] In one embodiment, the loading dose of the pharmaceutical composition comprises 3200 mg of cabotevir, wherein the loading dose is administered by two separate injections, each containing approximately 1600 mg of cabotevir.

[0075] In one embodiment, the loading dose is administered as a 1 mL injection. In one embodiment, the loading dose is administered as a 2 mL injection. In one embodiment, the loading dose is administered as a 2.25 mL injection. In one embodiment, the loading dose is administered as a 3 mL injection.

[0076] In one embodiment, the loading dose of the pharmaceutical composition comprises 2132 mg of cabotevir, wherein the loading dose is administered in two separate 2 mL injections, each containing approximately 1066 mg of cabotevir.

[0077] In one embodiment, the loading dose of the pharmaceutical composition comprises 2200 mg of cabotevir, wherein the loading dose is administered in two separate injections, one containing approximately 600 mg of cabotevir in a 2 mL injection and the other containing approximately 1600 mg of cabotevir in a 3 mL injection.

[0078] In one embodiment, the loading dose of the pharmaceutical composition comprises 2400 mg of cabotevir, wherein the loading dose is administered in two separate injections, each containing approximately 1200 mg of cabotevir in 2.25 mL of injection solution.

[0079] In one embodiment, the loading dose of the pharmaceutical composition comprises 3200 mg of cabotevir, wherein the loading dose is administered in two separate 3 mL injections, each containing approximately 1600 mg of cabotevir.

[0080] In another embodiment, the loading dose may refer to the first loading dose when one or more subsequent loading doses are administered at a later time point (e.g., a second loading dose is administered 2-6 weeks after the first loading dose). Subsequent loading doses are as described in any of the foregoing embodiments of the loading dose. In one embodiment, the first loading dose is followed by the second loading dose. In another embodiment, the first loading dose is followed by the second and third loading doses. In yet another embodiment, the first loading dose is followed by the second, third, and fourth loading doses (e.g., the second loading dose is administered 2-6 weeks after the first loading dose, the third loading dose is administered 6-11 weeks after the second loading dose, and the fourth loading dose is administered 6-11 weeks after the third loading dose).

[0081] Maintenance dose

[0082] In one embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1000 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1200 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1300 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1330 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1500 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1600 mg of cabobetavir. In one embodiment, the maintenance dose comprises about 1000 mg to about 1800 mg of cabobetavir. In one embodiment, the maintenance dose comprises about 1200 mg to about 1800 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises about 1250 mg to about 1800 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises about 1300 mg to about 1800 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises about 1400 mg to about 1800 mg, about 1400 mg to about 1700 mg, about 1450 mg to about 1700 mg, about 1450 mg to about 1650 mg, about 1500 mg to about 1650 mg, or about 1550 mg to about 1650 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises about 1550 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises 1550 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises about 1650 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises 1650 mg of cabobetavir.

[0083] In one embodiment, the maintenance dose is administered as a 1 mL injection. In one embodiment, the maintenance dose is administered as a 2 mL injection. In one embodiment, the maintenance dose is administered as a 3 mL injection.

[0084] In one embodiment, the maintenance dose of the pharmaceutical composition comprises approximately 1066 mg of cabotevir in 2 mL of injection, approximately 1332 mg of cabotevir in 2.5 mL of injection, or approximately 1600 mg of cabotevir in 3 mL of injection.

[0085] In one embodiment, the maintenance dose of the pharmaceutical composition comprises approximately 1066 mg of cabotevir in 2 mL of injection solution.

[0086] In one embodiment, the maintenance dose of the pharmaceutical composition comprises approximately 1600 mg of cabotevir in 3 mL of injection solution.

[0087] In one implementation, a first maintenance dose is administered 2 to 6 weeks after the loading dose, followed by the first maintenance dose every 15 to 24 weeks thereafter.

[0088] In one embodiment, the first maintenance dose is administered 2 to 6 weeks or 3 to 4 weeks after the loading dose. In one embodiment, the first maintenance dose is administered 1 month after the loading dose, i.e., 3 to 5 weeks after the loading dose. In one embodiment, the first maintenance dose is administered approximately 3 weeks, approximately 4 weeks, or approximately 5 weeks after the loading dose. In one embodiment, the first maintenance dose is administered 3 weeks, 4 weeks, or 5 weeks after the loading dose.

[0089] In another embodiment, a first maintenance dose is administered 6 to 11 weeks after the loading dose, followed by a first maintenance dose every 15 to 24 weeks thereafter.

[0090] In another embodiment, the first maintenance dose is administered 6 to 11 weeks, or 7 to 10 weeks after the loading dose. In one embodiment, the first maintenance dose is administered approximately 2 months after the loading dose. In another embodiment, the first maintenance dose is administered 2 months after the loading dose. In one embodiment, the first maintenance dose is administered approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, or approximately 10 weeks after the loading dose. In another embodiment, the first maintenance dose is administered 7 weeks, 8 weeks, 9 weeks, or 10 weeks after the loading dose.

[0091] In another embodiment, a first maintenance dose is administered 15 to 19 weeks after the loading dose, followed by a first maintenance dose every 15 to 24 weeks thereafter.

[0092] In another embodiment, the first maintenance dose is administered 15 to 19 weeks, or 16 to 18 weeks after the loading dose. In one embodiment, the first maintenance dose is administered approximately 4 months after the loading dose. In another embodiment, the first maintenance dose is administered 4 months after the loading dose. In one embodiment, the first maintenance dose is administered approximately 16 weeks, approximately 17 weeks, or approximately 18 weeks after the loading dose. In another embodiment, the first maintenance dose is administered 16 weeks, 17 weeks, or 18 weeks after the loading dose.

[0093] In one implementation, the maintenance dose is administered every 15 to 20 weeks or every 15 to 19 weeks.

[0094] In one embodiment, the maintenance dose is administered every 4 months, i.e., every 16 to 18 weeks. In another embodiment, the maintenance dose is administered every 16 weeks, every 17 weeks, or every 18 weeks.

[0095] In one embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1200 mg of cabobetavir and is administered every 4 months, i.e., every 16 to 18 weeks. In one embodiment, the maintenance dose of the pharmaceutical composition comprises 1200 mg to 1800 mg of cabobetavir and is administered every 4 months, i.e., every 16 to 18 weeks. In one embodiment, the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabobetavir and is administered every 4 months, i.e., every 16 to 18 weeks.

[0096] In one embodiment, the method includes first administering a loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition contains at least 1500 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition containing at least 1200 mg of cabotevir to a person 1 month or 3 to 5 weeks after administering the loading dose; and then administering the maintenance dose every 4 months or 16 to 18 weeks thereafter.

[0097] In one embodiment, the method includes first administering a loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition comprises about 1200 mg to 4000 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition comprising 1200 to 1800 mg of cabotevir to the person 1 month or 3 to 5 weeks after administering the loading dose; and then administering the maintenance dose thereafter every 4 months or 16 to 18 weeks.

[0098] In one embodiment, the method includes first administering a loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition comprises about 3,000 mg to 3,500 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition comprising 1,500 to 1,700 mg of cabotevir to the person 1 month or 3 to 5 weeks after administering the loading dose; and then administering the maintenance dose thereafter every 4 months or 16 to 18 weeks.

[0099] In one embodiment, the method includes first administering a loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition comprises approximately 3200 mg of cabobotevir administered in two injections, each injection containing 1600 mg of cabobotevir; administering a maintenance dose of the pharmaceutical composition comprising approximately 1600 mg of cabobotevir to a person 1 month or 3 to 5 weeks after the loading dose; and then administering the maintenance dose thereafter every 4 months or 16 to 18 weeks.

[0100] In one embodiment, the method includes first administering a first loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition comprises about 3200 mg of cabobotevir, wherein the first loading dose is optionally administered in two separate injections, each containing 1600 mg of cabobotevir; administering a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a person 4 months or 16-18 weeks after administration of the first loading dose; administering a maintenance dose of one or more pharmaceutical compositions comprising about 1600 mg of cabobotevir to a person 4 months or 16-18 weeks after administration of the second loading dose; and then administering a maintenance dose comprising about 1600 mg of cabobotevir to a person every 4 months or 16-18 weeks thereafter.

[0101] In one embodiment, the method includes first administering a first loading dose of a pharmaceutical composition to a human, wherein the pharmaceutical composition comprises about 1600 mg of cabobotevir; administering a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 1 month or 3-5 weeks after administering the first loading dose; administering a third loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administering the second loading dose; administering a maintenance dose of one or more pharmaceutical compositions comprising about 1600 mg of cabobotevir to a human 4 months or 16-18 weeks after administering the third loading dose; and then thereafter administering a maintenance dose to a human every 4 months or 16 to 18 weeks.

[0102] In one embodiment, the method includes first administering a first loading dose of a pharmaceutical composition to a human, wherein the pharmaceutical composition comprises about 2400 mg of cabobotevir, wherein the first loading dose is optionally administered in two separate injections, each injection comprising 1200 mg of cabobotevir; administering a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administration of the first loading dose; administering a maintenance dose of one or more pharmaceutical compositions comprising about 1600 mg of cabobotevir to a human 4 months or 16 weeks after administration of the second loading dose; and then administering a maintenance dose comprising about 1600 mg of cabobotevir to a human every 4 months or 16 to 18 weeks thereafter.

[0103] In one embodiment, the method includes first administering a first loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition comprises about 2200 mg of cabobotevir, wherein the first loading dose is optionally administered in two separate injections (e.g., one injection of about 600 mg of cabobotevir and another injection of about 1600 mg of cabobotevir); administering a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a person 2 months or 7-10 weeks after administration of the first loading dose; administering a third loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a person 2 months or 7-10 weeks after administration of the second loading dose; administering a maintenance dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a person 4 months or 16-18 weeks after administration of the third loading dose; and then administering a maintenance dose comprising about 1600 mg of cabobotevir to a person every 4 months or 16 to 18 weeks thereafter.

[0104] In one embodiment, the method includes first administering a first loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition comprises about 600 mg of cabobotevir; administering a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a person 1 month or 3-5 weeks after administering the first loading dose; administering a third loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a person 2 months or 7-10 weeks after administering the second loading dose; administering a maintenance dose of one or more pharmaceutical compositions comprising about 1600 mg of cabobotevir to a person 4 months or 16-18 weeks after administering the third loading dose; and then thereafter administering a maintenance dose to a person every 4 months or 16-18 weeks.

[0105] In one embodiment, the method includes administering a first loading dose of a pharmaceutical composition to a human, wherein the pharmaceutical composition comprises about 600 mg of cabobotevir; administering a second loading dose of a pharmaceutical composition comprising about 600 mg of cabobotevir to a human 1 month or 3-5 weeks after administering the first loading dose; administering a third loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administering the second loading dose; administering a fourth loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administering the third loading dose; administering a maintenance dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 4 months or 16-18 weeks after administering the fourth loading dose; and then administering the maintenance dose to a human every 4 months or 16-18 weeks thereafter.

[0106] Oral delivery and oral bridging

[0107] In one embodiment, an oral lead-in is administered to assess cabobetavir to the person prior to the loading dose. In one embodiment, the oral lead-in is administered once daily for at least 28 days, approximately one month prior to the loading dose. In one embodiment, the oral lead-in is a cabobetavir tablet taken once daily. In one embodiment, the tablet contains cabobetavir sodium. In one embodiment, the tablet contains approximately 30 mg of cabobetavir sodium. In one embodiment, the tablet contains 30 mg of cabobetavir (equivalent to 31.62 mg of cabobetavir sodium). In one embodiment, the loading dose is administered on the last day of the oral lead-in. In one embodiment, the loading dose is administered within 3 days of discontinuing the oral lead-in.

[0108] In one embodiment, the maintenance dose is discontinued and replaced with oral tablets. In one embodiment, the oral tablets are taken once daily. In one embodiment, the oral tablets are cabobotevir tablets taken once daily. In one embodiment, the tablets contain cabobotevir sodium. In one embodiment, the tablets contain about 30 mg of cabobotevir sodium. In one embodiment, the tablets contain 30 mg of cabobotevir (equivalent to 31.62 mg of cabobotevir sodium). In one embodiment, the person restarts the maintenance dose after taking the oral tablets daily for up to 4 months or up to 16 to 18 weeks. In this embodiment, the maintenance dose is discontinued and replaced with daily cabobotevir oral tablets for up to 4 months or up to 16 to 18 weeks, then the maintenance dose is restarted and taken once every 15 to 20 weeks thereafter.

[0109] In one separate embodiment, a person takes oral tablets daily for more than 4 months or more than 16 to 18 weeks, in which a loading dose is taken before restarting the maintenance dose. In another embodiment, the maintenance dose is discontinued and replaced with cabotevir oral tablets taken daily for at least 4 months or at least 16 to 18 weeks, and then the loading dose is administered to the person; 2 to 6 weeks after the administration of the loading dose, the person is given the maintenance dose of the pharmaceutical composition; and then the maintenance dose is administered every 15 to 24 weeks thereafter.

[0110] Pharmaceutical Composition

[0111] The pharmaceutical composition used in the method of the present invention comprises cabotevir as described herein.

[0112] In one embodiment, the pharmaceutical composition comprises about 100 to about 800 mg / mL of cabobetavir. In a further embodiment, the pharmaceutical composition comprises about 200 mg / mL to about 700 mg / mL, about 300 mg / mL to about 650 mg / mL, about 400 mg / mL to about 600 mg / mL, about 450 mg / mL to about 600 mg / mL, about 500 mg / mL to about 600 mg / mL, about 550 mg / mL to about 600 mg / mL, about 200 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 533 mg / mL of cabobetavir. In one embodiment, the pharmaceutical composition comprises about 200 mg / mL of cabobetavir. In one embodiment, the pharmaceutical composition comprises 200 mg / mL of cabobetavir. In one embodiment, the pharmaceutical composition comprises about 400 mg / mL of cabobetavir. In another embodiment, the pharmaceutical composition comprises 400 mg / mL of cabobetavir. In a further embodiment, the pharmaceutical composition comprises about 533 mg / mL of cabotevir. In another embodiment, the pharmaceutical composition comprises 533 mg / mL of cabotevir.

[0113] In one embodiment, the pharmaceutical composition is reconstituted from a lyophilized powder, and after reconstitution, the pharmaceutical composition contains about 100 to about 800 mg / mL of cabotevir. In a further embodiment, the pharmaceutical composition, after reconstitution, contains about 200 mg / mL to about 700 mg / mL, about 300 mg / mL to about 650 mg / mL, about 400 mg / mL to about 600 mg / mL, about 400, about 500, or about 533 mg / mL of cabotevir. In one embodiment, the pharmaceutical composition, after reconstitution, contains about 400 mg / mL of cabotevir. In another embodiment, the pharmaceutical composition, after reconstitution, contains about 533 mg / mL of cabotevir.

[0114] Wetting agents, or surfactants, are compounds that, when dissolved in a liquid, can reduce the surface tension of gaseous, liquid, or solid surfaces within that liquid. They are typically amphiphilic and can contribute to wetting and enhancing the manufacturability of pharmaceutical products. Furthermore, surfactants can impart long-term product stability through steric or electrostatic repulsion. Nonionic surfactants are preferred over ionic surfactants because they are generally nontoxic, non-irritating, and inert. Examples of surfactants include, but are not limited to, polysorbate 20 (Tween-20), polysorbate 80 (Tween-80), sorbitol monolaurate (Span-20), sorbitol monooleate (Span-80), poloxamer 188 (Kolliphor P188), poloxamer 338 (Kolliphor P338), and poloxamer 407 (Kolliphor P407).

[0115] In one embodiment, the pharmaceutical composition used in the method of the present invention comprises polysorbate 80 (PS80) as a wetting agent.

[0116] PS80 (IUPAC name: Polyoxyethylene (20) dehydrated sorbitan monooleate; CAS No. 9005-65-6) is a nonionic surfactant and emulsifier derived from polyethoxylated dehydrated sorbitan and oleic acid. The hydrophilic group in PS80 is a polyether, also known as a polyoxyethylene group, which is a polymer of ethylene oxide. In the nomenclature of polysorbates, the numerical name following "polysorbate" (e.g., "polysorbate 80") refers to the lipophilic group, in this case, oleic acid. The structure of PS80 is provided by formula (II): (II) In one embodiment, the pharmaceutical composition contains a wetting agent of about 0.1 mg / mL to about 150 mg / mL. In another embodiment, the pharmaceutical composition contains a wetting agent of about 1 mg / mL to about 80 mg / mL, about 2 mg / mL to about 40 mg / mL, about 2.5 mg / mL to about 6 mg / mL, or about 2.5 mg / mL to about 5 mg / mL.

[0117] In one embodiment, the pharmaceutical composition contains a wetting agent at a concentration of about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 mg / mL. In another embodiment, the pharmaceutical composition contains a wetting agent at a concentration of about 3.0 mg / mL. In another embodiment, the pharmaceutical composition contains a wetting agent at a concentration of about 4.0 mg / mL. In yet another embodiment, the pharmaceutical composition contains a wetting agent at a concentration of about 5.3 mg / mL.

[0118] In one embodiment, the pharmaceutical composition is reconstituted from a lyophilized powder and contains a wetting agent of about 0.1 mg / mL to about 150 mg / mL. In a further embodiment, the pharmaceutical composition, after reconstitution, contains a wetting agent of about 1 mg / mL to about 80 mg / mL, about 2 mg / mL to about 40 mg / mL, about 2.5 mg / mL to about 6 mg / mL, or about 2.5 mg / mL to about 5 mg / mL.

[0119] In one embodiment, the pharmaceutical composition is reconstituted from a lyophilized powder and contains a wetting agent at a concentration of about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 mg / mL. In another embodiment, the pharmaceutical composition, after reconstitution, contains a wetting agent at a concentration of about 3.0 mg / mL. In yet another embodiment, the pharmaceutical composition, after reconstitution, contains a wetting agent at a concentration of about 4.0 mg / mL. In another embodiment, the pharmaceutical composition, after reconstruction, comprises about 5.3 mg / mL of wetting agent.

[0120] In one embodiment, the pharmaceutical composition comprises about 0.1 mg to about 900 mg of wetting agent. In another embodiment, the pharmaceutical composition comprises about 0.5 mg to about 200 mg of wetting agent. In another embodiment, the pharmaceutical composition comprises about 1.0 mg to about 100 mg of wetting agent. In yet another embodiment, the pharmaceutical composition comprises about 2.0 mg to about 50 mg of wetting agent. In another embodiment, the pharmaceutical composition contains about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, and 6.6 mg. 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 1 5.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0、20.1、20.2、20.3、20.4、20.5、20.6、20.7、20.8、20.9、21.0、21.1、21.2、21.3、21.4、21.5、21.6、21.7、21.8、21.9、22.0、22.1、22.2、22.3、22.4、22.5、22.6、22.7、22.8、22.9、23.0、23.1、23.2、23.3、23.4、23.5、23.6、23.7、23.8、23.9、24.0、24.1、24.2、24.3、24.4、24.5、24.6、24.7、24.8、24.9、25.0、25.1、25.2、25.3、25.4、25.5、25.6、25.7、25.8、25.9、26.0、26.1、26.2、26.3、26.4、26.5、26.6、26.7、26.8、26.9、27.0、27.1、27.2、27.3、27.4、27.5、27.6、27.7、27.8、27.9、28.0、28.1、28.2、28.3、28.4、28.5、28.6、28.7、28.8、28.9、29.0、29.1、29.2、29.3、29.4、29.5、29.6、29.7、29.8、29.9、30.0、30.1、30.2、30.3、30.4、30.5、30.6、30.7、30.8、30.9、31.0、31.1、31.2、31.3、31.4、31.5、31.6、31.7、31.8、31.9、32.0、32.1、32.2、32.3、32.4、32.5、32.6、32.7、32.8、32.9、33.0、33.1、33.2、33.3、33.4、33.5、33.6、33.7、33.8、33.9、34.0、34.1、34.2、34.3、34.4、34.5、34.6、34.7、34.8、34.9、35.0、35.1、35.2、35.3、35.4、35.5、35.6、35.7、35.8、35.9、36.0、36.1、36.2、36.3、36.4、36.5、36.6、36.7、36.8、36.9、37.0、37.1、37.2、37.3、37.4、37.5、37.6、37.7、37.8、37.9、38.0、38.1、38.2、38.3、38.4、38.5、38.6、38.7、38.8、38.9、39.0、39.1、39.2、39.3、39.4、39.5、39.6、39.7、39.8、39.9、40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42. 6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45. 1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47. 6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.0 wetting agent. In one embodiment, the pharmaceutical composition comprises about 5.9 mg of wetting agent. In one embodiment, the pharmaceutical composition comprises about 8.0 mg of wetting agent.

[0121] In one embodiment, the weight ratio of the wetting agent to cabotevir ranges from 1:10 to 1:400. In another embodiment, the weight ratio of the wetting agent to cabotevir ranges from 1:50 to 1:200. In yet another embodiment, the weight ratio of the wetting agent to cabotevir ranges from 1:100 to 1:150. In another embodiment, the weight ratio of the wetting agent to cabotevir is about 1:100, about 1:101, about 1:102, about 1:103, about 1:104, about 1:105, about 1:106, about 1:107, about 1:108, about 1:109, about 1:110, about 1:111, about 1:112, about 1:113, about 1:114, about 1:115, about 1:116, about 1:117, about 1:118, about 1:119, about 1:120, about 1:121, about 1:122, about 1:123. The ratios are approximately 1:124, 1:125, 1:126, 1:127, 1:128, 1:129, 1:130, 1:131, 1:132, 1:133, 1:134, 1:135, 1:136, 1:137, 1:138, 1:139, 1:140, 1:141, 1:142, 1:143, 1:144, 1:145, 1:146, 1:147, 1:148, 1:149, or 1:150. In another embodiment, the weight ratio of the wetting agent to cabotevir is approximately 1:100. In another embodiment, the weight ratio of the wetting agent to cabotevir is approximately 1:105. In another embodiment, the weight ratio of the wetting agent to cabotevir is about 1:110. In another embodiment, the weight ratio of the wetting agent to cabotevir is about 1:115. In yet another embodiment, the weight ratio of the wetting agent to cabotevir is about 1:136.

[0122] Stabilizers are components added to help maintain key product properties throughout their shelf life. In the case of suspensions, stabilizers can be used to induce charge effects, increase steric stability, increase the viscosity of the medium, etc. These factors can maintain particle size, product resuspensibility, and / or improve manufacturability. Examples of stabilizers include, but are not limited to, sodium carboxymethyl cellulose (CMC), polyethylene glycol 3350, polyethylene glycol 4000, povidone K12, and povidone K17.

[0123] In one embodiment, the pharmaceutical composition of the present invention comprises sodium CMC as a stabilizer.

[0124] In one embodiment, the pharmaceutical composition contains about 0.1 to about 150 mg / mL of a stabilizer. In a further embodiment, the pharmaceutical composition contains about 1 mg / mL to about 25 mg / mL, about 2 mg / mL to about 15 mg / mL, about 2 mg / mL to about 10 mg / mL, or about 3 mg / mL to about 10 mg / mL of a stabilizer.

[0125] In one embodiment, the pharmaceutical composition contains about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, ... (mg / mL) Stabilizers of 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In another embodiment, the pharmaceutical composition comprises about 3.7 mg / mL of stabilizer. In another embodiment, the pharmaceutical composition comprises about 5.0 mg / mL of stabilizer. In another embodiment, the pharmaceutical composition comprises about 6.7 mg / mL of stabilizer.

[0126] In one embodiment, the pharmaceutical composition is reconstituted from a lyophilized powder and contains a stabilizer of about 0.1 to about 150 mg / mL. In a further embodiment, the pharmaceutical composition, after reconstitution, contains a stabilizer of about 1 mg / mL to about 25 mg / mL, about 2 mg / mL to about 15 mg / mL, about 2 mg / mL to about 10 mg / mL, or about 3 mg / mL to about 10 mg / mL.

[0127] In one embodiment, the pharmaceutical composition is reconstituted from a lyophilized powder and contains approximately 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, and 5.6 mg / mL. The pharmaceutical composition comprises a stabilizer of 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In another embodiment, the pharmaceutical composition comprises about 3.7 mg / mL of stabilizer after reconstitution. In another embodiment, the pharmaceutical composition comprises about 5.0 mg / mL of stabilizer after reconstitution. In another embodiment, the pharmaceutical composition comprises about 6.7 mg / mL of stabilizer after reconstitution.

[0128] In one embodiment, the pharmaceutical composition comprises about 0.1 mg to about 300 mg of stabilizer. In another embodiment, the pharmaceutical composition comprises about 1.0 mg to about 200 mg of stabilizer. In another embodiment, the pharmaceutical composition comprises about 2.0 mg to about 100 mg of stabilizer. In yet another embodiment, the pharmaceutical composition comprises about 4.0 mg to about 50 mg of stabilizer. In another embodiment, the pharmaceutical composition contains about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8 mg. 7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13 2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7、21.8、21.9、22.0、22.1、22.2、22.3、22.4、22.5、22.6、22.7、22.8、22.9、23.0、23.1、23.2、23.3、23.4、23.5、23.6、23.7、23.8、23.9、24.0、24.1、24.2、24.3、24.4、24.5、24.6、24.7、24.8、24.9、25.0、25.1、25.2、25.3、25.4、25.5、25.6、25.7、25.8、25.9、26.0、26.1、26.2、26.3、26.4、26.5、26.6、26.7、26.8、26.9、27.0、27.1、27.2、27.3、27.4、27.5、27.6、27.7、27.8、27.9、28.0、28.1、28.2、28.3、28.4、28.5、28.6、28.7、28.8、28.9、29.0、29.1、29.2、29.3、29.4、29.5、29.6、29.7、29.8、29.9、30.0、30.1、30.2、30.3、30.4、30.5、30.6、30.7、30.8、30.9、31.0、31.1、31.2、31.3、31.4、31.5、31.6、31.7、31.8、31.9、32.0、32.1、32.2、32.3、32.4、32.5、32.6、32.7、32.8、32.9、33.0、33.1、33.2、33.3、33.4、33.5、33.6、33.7、33.8、33.9、34.0、34.1、34.2、34.3、34.4、34.5、34.6、34.7、34.8、34.9、35.0、35.1、35.2、35.3、35.4、35.5、35.6、35.7、35.8、35.9、36.0、36.1、36.2、36.3、36.4、36.5、36.6、36.7、36.8、36.9、37.0、37.1、37.2、37.3、37.4、37.5、37.6、37.7、37.8、37.9、38.0、38.1、38.2、38.3、38.4、38.5、38.6、38.7、38.8、38.9、39.0、39.1、39.2、39.3、39.4、39.5、39.6、39.7、39.8、39.9、40.0、40.1、40.2、40.3、40.4、40.5、40.6、40.7、40.8、40.9、41.0、41.2、41.3、41.4、41.5、41.6、41.7、41.8, 41.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 4 5.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.0 stabilizers. In one embodiment, the pharmaceutical composition comprises about 7.4 mg of stabilizer. In one embodiment, the pharmaceutical composition comprises about 10.0 mg of stabilizer. .

[0129] In one embodiment, the weight ratio of the stabilizer to cabotevir is in the range of 1:10 to 1:400. In another embodiment, the weight ratio of the stabilizer to cabotevir is in the range of 1:40 to 1:200. In yet another embodiment, the weight ratio of the stabilizer to cabotevir is in the range of 1:70 to 1:120. In another embodiment, the weight ratio of the stabilizer to cabotevir is approximately 1:70, 1:71, 1:72, 1:73, 1:74, 1:75, 1:76, 1:77, 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84, 1:85, 1:86, 1:87, 1:88, 1:89, 1:90, 1:91, 1:92, 1:93, 1:94, or approximately 1... The ratios are approximately 1:95, 1:96, 1:97, 1:98, 1:99, 1:100, 1:101, 1:102, 1:103, 1:104, 1:105, 1:106, 1:107, 1:108, 1:109, 1:110, 1:111, 1:112, 1:113, 1:114, 1:115, 1:116, 1:117, 1:118, 1:119, or 1:120. In another embodiment, the weight ratio of the stabilizer to cabotevir is approximately 1:80. In another embodiment, the weight ratio of the stabilizer to cabotevir is approximately 1:100. In another embodiment, the weight ratio of the stabilizer to cabotevir is approximately 1:101. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:102. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:103. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:104. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:105. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:106. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:107. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:108.

[0130] Tensor modifiers are used to provide and maintain stable tension for the pharmaceutical compositions disclosed herein. In some embodiments, the tensor modifier also functions as a non-aqueous solvent, solubilizer, and / or stabilizer. In such cases, if the primary purpose of the tensor modifier is stability, it may be used at a concentration higher than that required for tension, or if the primary purpose of the tensor modifier is tension regulation, it may be used at a concentration higher than that required for stability.

[0131] In some embodiments, the tonic modifier is a pharmaceutically acceptable inorganic chloride, such as potassium chloride, sodium chloride, magnesium chloride, or calcium chloride. In other embodiments, the tonic modifier is a sugar, such as mannitol, sorbitol, lactose, trehalose, raffinose, dextrose, maltose, galactose, sucrose, or polysucrose. In another aspect, the tonic modifier is mannitol. In still other aspects, the tonic modifier is a non-aqueous polar aprotic or protic material, such as polyethylene glycol, N,N-dimethylacetamide, N-methylpyrrolidone, glycerol, propylene glycol, ethanol, tert-butanol, benzyl alcohol, benzyl benzoate, dimethyl sulfoxide, or glycerol. In yet another aspect, the tonic modifier is a polymer, such as polyethylene glycol, polygalacturonic acid, galacturonic acid, polyvinylpyrrolidone (PVP), such as PEG 300, PEG 400, PEG 3350, PEG 6000, or PEG 8000. In other respects, tension modifiers are amino acids, such as lysine, arginine, glycine, methionine, or other amino acids. In yet another respect, tension modifiers are cyclodextrins, such as dextran, sucrose, and polyvinylpyrrolidone, as well as other similar excipients and combinations of these agents.

[0132] In one embodiment, the pharmaceutical composition of the present invention comprises mannitol as a tension modulator.

[0133] In one embodiment, the pharmaceutical composition contains about 0.1 to about 250 mg / mL of a tonic modulator. In another embodiment, the pharmaceutical composition contains about 1 mg / mL to about 150 mg / mL, about 10 mg / mL to about 125 mg / mL, about 15 mg / mL to about 60 mg / mL, about 15 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 20 mg / mL to about 40 mg / mL of a tonic modulator.

[0134] In one embodiment, the pharmaceutical composition contains about 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, and 24 mg / mL. 4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26. 9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29. 4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31. 9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34. 4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36. 9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42 1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 4 The pharmaceutical composition comprises a tension modifier at concentrations of 7.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.0. In another embodiment, the pharmaceutical composition comprises about 25.9 mg / mL of a tension modifier. In another embodiment, the pharmaceutical composition comprises about 35.0 mg / mL of a tension modifier. In yet another embodiment, the pharmaceutical composition comprises about 46.6 mg / mL of a tension modifier.

[0135] In one embodiment, the pharmaceutical composition is reconstituted from a lyophilized powder and contains about 0.1 to about 250 mg / mL of a tonic modifier. In a further embodiment, the pharmaceutical composition, after reconstitution, contains about 1 mg / mL to about 150 mg / mL, about 10 mg / mL to about 125 mg / mL, about 15 mg / mL to about 60 mg / mL, about 15 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 20 mg / mL to about 40 mg / mL of a tonic modifier.

[0136] In one embodiment, the pharmaceutical composition has been reconstituted from lyophilized powder and contains approximately 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, and 24 mg / mL. 2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26. 7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29. 2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31. 7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34. 2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36. 7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41 9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 4 4.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, The pharmaceutical composition comprises a tonic modulator of 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.0 mg / mL. In another embodiment, the pharmaceutical composition, after reconstitution, comprises about 25.9 mg / mL of a tonic modulator. In another embodiment, the pharmaceutical composition, after reconstitution, comprises about 35.0 mg / mL of a tonic modulator. In yet another embodiment, the pharmaceutical composition, after reconstitution, comprises about 46.6 mg / mL of a tonic modulator.

[0137] In one embodiment, the pharmaceutical composition comprises about 0.1 mg to about 400 mg of a tension modulator. In another embodiment, the pharmaceutical composition comprises about 1.0 mg to about 300 mg of a tension modulator. In another embodiment, the pharmaceutical composition comprises about 10 mg to about 100 mg of a tension modulator. In yet another embodiment, the pharmaceutical composition comprises about 35 mg to about 80 mg of a tension modulator. In another embodiment, the pharmaceutical composition contains approximately 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38 mg. 7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 4 7.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, 50.0, 50.1, 50.2, 50.3, 50.4, 50.5, 50.6, 50.7, 50.8, 50.9, 51.0, 51.1, 51.2, 51.3, 51.4、51.5、51.6、51.7、51.8、51.9、52.0、52.1、52.2、52.3、52.4、52.5、52.6、52.7、52.8、52.9、53.0、53.1、53.2、53.3、53.4、53.5、53.6、53.7、53.8、53.9、54.0、54.1、54.2、54.3、54.4、54.5、54.6、54.7、54.8、54.9、55.0、55.1、55.2、55.3、55.4、55.5、55.6、55.7、55.8、55.9、56.0、56.1、56.2、56.3、56.4、56.5、56.6、56.7、56.8、56.9、57.0、57.1、57.2、57.3、57.4、57.5、57.6、57.7、57.8、57.9、58.0、58.1、58.2、58.3、58.4、58.5、58.6、58.7、58.8、58.9、59.0、59.1、59.2、59.3、59.4、59.5、59.6、59.7、59.8、59.9、60.0、60.1、60.2、60.3、60.4、60.5、60.6、60.7、60.8、60.9、61.0、61.1、61.2、61.3、61.4、61.5、61.6、61.7、61.8、61.9、62.0、62.1、62.2、62.3、62.4、62.5、62.6、62.7、62.8、62.9、63.0、63.1、63.2、63.3、63.4、63.5、63.6、63.7、63.8、63.9、64.0、64.1、64.2、64.3、64.4、64.5、64.6、64.7、64.8、64.9、65.0、65.1、65.2、65.3、65.4、65.5、65.6、65.7、65.8、65.9、66.0、66.1、66.2、66.3、66.4、66.5、66.6、66.7、66.8、66.9、67.0、67.1、67.2、67.3、67.4、67.5、67.6、67.7、67.8、67.9、68.0、68.1、68.2、68.3、68.4、68.5、68.6、68.7、68.8、68.9、69.0、69.1、69.2、69.3、69.4、69.5、69.6、69.7、69.8、69.9、70.0、70.1、70.2、70.3、70.4、70.5、70.6、70.7、70.8、70.9、71.0、71.1、71.2、71.3、71.4, 71.5, 71.6, 71.7, 71.8, 71.9, 72.0, 72.1, 72.2, 72.3, 72.4, 72.5, 72.6, 72.7, 72.8, 72.9, 73.0, 73.1, 73.2, 73.3, 73.4, 73.5, 73.6, 73.7, 73.8, 73.9, 74.0, 74.1, 74.2, 74.3, 74.4, 74.5, 74.6, 74.7, 74.8, 74.9, 75.0, 75.1, 75.2, 75.3, 75.4, 75.5, 75.6, 7 Isotonic modifiers of 5.7, 75.8, 75.9, 76.0, 76.1, 76.2, 76.3, 76.4, 76.5, 76.6, 76.7, 76.8, 76.9, 77.0, 77.1, 77.2, 77.3, 77.4, 77.5, 77.6, 77.7, 77.8, 77.9, 78.0, 78.1, 78.2, 78.3, 78.4, 78.5, 78.6, 78.7, 78.8, 78.9, 79.0, 79.1, 79.2, 79.3, 79.4, 79.5, 79.6, 79.7, 79.8, 79.9, or 80.0. In one embodiment, the pharmaceutical composition comprises about 51.8 mg of a tonic modifier. In one embodiment, the pharmaceutical composition comprises about 70 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 105 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 140 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 175 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 210 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 245 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 280 mg of a tension modulator.

[0138] In one embodiment, the weight ratio of the tension modifier to cabobetavir is in the range of 1:1 to 1:100. In another embodiment, the weight ratio of the tension modifier to cabobetavir is in the range of 1:5 to 1:50. In another embodiment, the weight ratio of the tension modifier to cabobetavir is in the range of 1:8 to 1:25. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, or about 1:25. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:8. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:9. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:10. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:11. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:12. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:13. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:14. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:15.

[0139] In one embodiment, the pharmaceutical composition of the present invention comprises crystalline cabotevir particles. In one embodiment, the cabotevir particles of the pharmaceutical composition have an X50 value greater than or equal to 2.5 μm and less than or equal to 10 μm (i.e., 2.5 μm ≤ X50 ≤ 10 μm). The particle size distribution can be measured by any suitable method, for example, by laser diffraction as described in the Examples section herein.

[0140] As used herein, X50 (or “X50 value”) is the diameter of Cabotene particles in micrometers, where 50% by volume of Cabotene particles have a smaller diameter and 50% by volume have a larger diameter, also known as the mass median diameter (MMD) or the median of the particle size distribution by volume.

[0141] As used herein, X90 (or “X90 value”) is the diameter of Cabotene particles in micrometers, where 90% by volume of Cabotene particles have a smaller diameter and 10% by volume have a larger diameter.

[0142] As used herein, X10 (or “X10 value”) is the diameter of the cabotubevir particles in micrometers, where 10% by volume of the cabotubevir particles have a smaller diameter and 90% by volume have a larger diameter.

[0143] In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 90% of the cabotevir particles have a particle size of less than or equal to 25 μm (i.e., x90 = 25 μm). In one embodiment, the cabotevir particles of the pharmaceutical composition have an x90 value greater than or equal to 5 μm and less than or equal to 25 μm (i.e., 5 μm ≤ x90 ≤ 25 μm). In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 90% of the cabotevir particles have a particle size of less than or equal to 20 μm (i.e., x90 = 20 μm). In one embodiment, the cabotevir particles of the pharmaceutical composition have an x90 value greater than or equal to 6 μm and less than or equal to 20 μm (i.e., 6 μm ≤ x90 ≤ 20 μm). In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 90% of the cabotevir particles have a particle size of less than or equal to 18 μm (i.e., x90 = 18 μm). In one embodiment, the cabotevir particles of the pharmaceutical composition have an X90 value greater than or equal to 7 μm and less than or equal to 18 μm (i.e., 7 μm ≤ X90 ≤ 18 μm).

[0144] In one embodiment, the pharmaceutical composition has a particle size distribution such that 90% of the carbon particles (X90) have less than or equal to 7.0 µm, 7.1 µm, 7.2 µm, 7.3 µm, 7.4 µm, 7.5 µm, 7.6 µm, 7.7 µm, 7.8 µm, 7.9 µm, 8.0 µm, 8.1 µm, 8.2 µm, 8.3 µm. m、8.4 μ m、8.5 μ m、8.6 μ m、8.7 μ m、8.8 μ m、8.9 μ m、9.0 μ m、9.1 μ m、9.2 μ m、9.3 μ m、9.4 μ m、9.5 μ m、9.6 μ m、9.7 μ m、9.8 μ m、9.9 μ m、10.0 μ m、10.1 μ m、10.2 μ m m、10.3 m m、10.4 μm、10.5 μ m、10.6 μ m、10.7 μ m、10.8 μ m、10.9 μ m、11.0 μ m、11.1 μ m、11.2 μ m、11.3 μ m、11.4 μ m、11.5 μ m、11.6 μ m、11.7 μ m、11.8 μ m、11.9 μ m、12.0 μ m、12.1μ m、12.2 μ m、12.3 μ m、12.4 μ m、12.5 μ m、12.5 μ m、12.6 μ m、12.7 μ m、12.8 μ m、12.9 μ m、11.0 μ m、11.1 μ m、11.2 μ m、11.3 μ m、11.4 μ m、11.5 μ m、11.6 μ m、11.7μ m、11.8 μ m、11.9 μ m、12.0 μ m、12.1 μ m、12.2 μ m、12.3 μ m、12.4 μ m、12.5 μ m、12.8 μ m、11.9 μ m、11.0 μ m、11.1 μ m、11.2 μ m、11.3 μ m、11.4 μ m、11.5 μ m m、11.6μ m、11.7 μ m、11.8 μ m、11.9 μ m、11.0 μ m、11.1 μ m、11.2 μ m、11.3 μ m、11.4 μ m、11.5 μ m、11.7 μ m、11.8 μ m、11.9 μ m、16.3 μ M、16.4 μ M、16.5 μ M、16.6 μ m m M、16.7m M、16.8m M、16.9 μ M、17.0 μ M、17.1 μ M、17.2 μ M、17.3 μ M、17.4 μM, 17.5 μM, 17.6 μM, 17.7 μM, 17.8 μM, 17.9 μM, or 18.0 μM. In another embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 90% of the cabotevir particles (X90) have a particle size of less than or equal to 9 μm (i.e., X90 is 9 μm). In another embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 90% of the cabotevir particles (X90) have a particle size of less than or equal to 14 μm (i.e., X90 is 14 μm). In yet another embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 90% of the cabotevir particles (X90) have a particle size of less than or equal to 17 μm (i.e., X90 is 17 μm).

[0145] In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 50% of the cabotevir particles have a particle size of less than or equal to 10 μm (i.e., X50 is 10 μm). In one embodiment, the cabotevir particles of the pharmaceutical composition have an X50 value greater than or equal to 2.5 μm and less than or equal to 10 μm (i.e., 2.5 μm ≤ X50 ≤ 10 μm). In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 50% of the cabotevir particles have a particle size of less than or equal to 8.5 μm (i.e., X50 is 8.5 μm). In one embodiment, the cabotevir particles of the pharmaceutical composition have an X50 value greater than or equal to 3 μm and less than or equal to 8.5 μm (i.e., 3 μm ≤ X50 ≤ 8.5 μm). In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 50% of the cabotevir particles have a particle size of less than or equal to 8 μm (i.e., X50 is 8 μm). In one embodiment, the cabotevir particles of the pharmaceutical composition have an X50 value greater than or equal to 3.5 μm and less than or equal to 8 μm (i.e., 3.5 μm ≤ X50 ≤ 8 μm).

[0146] In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 50% of the cabotevir particles (X50) have particle sizes less than or equal to 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, 4.1 μm, 4.2 μm, 4.3 μm, 4.4 μm, 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.0 μm, 5.1 μm, 5.2 μm, 5.3 μm, 5.4 μm, 5.5 μm, 5.6 μm, 5.7 μm, 5.8 μm, 5.9 μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, etc. Particle sizes of 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm, 7.1 μm, 7.2 μm, 7.3 μm, 7.4 μm, 7.5 μm, 7.6 μm, 7.7 μm, 7.8 μm, 7.9 μm, or 8.0 μm are specified. In another embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 50% of the cabotevir particles (X50) have a particle size of less than or equal to 4 μm (i.e., X50 is 4 μm). In yet another embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 50% of the cabotevir particles (X50) have a particle size of less than or equal to 6 μm (i.e., X50 is 6 μm).

[0147] In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 10% of the cabotevir particles have a particle size of less than or equal to 4 μm (i.e., x10 = 4 μm). In one embodiment, the cabotevir particles of the pharmaceutical composition have a x10 value greater than or equal to 0.5 μm and less than or equal to 4 μm (i.e., 0.5 μm ≤ x10 ≤ 4 μm). In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 10% of the cabotevir particles have a particle size of less than or equal to 3.5 μm. In one embodiment, the cabotevir particles of the pharmaceutical composition have a x10 value greater than or equal to 1 μm and less than or equal to 3.5 μm (i.e., 1 μm ≤ x10 ≤ 3.5 μm). In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 10% of the cabotevir particles have a particle size of less than or equal to 3 μm. In one embodiment, the cabotevir particles of the pharmaceutical composition have an X10 value greater than or equal to 1.5 μm and less than or equal to 3 μm (i.e., 1.5 μm ≤ X10 ≤ 3 μm).

[0148] In one embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 10% of cabotevir particles (X10) have a particle size less than or equal to 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, or 4.0 μm. In another embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 10% of the cabotabevir particles (X10) have a particle size of less than or equal to 1.7 μm (i.e., X10 is 1.7 μm). In another embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 10% of the cabotabevir particles (X10) have a particle size of less than or equal to 2.2 μm (i.e., X10 is 2.2 μm). In yet another embodiment, the pharmaceutical composition has a volumetric particle size distribution such that 10% of the cabotabevir particles (X10) have a particle size of less than or equal to 2.6 μm (i.e., X10 is 2.6 μm).

[0149] In one embodiment, all X90, X50, and X10 values ​​described herein are volumetric and determined by laser diffraction. Laser diffraction is sensitive to particle volume and provides a volume-average particle size, which, if the density is constant, is equal to the weight-average particle size. It will be apparent to those skilled in the art that a particle size distribution determined by one technique can be correlated with a particle size distribution determined by another technique, for example, empirically based on routine experiments. Alternatively, the particle size distribution can be determined by microscopy, particularly electron microscopy or scanning electron microscopy.

[0150] Freeze-drying includes at least a freezing step and a sublimation step. Freeze-drying can be used to manufacture pharmaceutical products and their intermediates. During freezing, materials are cooled to temperatures in which the solid, liquid, and gaseous phases of the material can exist. Active pharmaceutical product ingredients (APIs) can be freeze-dried to achieve chemical and physical stability that allows for storage at room temperature. This differs from traditional methods that use heat to evaporate water. The advantages of freeze-drying include, but are not limited to, enhanced stability of dry powders, removal of water without overheating the product, and enhanced product stability in the dry state.

[0151] In an exemplary method for preparing the lyophilized formulation of the present invention, micronized cabotevir free acid is packaged in an antistatic linear low-density polyethylene bag. The packaged cabotevir is sealed in a corrugated plastic box and subjected to gamma irradiation as a bioburden reduction step, and is referred to as gamma-irradiated cabotevir. The gamma-irradiated cabotevir is dispersed in a filtered aqueous medium containing a stabilizer (e.g., sodium CMC), a tensile agent (e.g., mannitol), and a wetting agent (e.g., PS80). The resulting suspension is filled into 10 mL Type I clear glass vials that have been washed, sterilized / depyrogenated. The container material is then treated: the vials are depyrogenated by dry heat and the stopper and top seal are sterilized by steam. The product vials are lyophilized, backwashed with nitrogen, sealed with halogenated butyl rubber stoppers, and secured with an aluminum outer seal. The sealed vials are then subjected to final sterilization by gamma radiation.

[0152] In one embodiment, the lyophilized pharmaceutical composition is a suspension. When reconstituted in an aqueous or non-aqueous solution, the lyophilized pharmaceutical composition is advantageously suspended, i.e., all or substantially all, for example at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% of the lyophilized pharmaceutical composition is suspended during reconstitution.

[0153] Reconstruction can be visually assessed with the naked eye. A lyophilized material is considered reconstructed when a homogeneous suspension is observed. In particular, a suspension with a turbid appearance is considered appropriately reconstructed.

[0154] It will be apparent to those skilled in the art that the pharmaceutical compositions described herein can be reconstituted to the desired concentrations in aqueous or non-aqueous solutions. For example, the pharmaceutical compositions described in Examples 1-3 below can be reconstituted in 1.7 mL of water to achieve a cabotevir concentration of 400 mg / mL. Similarly, the same pharmaceutical compositions described in Examples 1-3 below can be reconstituted in 1.1 mL of water to achieve a cabotevir concentration of 533 mg / mL.

[0155] In one embodiment, this disclosure provides a lyophilized pharmaceutical composition comprising cabotegravir, wherein cabotegravir is present in particulate form having a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive); a wetting agent; a stabilizer; and a tension modifier; wherein the lyophilized pharmaceutical composition has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5 minutes or less when reconstituted in an aqueous solution. In another embodiment, this disclosure provides a lyophilized pharmaceutical composition comprising cabotegravir, wherein cabotegravir is present in particulate form having a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive); PS80; sodium CMC; and mannitol; wherein the lyophilized pharmaceutical composition has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5 minutes or less when reconstituted in an aqueous or non-aqueous solution.

[0156] In one embodiment, the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0157] In one embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X50 = 6 μm); 51.8 mg mannitol; 5.9 mg PS80; and 7.4 mg CMC sodium. In another embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X10 = 2.2 μm); 51.8 mg mannitol; 5.9 mg PS80; and 7.4 mg CMC sodium. In yet another embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X90 = 17 μm); 51.8 mg mannitol; 5.9 mg PS80; and 7.4 mg CMC sodium.

[0158] In one embodiment, the pharmaceutical composition comprises 800 mg cabotevir (x50 = 6 μm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium. In another embodiment, the pharmaceutical composition comprises 800 mg (x10 = 2.6 μm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium. In yet another embodiment, the pharmaceutical composition comprises 800 mg cabotevir (x90 = 14 μm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium.

[0159] In one embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X50 = 4 μm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium. In another embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X10 = 1.7 μm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium. In yet another embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X90 = 9 μm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium.

[0160] In another embodiment, the pharmaceutical composition comprises cabotevir, wherein cabotevir is present in particulate form with an X50 value greater than or equal to 3.5 μm and less than or equal to 8 μm; PS80; sodium CMC; and mannitol; wherein the weight ratio of cabotevir:PS80:sodium CMC:mannitol is about 100:1:1.25:8.75.

[0161] In another embodiment, the pharmaceutical composition comprises cabotevir, wherein cabotevir is present in particulate form with an X50 value greater than or equal to 3.5 μm and less than or equal to 8 μm; PS80; sodium CMC; and mannitol; wherein the weight ratio of cabotevir:PS80:sodium CMC:mannitol is about 400:3:3.7:25.9.

[0162] In another embodiment, the pharmaceutical composition, after lyophilization and reconstitution, is as described in Table 1a-1 or 1a-2: Table 1a-1

[0163] Table 1a-2

[0164] In another embodiment, the pharmaceutical composition, after lyophilization and reconstitution, is as described in Table 1b: Table 1b

[0165] In another embodiment, the pharmaceutical composition, after lyophilization and reconstruction with 1.7 or 1.1 mL of water, is as described in Table 1c: Table 1c

[0166] In another embodiment, the pharmaceutical composition, after lyophilization and reconstruction with 1.7 or 1.1 mL of water, is as described in Table 1d: Table 1d

[0167] In another embodiment, the pharmaceutical composition, after lyophilization and reconstruction with 1.7 or 1.1 mL of water, is as described in Table 1e: Table 1e

[0168] In one embodiment, the pharmaceutical composition of the present invention has a pH of about 4 or higher. If the composition is administered by injection, a pH of about 4 or higher relieves the patient's pain. In one embodiment, the pharmaceutical composition of the present invention has a pH of about 6.5. In an alternative embodiment, the pH of the pharmaceutical composition is in the range of about 4 to about 8. In an alternative embodiment, the pH of the pharmaceutical composition is in the range of about 5 to about 7. In an alternative embodiment, the pH of the pharmaceutical composition is in the range of about 6 to about 7.

[0169] In another embodiment, the pharmaceutical composition comprises about 200 mg / mL of cabobetavir. In one embodiment, the pharmaceutical composition comprises about 200 mg / mL of cabobetavir and at least one pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprises 200 mg / mL of cabobetavir. In one embodiment, the pharmaceutical composition comprises 200 mg / mL of cabobetavir and at least one pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is an injectable suspension. In one embodiment, the pharmaceutical composition comprises about 600 mg of cabobetavir. In one embodiment, the pharmaceutical composition comprises about 600 mg of cabobetavir and at least one pharmaceutically acceptable excipient. In another embodiment of the invention, the pharmaceutical composition comprises 600 mg of cabobetavir. In another embodiment, the pharmaceutical composition comprises 600 mg of cabobetavir and at least one pharmaceutically acceptable excipient.

[0170] In one embodiment, the pharmaceutical composition further comprises polyethylene glycol (PEG), which is a pharmaceutically acceptable excipient. In one embodiment, the PEG is PEG 3350. In one embodiment, the pharmaceutical composition further comprises polysorbate 20, which is a pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition further comprises mannitol, which is a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprises 600 mg cabotevir, PEG 3350, polysorbate 20, and mannitol. In one embodiment, the pharmaceutical composition is as described in WO2012 / 037320, which is incorporated herein by reference.

[0171] In one embodiment, the pharmaceutical composition is suitable for use as an injectable formulation. In one embodiment, the pharmaceutical composition is an injectable suspension. In one embodiment, the pharmaceutical composition is an injectable suspension suitable for intramuscular administration.

[0172] In one embodiment, the pharmaceutical composition is APRETUDE®. APRETUDE®, also referred to herein as Apretude, is an approved extended-release cabotevir injectable suspension for the prevention of HIV infection. Apretude comprises 3 mL of the composition shown in Table 2.

[0173]

[0174] Table 2

[0175] Co-administration

[0176] In one embodiment, the method is a method of treating HIV, and the pharmaceutical composition is administered to a patient in combination with a second anti-HIV agent. In this embodiment, the second anti-HIV agent can be any known anti-HIV agent. In one embodiment, the second anti-HIV agent is a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a capsid inhibitor, or a broad-spectrum neutralizing antibody.

[0177] Exemplary Implementation

[0178] In one embodiment, cabotevir provides a Ctau of at least 1 μg / mL, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and sodium CMC; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0179] In one embodiment, cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and sodium CMC; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0180] In one embodiment, the method includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter, wherein cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0181] In one embodiment, the method includes first administering a loading dose of the pharmaceutical composition to a person, wherein the first loading dose comprises at least 1600 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition to the person 2 to 6 weeks after administering the loading dose; and then administering a maintenance dose every 15 to 24 weeks thereafter, wherein the maintenance dose comprises at least 1000 mg of cabotevir, and wherein the cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein the cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0182] In one embodiment, the method includes first administering a loading dose of the pharmaceutical composition to a person, wherein the first loading dose comprises at least 1600 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition to the person 1 month after the administration of the loading dose, i.e., 3 to 5 weeks; and then administering a maintenance dose every 4 months (i.e., 6 to 8 weeks thereafter), wherein the maintenance dose comprises at least 1000 mg of cabotevir, and wherein the cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein the cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0183] In one embodiment, the method includes first administering a loading dose of the pharmaceutical composition to a person, wherein the first loading dose comprises at least 1600 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition to the person 2 to 6 weeks after administering the loading dose; and then administering a maintenance dose every 15 to 24 weeks thereafter, wherein the maintenance dose comprises at least 1000 mg of cabotevir, and wherein the cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium at a concentration of 533 mg / mL; wherein the cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0184] In one embodiment, the method includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after administering the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter, wherein the pharmaceutical composition is as described in Table 1a-1.

[0185] In one embodiment, the method includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after administering the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter, wherein the pharmaceutical composition is as described in Tables 1a-2.

[0186] In one embodiment, the method includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter, wherein the pharmaceutical composition is as described in Table 1a-1, and wherein cabotevir provides at least 1.05 μg / mL of Ctau.

[0187] In one embodiment, the method includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter, wherein the pharmaceutical composition is as described in Tables 1a-2, and wherein cabotevir provides at least 1.05 μg / mL of Ctau.

[0188] In one embodiment, the loading dose of the pharmaceutical composition comprises 1,600 to 4,000 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, and thereafter maintenance doses are administered every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises 1,000 to 1,800 mg of cabotevir.

[0189] In one embodiment, the loading dose of the pharmaceutical composition comprises 3,000 to 4,000 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, and thereafter maintenance doses are administered every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises 1,400 to 1,800 mg of cabotevir.

[0190] In one embodiment, the loading dose of the pharmaceutical composition comprises 3,000 to 4,000 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, followed by maintenance doses every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises 1,400 to 1,800 mg of cabotevir, wherein the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (including 2.5 μm and 10 μm), and the pharmaceutical composition has a cabotevir concentration of approximately 533 mg / mL.

[0191] In one embodiment, the loading dose of the pharmaceutical composition comprises 3,000 to 4,000 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, followed by maintenance doses every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises 1,400 to 1,800 mg of cabotevir, wherein the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (including 2.5 μm and 10 μm), and the pharmaceutical composition has a cabotevir concentration of about 400 mg / mL.

[0192] In one embodiment, the loading dose of the pharmaceutical composition comprises about 3200 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, followed by maintenance doses every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabotevir, wherein the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (including 2.5 μm and 10 μm), and the pharmaceutical composition has a cabotevir concentration of about 533 mg / mL.

[0193] In one embodiment, the loading dose of the pharmaceutical composition comprises about 3200 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, followed by maintenance doses every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabotevir, wherein the pharmaceutical composition comprises cabotevir, mannitol, PS80 and CMC sodium; wherein cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (including 2.5 μm and 10 μm), and the pharmaceutical composition has a cabotevir concentration of about 400 mg / mL.

[0194] Use in the treatment or prevention of HIV

[0195] In a third aspect, the present invention provides a pharmaceutical composition for treating HIV, wherein the pharmaceutical composition comprises cabotevir and the treatment comprises administering the pharmaceutical composition to a person once every 15 to 24 weeks.

[0196] In a fourth aspect, the present invention provides a pharmaceutical composition for the prevention of HIV, wherein the pharmaceutical composition comprises cabotevir, and the prevention comprises administering the pharmaceutical composition to a person once every 15-24 weeks.

[0197] The implementation plan discussed below also applies to aspects three and four.

[0198] Caboteway is as discussed above.

[0199] In one embodiment of the invention, cabotevir is present in the pharmaceutical composition as a free acid.

[0200] The dosage of cabotevir (which is the amount of cabotevir used in the composition of the present invention) can be selected such that: the plasma concentration of cabotevir in humans is maintained above the trough plasma concentration (Ctau); or the plasma concentration of cabotevir in humans is maintained at or above the approved 200 mg / mL cabotevir regimen (i.e., CABENUVA® or APRETUDE®).

[0201] Glutamic plasma level (Ctau) refers to glutathione concentration, which is the concentration reached immediately before the next dose is administered. The Ctau value represents the lowest plasma level. Ctau can be measured in any suitable manner.

[0202] The inventors have discovered that, in order to maintain an effective dosing regimen for the treatment or prevention of HIV, the dose of cabozantvir (which is the amount of cabozantvir in the pharmaceutical composition used in this invention) should maintain Ctau at a level higher than the 10th percentile of Ctau observed in Phase 3 studies 201738 (HPTN 083) (for those designated as male at birth) (1.05 μg / mL) and 201739 (HPTN 084) (for those designated as female at birth) (1.39 μg / mL). The 10th percentile of Ctau observed in the aforementioned Phase 3 studies is a sex-specific PrEP benchmark, which is achieved in at least 90% of participants, or the dose of cabozantvir needs to maintain the median and 10th percentile of Ctau higher than the median and 10th percentile of the approved 200 mg / mL cabozantvir intramuscular injection regimen in those designated as male at birth and those designated as female at birth.

[0203] In one embodiment, the dose of cabobetavir administered is selected such that Ctau is higher than that observed in the approved 200 mg / mL cabobetavir intramuscular injection regimen in individuals designated as male at birth and individuals designated as female at birth. In one embodiment, the dose of cabobetavir administered is selected such that Ctau is higher than that observed in the APRETUDE® dosing regimen. In one embodiment, the dose of cabobetavir administered is selected such that Ctau is higher than that observed in the 10th percentile of the APRETUDE® dosing regimen.

[0204] In one embodiment, the dose of cabotevir administered is selected such that Ctau is at least 1 μg / mL, meaning that cabotevir provides at least about 1 μg / mL of Ctau. In another embodiment, cabotevir provides at least 1.05 μg / mL of Ctau. In another embodiment, the person is designated female at birth and cabotevir provides at least about 1.35 μg / mL of Ctau. In another embodiment, the person is designated female at birth and cabotevir provides at least about 1.39 μg / mL of Ctau. In another embodiment, the person is designated female at birth and cabotevir provides at least 1.39 μg / mL of Ctau. In one embodiment, the person is designated male at birth and cabotevir provides at least about 1.05 μg / mL of Ctau. In another embodiment, the person is designated male at birth and cabotevir provides at least 1.05 μg / mL of Ctau. In one implementation, the person is designated female at birth and cabotevir provides at least about 1.39 μg / mL of Ctau; or the person is designated male at birth and cabotevir provides at least about 1.05 μg / mL of Ctau.

[0205] In one implementation, the aforementioned Ctau level was achieved in at least 90% of individuals administering the dosing regimen.

[0206] Cabotevir plasma levels in humans can remain above these Ctau levels because at lower levels the drug may no longer be effective, increasing the risk of HIV transmission and potentially being suboptimal for treating HIV infection. Maintaining higher cabotevir plasma levels helps prevent the development of HIV mutations while preserving a safety margin.

[0207] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 15 to 24 weeks after administering the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter.

[0208] In one embodiment, a person is screened for HIV-1 infection immediately before receiving a loading dose or oral administration. In another embodiment, the pharmaceutical composition is used for HIV prevention, and a person is screened for HIV-1 infection immediately before receiving a loading dose or oral administration.

[0209] A loading dose is a single dose of the pharmaceutical composition administered at the start of use. A maintenance dose is then given to the person every 15 to 24 weeks thereafter.

[0210] The pharmaceutical compositions used for the loading dose and maintenance dose are the same composition, but they may contain different concentrations or amounts of cabobetavir. In embodiments of the invention, the pharmaceutical compositions used for the loading dose and maintenance dose are of the same concentration, but the loading dose is administered at a higher volume. In one embodiment, the loading dose and maintenance dose are the same dose (e.g., the loading dose and maintenance dose are the same volume and each contains the same pharmaceutical composition having the same concentration and the same amount of cabobetavir). In one embodiment, the loading dose and maintenance dose are different doses (e.g., the loading dose and maintenance dose are different volumes of the same pharmaceutical composition having the same concentration of cabobetavir, or the loading dose and maintenance dose are different volumes of different pharmaceutical compositions having different concentrations of cabobetavir). In one embodiment, the loading dose of cabobetavir is higher than the maintenance dose of cabobetavir (e.g., the loading dose and maintenance dose each contain the same concentration of cabobetavir, wherein the volume of the loading dose is larger than the volume of the maintenance dose, or the loading dose and maintenance dose contain different concentrations of cabobetavir, wherein the volume of the loading dose is larger than the volume of the maintenance dose).

[0211] In another embodiment, the pharmaceutical composition for the loading dose is a different pharmaceutical composition from the pharmaceutical composition for the maintenance dose (e.g., the pharmaceutical composition for the loading dose has a different excipient than the pharmaceutical composition for the maintenance dose).

[0212] In yet another embodiment, the loading dose comprises two different pharmaceutical compositions.

[0213] Administration method

[0214] The pharmaceutical composition of this invention is suitable for injection. In one embodiment, the pharmaceutical composition is administered intramuscularly or subcutaneously. In one embodiment, the pharmaceutical composition is administered subcutaneously. In one embodiment, the pharmaceutical composition is administered intramuscularly. In one embodiment, the pharmaceutical composition is administered to the gluteal muscles. In a specific embodiment, the pharmaceutical composition is administered to the abdominal or back gluteal muscles. In one embodiment, the pharmaceutical composition is administered to the gluteus medius, gluteus maximus, or both. In one embodiment, the pharmaceutical composition is administered to the gluteus medius. In one embodiment, the pharmaceutical composition is administered to the gluteus maximus.

[0215] Loading dose

[0216] In one embodiment, the loading dose of the pharmaceutical composition comprises at least 600 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises at least 1200 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises at least 1400 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises at least 1500 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 1600 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 1800 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2000 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2200 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2400 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2600 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 2800 mg of cabobetavir. In another embodiment, the loading dose of the pharmaceutical composition comprises at least 3000 mg of cabobetavir. In one embodiment, the loading dose comprises about 600 mg to about 4000 mg of cabobetavir. In one embodiment, the loading dose comprises about 1200 mg to about 4000 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2000 mg to about 3500 mg of cabobetavir. In an alternative embodiment, the loading dose of the pharmaceutical composition comprises 3000 mg to about 3500 mg of cabobetavir. In an alternative embodiment, the loading dose of the pharmaceutical composition comprises 3100 mg to about 3300 mg of cabobetavir. In an alternative embodiment, the loading dose of the pharmaceutical composition comprises 3150 mg to about 3250 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 600 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 1600 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2000 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2132 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2200 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 2400 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises about 3200 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises 3200 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises 600 mg of cabobetavir.In one embodiment, the loading dose of the pharmaceutical composition comprises 1600 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises 2200 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises 2400 mg of cabobetavir. In one embodiment, the loading dose of the pharmaceutical composition comprises 3200 mg of cabobetavir.

[0217] The loading dose can be administered in a single injection or in two separate injections. In embodiments where the loading dose is administered in two separate injections, these injections are administered sequentially. In embodiments where the loading dose is administered in two separate injections, the two separate injections are administered at the same or different sites. In embodiments where the loading dose is administered in two separate injections, the two separate injections are administered sequentially at the same site. In another embodiment where the loading dose is administered in two separate injections, the two separate injections are administered sequentially at sites at least 2 cm apart (e.g., one injection in the left gluteus maximus and one injection in the right gluteus maximus, or one injection in the left gluteus medius and another injection in the right gluteus medius). In one embodiment, each of the two separate injections contains the same amount of cabotabine. In one embodiment, each of the two separate injections contains different amounts of cabotabine (e.g., one injection contains about 600 mg of cabotabine, and the other injection contains about 1600 mg of cabotabine).

[0218] In embodiments where the loading dose is administered via two separate injections, each injection contains either the same or different pharmaceutical compositions. In embodiments where the loading dose is administered via two separate injections, each injection contains the same pharmaceutical composition. In embodiments where the loading dose is administered via two separate injections, the injections contain different pharmaceutical compositions.

[0219] In one embodiment, the loading dose of the pharmaceutical composition comprises 600 mg of cabotevir, wherein the loading dose is administered as a single 2 mL injection.

[0220] In one embodiment, the loading dose of the pharmaceutical composition comprises 1600 mg cabotevir, wherein the loading dose is administered as a single 3 mL injection.

[0221] In one embodiment, the loading dose of the pharmaceutical composition comprises 2200 mg of cabotevir, wherein the loading dose is administered by two separate injections, one of which contains about 600 mg of cabotevir and the other of which contains about 1600 mg of cabotevir.

[0222] In one embodiment, the loading dose of the pharmaceutical composition comprises 2400 mg of cabotevir, wherein the loading dose is administered by two separate injections, each containing approximately 1200 mg of cabotevir.

[0223] In one embodiment, the loading dose of the pharmaceutical composition comprises 3200 mg of cabotevir, wherein the loading dose is administered by two separate injections, each containing approximately 1600 mg of cabotevir.

[0224] In one embodiment, the loading dose is administered as a 1 mL injection. In one embodiment, the loading dose is administered as a 2 mL injection. In one embodiment, the loading dose is administered as a 2.25 mL injection. In one embodiment, the loading dose is administered as a 3 mL injection.

[0225] In one embodiment, the loading dose of the pharmaceutical composition comprises 2132 mg of cabotevir, wherein the loading dose is administered in two separate 2 mL injections, each containing approximately 1066 mg of cabotevir.

[0226] In one embodiment, the loading dose of the pharmaceutical composition comprises 2200 mg of cabotevir, wherein the loading dose is administered in two separate injections, one containing approximately 600 mg of cabotevir in a 2 mL injection and the other containing approximately 1600 mg of cabotevir in a 3 mL injection.

[0227] In one embodiment, the loading dose of the pharmaceutical composition comprises 2400 mg of cabotevir, wherein the loading dose is administered in two separate injections, each containing approximately 1200 mg of cabotevir in 2.25 mL of injection solution.

[0228] In one embodiment, the loading dose of the pharmaceutical composition comprises 3200 mg of cabotevir, wherein the loading dose is administered in two separate 3 mL injections, each containing approximately 1600 mg of cabotevir.

[0229] In another embodiment, a loading dose may refer to a first loading dose when one or more subsequent loading doses are administered at a later time point (e.g., a second loading dose is administered 2-6 weeks after the first loading dose). Subsequent loading doses are as described in any of the foregoing embodiments of loading doses. In one embodiment, a second loading dose follows a first loading dose. In another embodiment, a second and a third loading dose follow a first loading dose. In yet another embodiment, a second, a third, and a fourth loading dose follow a first loading dose (e.g., a second loading dose is administered 2-6 weeks after the first loading dose, a third loading dose is administered 6-11 weeks after the second loading dose, and a fourth loading dose is administered 6-11 weeks after the third loading dose).

[0230] Maintenance dose

[0231] In one embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1000 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1200 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1300 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1330 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1500 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1600 mg of cabobetavir. In one embodiment, the maintenance dose comprises about 1000 mg to about 1800 mg of cabobetavir. In one embodiment, the maintenance dose comprises about 1200 mg to about 1800 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises about 1250 mg to about 1800 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises about 1300 mg to about 1800 mg of cabobetavir. In another embodiment, the maintenance dose of the pharmaceutical composition comprises about 1400 mg to about 1800 mg, about 1400 mg to about 1700 mg, about 1450 mg to about 1700 mg, about 1450 mg to about 1650 mg, about 1500 mg to about 1650 mg, or about 1550 mg to about 1650 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises about 1550 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises 1550 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises about 1650 mg of cabobetavir. In one embodiment, the maintenance dose of the pharmaceutical composition comprises 1650 mg of cabobetavir.

[0232] In one embodiment, the maintenance dose is administered as a 1 mL injection. In one embodiment, the maintenance dose is administered as a 2 mL injection. In one embodiment, the maintenance dose is administered as a 3 mL injection.

[0233] In one embodiment, the maintenance dose of the pharmaceutical composition comprises approximately 1066 mg of cabotevir in 2 mL of injection, approximately 1332 mg of cabotevir in 2.5 mL of injection, or approximately 1600 mg of cabotevir in 3 mL of injection.

[0234] In one embodiment, the maintenance dose of the pharmaceutical composition comprises approximately 1066 mg of cabotevir in 2 mL of injection solution.

[0235] In one embodiment, the maintenance dose of the pharmaceutical composition comprises approximately 1600 mg of cabotevir in 3 mL of injection solution.

[0236] In one implementation, a first maintenance dose is administered 2 to 6 weeks after the loading dose, followed by the first maintenance dose every 15 to 24 weeks thereafter.

[0237] In one embodiment, the first maintenance dose is administered 2 to 6 weeks or 3 to 4 weeks after the loading dose. In one embodiment, the first maintenance dose is administered 1 month after the loading dose, i.e., 3 to 5 weeks after the loading dose. In one embodiment, the first maintenance dose is administered approximately 3 weeks, approximately 4 weeks, or approximately 5 weeks after the loading dose. In one embodiment, the first maintenance dose is administered 3 weeks, 4 weeks, or 5 weeks after the loading dose.

[0238] In another embodiment, a first maintenance dose is administered 6 to 11 weeks after the loading dose, followed by a first maintenance dose every 15 to 24 weeks thereafter.

[0239] In another embodiment, the first maintenance dose is administered 6 to 11 weeks, or 7 to 10 weeks after the loading dose. In one embodiment, the first maintenance dose is administered approximately 2 months after the loading dose. In another embodiment, the first maintenance dose is administered 2 months after the loading dose. In one embodiment, the first maintenance dose is administered approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, or approximately 10 weeks after the loading dose. In another embodiment, the first maintenance dose is administered 7 weeks, 8 weeks, 9 weeks, or 10 weeks after the loading dose.

[0240] In one implementation, the maintenance dose is administered every 15 to 20 weeks or every 15 to 19 weeks.

[0241] In one embodiment, the maintenance dose is administered every 4 months, i.e., every 16 to 18 weeks. In another embodiment, the maintenance dose is administered every 16 weeks, every 17 weeks, or every 18 weeks.

[0242] In one embodiment, the maintenance dose of the pharmaceutical composition comprises at least 1200 mg of cabobetavir and is administered every 4 months, i.e., every 16 to 18 weeks. In one embodiment, the maintenance dose of the pharmaceutical composition comprises 1200 mg to 1800 mg of cabobetavir and is administered every 4 months, i.e., every 16 to 18 weeks. In one embodiment, the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabobetavir and is administered every 4 months, i.e., every 16 to 18 weeks.

[0243] In one embodiment, the use includes first administering a loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition comprises about 1200 mg to 4000 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition comprising 1200 to 1800 mg of cabotevir to the person 1 month or 3 to 5 weeks after administering the loading dose; and then administering the maintenance dose thereafter every 4 months or 16 to 18 weeks.

[0244] In one embodiment, the use includes first administering a loading dose of a pharmaceutical composition to a person, wherein the pharmaceutical composition comprises about 3000 mg to 3500 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition comprising 1500 to 1700 mg of cabotevir to the person 1 month or 3 to 5 weeks after administering the loading dose; and then administering the maintenance dose thereafter every 4 months or 16 to 18 weeks.

[0245] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person, wherein the pharmaceutical composition comprises approximately 3200 mg of cabobotevir administered in two injections, each injection containing 1600 mg of cabobotevir; administering a maintenance dose of the pharmaceutical composition comprising approximately 1600 mg of cabobotevir to the person 1 month or 3 to 5 weeks after the loading dose; and then administering the maintenance dose thereafter every 4 months or 16 to 18 weeks.

[0246] In one embodiment, the use includes first administering to a person a first loading dose of a pharmaceutical composition comprising about 3200 mg of cabobotevir, wherein the first loading dose is optionally administered in two separate injections, each containing 1600 mg of cabobotevir; administering to a person a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir 4 months or 16-18 weeks after administration of the first loading dose; administering to a person a maintenance dose of one or more pharmaceutical compositions comprising about 1600 mg of cabobotevir 4 months or 16-18 weeks after administration of the second loading dose; and then administering to a person a maintenance dose comprising about 1600 mg of cabobotevir every 4 months or 16-18 weeks thereafter.

[0247] In one embodiment, the use includes administering a first loading dose of a pharmaceutical composition to a human, wherein the pharmaceutical composition comprises about 1600 mg of cabobotevir; administering a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 1 month or 3-5 weeks after administration of the first loading dose; administering a third loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administration of the second loading dose; administering a maintenance dose of one or more pharmaceutical compositions comprising about 1600 mg of cabobotevir to a human 4 months or 16-18 weeks after administration of the third loading dose; and then thereafter administering a maintenance dose to a human every 4 months or 16 to 18 weeks.

[0248] In one embodiment, the use includes first administering to a person a first loading dose of a pharmaceutical composition comprising about 2400 mg of cabobotevir, wherein the first loading dose is optionally administered in two separate injections, each containing 1200 mg of cabobotevir; administering to a person a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir 2 months or 7-10 weeks after administration of the first loading dose; administering to a person a maintenance dose of one or more pharmaceutical compositions comprising about 1600 mg of cabobotevir 4 months or 16 weeks after administration of the second loading dose; and then administering to a person a maintenance dose comprising about 1600 mg of cabobotevir every 4 months or 16 to 18 weeks thereafter.

[0249] In one embodiment, the use includes first administering a first loading dose of the pharmaceutical composition to a human, wherein the pharmaceutical composition comprises about 2200 mg of cabobotevir, wherein the first loading dose is optionally administered in two separate injections (e.g., one injection of about 600 mg of cabobotevir and another injection of about 1600 mg of cabobotevir); administering a second loading dose of the pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administration of the first loading dose; administering a third loading dose of the pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administration of the second loading dose; administering a maintenance dose of the pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 4 months or 16-18 weeks after administration of the third loading dose; and then administering a maintenance dose comprising about 1600 mg of cabobotevir to a human every 4 months or 16 to 18 weeks thereafter.

[0250] In one embodiment, the use includes administering a first loading dose of a pharmaceutical composition to a human, wherein the pharmaceutical composition comprises about 600 mg of cabobotevir; administering a second loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 1 month or 3-5 weeks after administration of the first loading dose; administering a third loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administration of the second loading dose; administering a maintenance dose of one or more pharmaceutical compositions comprising about 1600 mg of cabobotevir to a human 4 months or 16-18 weeks after administration of the third loading dose; and then thereafter administering a maintenance dose to a human every 4 months or 16-18 weeks.

[0251] In one embodiment, the use includes administering a first loading dose of a pharmaceutical composition to a human, wherein the pharmaceutical composition comprises about 600 mg of cabobotevir; administering a second loading dose of a pharmaceutical composition comprising about 600 mg of cabobotevir to a human 1 month or 3-5 weeks after administering the first loading dose; administering a third loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administering the second loading dose; administering a fourth loading dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 2 months or 7-10 weeks after administering the third loading dose; administering a maintenance dose of a pharmaceutical composition comprising about 1600 mg of cabobotevir to a human 4 months or 16-18 weeks after administering the fourth loading dose; and then thereafter administering a maintenance dose to a human every 4 months or 16-18 weeks.

[0252] Oral delivery and oral bridging

[0253] In one embodiment, an oral delivery dose is administered to assess cabobetavir to a person prior to the loading dose. In one embodiment, the oral delivery dose is taken once daily for at least 28 days, approximately one month prior to the administration of the loading dose. In one embodiment, the oral delivery is a cabobetavir tablet taken once daily. In one embodiment, the tablet contains cabobetavir sodium. In one embodiment, the tablet contains approximately 30 mg of cabobetavir sodium. In one embodiment, the tablet contains 30 mg of cabobetavir (equivalent to 31.62 mg of cabobetavir sodium). In one embodiment, the loading dose is administered on the last day of the oral delivery. In one embodiment, the loading dose is administered within 3 days of discontinuing the oral delivery.

[0254] In one embodiment, the maintenance dose is discontinued and replaced with oral tablets. In one embodiment, the oral tablets are taken once daily. In one embodiment, the oral tablets are cabobotevir tablets taken once daily. In one embodiment, the tablets contain cabobotevir sodium. In one embodiment, the tablets contain about 30 mg of cabobotevir sodium. In one embodiment, the tablets contain 30 mg of cabobotevir (equivalent to 31.62 mg of cabobotevir sodium). In one embodiment, the person restarts the maintenance dose after taking the oral tablets daily for up to 4 months or up to 16 to 18 weeks. In this embodiment, the maintenance dose is discontinued and replaced with daily cabobotevir oral tablets for up to 4 months or up to 16 to 18 weeks, then the maintenance dose is restarted and taken once every 15 to 20 weeks thereafter.

[0255] In one separate embodiment, a person takes oral tablets daily for more than 4 months or more than 16 to 18 weeks, in which a loading dose is taken before restarting the maintenance dose. In another embodiment, the maintenance dose is discontinued and replaced with cabotevir oral tablets taken daily for at least 4 months or at least 16 to 18 weeks, and then the loading dose is administered to the person; 2 to 6 weeks after the administration of the loading dose, the person is given the maintenance dose of the pharmaceutical composition; and then the maintenance dose is administered every 15 to 24 weeks thereafter.

[0256] Pharmaceutical Composition

[0257] The pharmaceutical composition is as described above with respect to the first and second aspects.

[0258] Co-administration

[0259] In one embodiment, the use is for the treatment of HIV, and the pharmaceutical composition is administered to a patient in combination with a second anti-HIV agent. In this embodiment, the second anti-HIV agent can be any known anti-HIV agent. In one embodiment, the second anti-HIV agent is a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a capsid inhibitor, or a broad-spectrum neutralizing antibody.

[0260] Exemplary Implementation

[0261] In one embodiment, cabotevir provides a Ctau of at least 1 μg / mL, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and sodium CMC; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0262] In one embodiment, cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and sodium CMC; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0263] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a human; administering a maintenance dose of the pharmaceutical composition to a human 2 to 6 weeks after the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter, wherein cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0264] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person, wherein the first loading dose comprises at least 1600 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition to the person 2 to 6 weeks after the administration of the loading dose; and then thereafter administering a maintenance dose every 15 to 24 weeks, wherein the maintenance dose comprises at least 1200 mg of cabotevir, and wherein the cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein the cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0265] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person, wherein the first loading dose comprises at least 1600 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition to the person 2 to 6 weeks after the loading dose; and then administering a maintenance dose every 15 to 24 weeks thereafter, wherein the maintenance dose comprises at least 1000 mg of cabotevir, and wherein the cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium at a concentration of 533 mg / mL; wherein the cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0266] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person, wherein the first loading dose comprises at least 1600 mg of cabotevir; administering a maintenance dose of the pharmaceutical composition to the person 1 month after the administration of the loading dose, i.e., 3 to 5 weeks; and then administering a maintenance dose every 4 months (i.e., 6 to 8 weeks thereafter), wherein the maintenance dose comprises at least 1200 mg of cabotevir, and wherein the cabotevir provides at least 1.05 μg / mL of Ctau, and the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein the cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (inclusive).

[0267] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after administering the loading dose; and then administering a maintenance dose every 15 to 24 weeks thereafter, wherein the pharmaceutical composition is as described in Table 1a-1.

[0268] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after the loading dose; and then administering a maintenance dose every 15 to 24 weeks thereafter, wherein the pharmaceutical composition is as described in Tables 1a-2.

[0269] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter, wherein the pharmaceutical composition is as described in Table 1a-1, and wherein cabotevir provides at least 1.05 μg / mL of Ctau.

[0270] In one embodiment, the use includes first administering a loading dose of the pharmaceutical composition to a person; administering a maintenance dose of the pharmaceutical composition to a person 2 to 6 weeks after the loading dose; and then administering the maintenance dose every 15 to 24 weeks thereafter, wherein the pharmaceutical composition is as described in Tables 1a-2, and wherein cabotevir provides at least 1.05 μg / mL of Ctau.

[0271] In one embodiment, the loading dose of the pharmaceutical composition comprises 1,600 to 4,000 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, and thereafter maintenance doses are administered every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises 1,000 to 1,800 mg of cabotevir.

[0272] In one embodiment, the loading dose of the pharmaceutical composition comprises 3,000 to 4,000 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, and thereafter maintenance doses are administered every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises 1,400 to 1,800 mg of cabotevir.

[0273] In one embodiment, the loading dose of the pharmaceutical composition comprises 3,000 to 4,000 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, followed by maintenance doses every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises 1,400 to 1,800 mg of cabotevir, wherein the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (including 2.5 μm and 10 μm), and the pharmaceutical composition has a cabotevir concentration of approximately 533 mg / mL.

[0274] In one embodiment, the loading dose of the pharmaceutical composition comprises 3,000 to 4,000 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, followed by maintenance doses every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises 1,400 to 1,800 mg of cabotevir, wherein the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is present in particulate form with a median mass diameter (X50) of 2.5 μm to 10 μm (including 2.5 μm and 10 μm), and the pharmaceutical composition has a cabotevir concentration of about 400 mg / mL.

[0275] In one embodiment, the loading dose of the pharmaceutical composition comprises about 3200 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, followed by maintenance doses every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabotevir, wherein the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (including 2.5 μm and 10 μm), and the pharmaceutical composition has a cabotevir concentration of about 533 mg / mL.

[0276] In one embodiment, the loading dose of the pharmaceutical composition comprises about 3200 mg of cabotevir; a first maintenance dose is administered 1 month (i.e., 3 to 5 weeks) after the loading dose, followed by maintenance doses every 4 months (i.e., 16 to 18 weeks), and the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabotevir, wherein the pharmaceutical composition comprises cabotevir, mannitol, PS80 and CMC sodium; wherein cabotevir is in the form of particles with a median mass diameter (X50) of 2.5 μm to 10 μm (including 2.5 μm and 10 μm), and the pharmaceutical composition has a cabotevir concentration of about 400 mg / mL.

[0277] In a fifth aspect, use of the pharmaceutical composition in the preparation of a medicament for treating HIV infection is provided. Cabotevir, dosage of cabotevir, method of administration, loading dose, maintenance dose, oral delivery and oral bridging, pharmaceutical composition, co-administration, and exemplary embodiments are as described above with respect to the first, second, third, and fourth aspects.

[0278] In a sixth aspect, the use of the pharmaceutical composition in the preparation of a medicament for the prevention of HIV infection is provided. Cabotevir, dosage of cabotevir, method of administration, loading dose, maintenance dose, oral delivery and oral bridging, pharmaceutical composition, co-administration, and exemplary embodiments are as described above with respect to the first, second, third, and fourth aspects.

[0279] The following numbered embodiments are exemplary and not limiting: Implementation Scheme 1: A method for preventing HIV in a person, comprising administering a pharmaceutical composition containing cabotevir to the person once every 15 to 24 weeks.

[0280] Implementation Scheme 2: A method of treating HIV in a person in need, comprising administering a pharmaceutical composition containing cabotevir to the person every 15 to 24 weeks.

[0281] Implementation Scheme 3: The method of Implementation Scheme 1 or Implementation Scheme 2, wherein cabotevir provides at least 1 μg / mL of Ctau.

[0282] Implementation Scheme 4: The method of Implementation Scheme 3, wherein the person is designated as female at birth and cabotevir provides at least about 1.39 μg / mL of Ctau; or wherein the person is designated as male at birth and cabotevir provides at least about 1.05 μg / mL of Ctau.

[0283] Implementation Plan 5: The method of Implementation Plan 1 or Implementation Plan 2, wherein the Ctau provided by cabotevir is higher than the Ctau achieved in the APRETUDE® dosing regimen.

[0284] Example 6: The method according to any one of the foregoing embodiments, wherein the method includes: a. First, administer a loading dose of the pharmaceutical composition to the person; b. Two to six weeks after administering the loading dose, administer a maintenance dose of the pharmaceutical composition to the individual; then c. Thereafter administer the maintenance dose every 15 to 24 weeks.

[0285] Implementation Scheme 7: According to the method of Implementation Scheme 6, the loading dose of the pharmaceutical composition contains at least 1600 mg of cabotevir.

[0286] Implementation Scheme 8: According to the method of Implementation Scheme 7, the loading dose of the pharmaceutical composition comprises about 1600 mg to about 4000 mg of cabotevir.

[0287] Implementation Scheme 9: According to the method of Implementation Scheme 8, the loading dose of the pharmaceutical composition comprises about 3200 mg of cabotevir.

[0288] Implementation Scheme 10: According to the method of Implementation Scheme 9, the loading dose of the pharmaceutical composition is administered in two separate injections, each containing approximately 1600 mg of cabotevir.

[0289] Implementation Scheme 11: The method according to any one of Implementation Schemes 6 to 10, wherein the maintenance dose of the pharmaceutical composition comprises at least 1050 mg of cabotevir.

[0290] Implementation Scheme 12: According to the method of Implementation Scheme 11, the maintenance dose of the pharmaceutical composition comprises about 1300 to about 1700 mg of cabotevir.

[0291] Implementation Scheme 13: According to the method of Implementation Scheme 12, the maintenance dose of said pharmaceutical composition comprises about 1550 to about 1650 mg of cabotevir.

[0292] Implementation Scheme 14: According to the method of Implementation Scheme 12, the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabotevir.

[0293] Implementation Scheme 15: The method according to any one of Implementation Schemes 6 to 14, wherein the maintenance dose is administered once every 15 to 19 weeks.

[0294] Implementation Scheme 16: The method according to Implementation Scheme 15, wherein the maintenance dose is administered every 4 months, i.e. every 16 to 18 weeks.

[0295] Implementation Scheme 17: The method according to any of the foregoing embodiments, wherein the pharmaceutical composition further comprises polysorbate 80.

[0296] Implementation Scheme 18: The method according to any of the foregoing embodiments, wherein the pharmaceutical composition further comprises sodium carboxymethyl cellulose.

[0297] Implementation Scheme 19: The method according to any of the foregoing embodiments, wherein the pharmaceutical composition further comprises mannitol.

[0298] Implementation Scheme 20: The method according to any of the foregoing embodiments, wherein the cabotevir in the pharmaceutical composition is in the form of particles with an X90 value greater than or equal to 5 μm and less than or equal to 25 μm.

[0299] Implementation Scheme 21: The method according to any of the foregoing embodiments, wherein the cabotevir in the pharmaceutical composition is in particulate form with an X50 value between 2.5 μm and 10 μm (inclusive).

[0300] Implementation Scheme 22: The method of Implementation Scheme 20 or 21, wherein the X50 value of the cabotevir particles is greater than or equal to 3 μm and less than or equal to 8.5 μm, and wherein the X90 value of the cabotevir particles is greater than or equal to 6 μm and less than or equal to 20 μm.

[0301] Implementation Scheme 23: The method of Implementation Scheme 21, wherein the X50 value of the cabotevir particles is greater than or equal to 3.5 μm and less than or equal to 8.0 μm.

[0302] Implementation Scheme 24: The method of Implementation Scheme 23, wherein the X50 value of the cabotevir particles is greater than or equal to 3.5 μm and less than or equal to 8.0 μm, and wherein the X90 value of the cabotevir particles is greater than or equal to 7.0 μm and less than or equal to 18.0 μm.

[0303] Implementation Scheme 25: The method according to any of the foregoing embodiments, wherein the pharmaceutical composition comprises polysorbate 80, sodium carboxymethyl cellulose and mannitol, and wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 100:1:1.25:8.75.

[0304] Implementation Scheme 26: The method according to any of the foregoing embodiments, wherein the pharmaceutical composition comprises polysorbate 80, sodium carboxymethyl cellulose and mannitol, and wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 400:3:3.7:25.9.

[0305] Implementation Scheme 27: The method according to any of the foregoing embodiments, wherein the concentration of cabotevir in the pharmaceutical composition is in the range of about 300 mg / mL to about 650 mg / mL.

[0306] Implementation Scheme 28: The method of Implementation Scheme 27, wherein the concentration of cabotevir is approximately 533 mg / mL.

[0307] Implementation Scheme 29: The method according to any of the foregoing embodiments, wherein the pharmaceutical composition has been reconstituted from lyophilized powder with a suitable liquid.

[0308] Implementation Scheme 30: The method according to any of the foregoing implementation schemes, wherein the pharmaceutical composition is administered via intramuscular or subcutaneous injection.

[0309] Implementation Scheme 31: The method according to Implementation Scheme 30, wherein the pharmaceutical composition is administered intramuscularly.

[0310] Implementation Scheme 32: The method according to Implementation Scheme 31, wherein the pharmaceutical composition is applied to the gluteus medius muscle.

[0311] Implementation Scheme 33: The method according to any of the foregoing embodiments, wherein the person is screened for HIV before the administration of the pharmaceutical composition.

[0312] Implementation Scheme 34: A pharmaceutical composition for treating HIV, wherein the pharmaceutical composition comprises cabotevir and the treatment comprises administering the pharmaceutical composition to a person once every 15-24 weeks.

[0313] Implementation Scheme 35: A pharmaceutical composition for HIV prevention, wherein the pharmaceutical composition comprises cabotevir, and the prevention comprises administering the pharmaceutical composition to a person once every 15 to 24 weeks.

[0314] Implementation Scheme 36: The pharmaceutical composition used according to Implementation Scheme 34 or Implementation Scheme 35, wherein the cabotevir provides at least 1 μg / mL of Ctau.

[0315] Implementation Scheme 37: A pharmaceutical composition for the said use according to Implementation Scheme 36, wherein the human being is designated as female at birth and the cabotevir provides at least about 1.39 μg / mL of Ctau; or wherein the human being is designated as male at birth and the cabotevir provides at least about 1.05 μg / mL of Ctau.

[0316] Implementation Scheme 38: The pharmaceutical composition used according to Implementation Scheme 34 or Implementation Scheme 35, wherein cabotevir provides a higher Ctau than the Ctau achieved in the APRETUDE® dosing regimen.

[0317] Implementation Scheme 39: A pharmaceutical composition for use according to Implementation Scheme 34 or 35, wherein the use includes: a. First, administer a loading dose of the pharmaceutical composition to the person; b. Two to six weeks after administering the loading dose, administer a maintenance dose of the pharmaceutical composition to the individual; then c. Thereafter administer the maintenance dose every 15 to 24 weeks.

[0318] Implementation Scheme 40: The pharmaceutical composition used according to Implementation Scheme 39, wherein the loading dose of the pharmaceutical composition contains at least 1600 mg of cabotevir.

[0319] Implementation Scheme 41: The pharmaceutical composition used according to Implementation Scheme 40, wherein the loading dose of the pharmaceutical composition comprises about 1600 mg to about 4000 mg of cabotevir.

[0320] Implementation Scheme 42: The pharmaceutical composition used according to Implementation Scheme 41, wherein the loading dose of the pharmaceutical composition comprises about 3200 mg of cabotevir.

[0321] Implementation Scheme 43: The pharmaceutical composition used according to Implementation Scheme 42, wherein the loading dose of the pharmaceutical composition is administered in two separate injections, each containing approximately 1600 mg of cabotevir.

[0322] Implementation Scheme 44: A pharmaceutical composition for the purpose according to any one of Implementation Schemes 34 to 43, wherein the maintenance dose of the pharmaceutical composition comprises at least 1050 mg of cabotevir.

[0323] Implementation Scheme 45: The pharmaceutical composition used according to Implementation Scheme 44, wherein the maintenance dose of the pharmaceutical composition comprises about 1300 to about 1800 mg of cabotevir.

[0324] Implementation Scheme 46: The pharmaceutical composition used according to Implementation Scheme 45, wherein the maintenance dose of the pharmaceutical composition comprises about 1550 to about 1650 mg of cabotevir.

[0325] Implementation Scheme 47: The pharmaceutical composition used according to Implementation Scheme 46, wherein the maintenance dose of the pharmaceutical composition comprises about 1600 mg of cabotevir.

[0326] Implementation Scheme 48: A pharmaceutical composition for the stated purpose according to any one of Implementation Schemes 34 to 47, wherein the maintenance dose is administered once every 15 to 20 weeks.

[0327] Implementation Scheme 49: The pharmaceutical composition used according to Implementation Scheme 48, wherein the maintenance dose is administered once every 4 months, i.e. every 16 to 18 weeks.

[0328] Implementation Scheme 50: A pharmaceutical composition for the said use according to any one of Implementation Schemes 34 to 49, wherein the pharmaceutical composition further comprises polysorbate 80.

[0329] Implementation Scheme 51: A pharmaceutical composition for the said use according to any one of Implementation Schemes 34 to 50, wherein the pharmaceutical composition further comprises sodium carboxymethyl cellulose.

[0330] Implementation Scheme 52: A pharmaceutical composition for the said use according to any one of Implementation Schemes 34 to 51, wherein the pharmaceutical composition further comprises mannitol.

[0331] Implementation Scheme 53: A pharmaceutical composition for use according to any one of Implementation Schemes 34 to 52, wherein the cabotevir in the pharmaceutical composition is present in particulate form with an X90 value greater than or equal to 5 μm and less than or equal to 25 μm.

[0332] Implementation Scheme 54: A pharmaceutical composition for use according to any one of Implementation Schemes 34 to 53, wherein the cabotevir in the pharmaceutical composition is present in particulate form with an X50 value greater than or equal to 3 μm and less than or equal to 8.5 μm.

[0333] Implementation Scheme 55: A pharmaceutical composition for use according to Implementation Scheme 53 or 54, wherein the X50 value of the cabotevir particles is greater than or equal to 3 μm and less than or equal to 8.5 μm, and wherein the X90 value of the cabotevir particles is greater than or equal to 6 μm and less than or equal to 20 μm.

[0334] Implementation Scheme 56: A pharmaceutical composition for use according to Implementation Scheme 55, wherein the X50 value of cabotevir particles is greater than or equal to 3.5 μm and less than or equal to 8.0 μm.

[0335] Implementation Scheme 57: A pharmaceutical composition for use according to Implementation Scheme 56, wherein the X50 value of the cabotevir particles is greater than or equal to 3.5 μm and less than or equal to 8.0 μm, and wherein the X90 value of the cabotevir particles is greater than or equal to 7.0 μm and less than or equal to 18.0 μm.

[0336] Implementation Scheme 58: A pharmaceutical composition for use according to any one of Implementation Schemes 34-57, wherein the pharmaceutical composition comprises polysorbate 80, sodium carboxymethyl cellulose and mannitol, and wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 100:1:1.25:8.75.

[0337] Implementation Scheme 59: A pharmaceutical composition for use according to any one of Implementation Schemes 34-58, wherein the pharmaceutical composition comprises polysorbate 80, sodium carboxymethyl cellulose and mannitol, and wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 400:3:3.7:25.9.

[0338] Implementation Scheme 60: A pharmaceutical composition used according to any one of Implementation Schemes 34 to 59, wherein the concentration of cabotevir in the pharmaceutical composition is in the range of about 300 mg / mL to about 650 mg / mL.

[0339] Implementation Scheme 61: The pharmaceutical composition used according to Implementation Scheme 60, wherein the concentration of cabotevir is approximately 533 mg / mL.

[0340] Implementation Scheme 62: A pharmaceutical composition for the purpose according to any one of Implementation Schemes 34 to 61, wherein the pharmaceutical composition has been reconstituted from lyophilized powder with a suitable liquid.

[0341] Implementation Scheme 63: A pharmaceutical composition for the stated purpose according to any one of Implementation Schemes 34 to 62, wherein the pharmaceutical composition is administered via intramuscular or subcutaneous injection.

[0342] Implementation Scheme 64: The pharmaceutical composition used according to Implementation Scheme 63, wherein the pharmaceutical composition is administered intramuscularly.

[0343] Implementation Scheme 65: The pharmaceutical composition used according to Implementation Scheme 64, wherein the pharmaceutical composition is applied to the gluteus medius muscle.

[0344] Implementation Scheme 66: A pharmaceutical composition for the purpose according to any one of Implementation Schemes 34 to 65, wherein the person is HIV screened prior to administration of the pharmaceutical composition.

[0345] Implementation Scheme 67: A method for preventing or treating HIV infection in humans, or cabotevir for preventing or treating HIV infection in humans, wherein said method or use includes: a. Administering a first loading dose to a person, wherein the first loading dose comprises a pharmaceutical composition (pharmaceutical composition A) containing cabotevir at a concentration of about 300 mg / mL to about 650 mg / mL or a pharmaceutical composition (pharmaceutical composition B) containing cabotevir at a concentration of about 150 mg / mL to about 230 mg / mL. b. Administering a second loading dose to the person, wherein the second loading dose comprises pharmaceutical composition A; c. Administering a third loading dose to the person, wherein the third loading dose comprises pharmaceutical composition A; d. Administering a maintenance dose of pharmaceutical composition A to a human; and e. Thereafter, a maintenance dose of pharmaceutical composition A shall be administered every 15-24 weeks.

[0346] Implementation Scheme 68: The method of Implementation Scheme 67 or Cabotvir for the stated purpose, wherein step (b) occurs 2-6 weeks after step (a); step (c) occurs 6-11 weeks after step (b); step (d) occurs 15-19 weeks after step (c); and step (e) begins 15-19 weeks after step (d) and is thereafter performed every 15-24 weeks.

[0347] Implementation Scheme 69: The method of Implementation Scheme 67 or Cabotvir for the stated purpose, wherein step (b) is performed 3-5 weeks after step (a); step (c) occurs 7-10 weeks after step (b); step (d) occurs 16-18 weeks after step (c); and step (e) begins 16-18 weeks after step (d) and is performed every 16-18 weeks thereafter.

[0348] Implementation Scheme 70: The method of any one of Implementation Schemes 67-69 or cabotevir for the stated purpose, wherein the first loading dose comprises the pharmaceutical composition A.

[0349] Implementation Scheme 71: The method of any one of Implementation Schemes 67-69 or cabotevir for the stated purpose, wherein the first loading dose comprises the pharmaceutical composition B.

[0350] Implementation Plan 72: A method for preventing or treating HIV infection in humans, or cabotevir for preventing or treating HIV infection in humans, wherein said method or use includes: a. Administering a first loading dose to a person, wherein the first loading dose comprises a pharmaceutical composition (pharmaceutical composition A) containing cabotevir at a concentration of about 300 mg / mL to about 650 mg / mL or a pharmaceutical composition (pharmaceutical composition B) containing cabotevir at a concentration of about 150 mg / mL to about 230 mg / mL. b. Administering a second loading dose to the person, wherein the second loading dose comprises pharmaceutical composition A; c. Administering a maintenance dose of pharmaceutical composition A to a human; and d. Administer a maintenance dose of pharmaceutical composition A every 15-24 weeks.

[0351] Implementation Scheme 73: The method of Implementation Scheme 72 or Cabotvir for the stated purpose, wherein step (b) occurs 15-19 weeks after step (a); step (c) occurs 15-19 weeks after step (b); and step (d) begins 15-19 weeks after step (c) and is performed every 15-19 weeks thereafter.

[0352] Implementation Scheme 74: The method of Implementation Scheme 72 or Cabotevir for the stated purpose, wherein step (b) occurs 16-18 weeks after step (a); step (c) occurs 16-18 weeks after step (b); and step (d) begins 16-18 weeks after step (c) and is performed every 16-18 weeks thereafter.

[0353] Implementation Plan 75: A method for preventing or treating HIV infection in humans, or cabotevir for preventing or treating HIV infection in humans, wherein said method or use includes: a. Administering a first loading dose to a person, wherein the first loading dose comprises a pharmaceutical composition (pharmaceutical composition A) containing cabotevir at a concentration of about 300 mg / mL to about 650 mg / mL. b. Administering a second loading dose to the person, wherein the second loading dose comprises pharmaceutical composition A; c. Administering a maintenance dose of pharmaceutical composition A to a human; and d. Thereafter administer a maintenance dose of pharmaceutical composition A every 15-24 weeks.

[0354] Implementation Scheme 76: The method of Implementation Scheme 75 or Cabotvir for the stated purpose, wherein step (b) is performed 6-11 weeks after step (a); step (c) occurs 15-19 weeks after step (b); and step (d) begins 15-19 weeks after step (c) and is performed every 15-19 weeks thereafter.

[0355] Implementation Scheme 77: The method of Implementation Scheme 75 or Cabotevir for the stated purpose, wherein step (b) is performed 7-10 weeks after step (a); step (c) occurs 16-18 weeks after step (b); and step (d) begins 16-18 weeks after step (c) and is performed every 16-18 weeks thereafter.

[0356] Implementation Scheme 78: A method for preventing or treating HIV infection in humans, or cabotevir for preventing or treating HIV infection in humans, wherein said method or use includes: a. Administering a first loading dose to a person, wherein the first loading dose comprises a pharmaceutical composition (pharmaceutical composition A) containing cabotevir at a concentration of about 300 mg / mL to about 630 mg / mL and a pharmaceutical composition (pharmaceutical composition B) containing cabotevir at a concentration of about 150 mg / mL to about 230 mg / mL, wherein pharmaceutical composition A and pharmaceutical composition B are injected separately; b. Administering a second loading dose to the person, wherein the second loading dose comprises pharmaceutical composition A; c. Administering a third loading dose to the person, wherein the third loading dose comprises pharmaceutical composition A; d. Administering a third loading dose, followed by a maintenance dose of pharmaceutical composition A to a person; and e. Thereafter, a maintenance dose of pharmaceutical composition A shall be administered every 15-24 weeks.

[0357] Implementation Scheme 79: The method of Implementation Scheme 78 or Cabotvir for the stated purpose, wherein step (b) is performed 6-11 weeks after step (a); step (c) occurs 6-11 weeks after step (b); step (d) occurs 15-19 weeks after step (c); and step (e) begins 15-19 weeks after step (d) and is performed every 15-19 weeks thereafter.

[0358] Implementation Scheme 80: The method of Implementation Scheme 78 or Cabotvir for the stated purpose, wherein step (b) is performed 7-10 weeks after step (a); step (c) occurs 7-10 weeks after step (b); step (d) occurs 16-18 weeks after step (c); and step (e) begins 16-18 weeks after step (d) and is performed every 16-18 weeks thereafter.

[0359] Implementation Scheme 81: A method for preventing or treating HIV infection in humans, or cabotevir for preventing or treating HIV infection in humans, wherein said method or use includes: a. Administering a first loading dose to a person, wherein the first loading dose comprises a pharmaceutical composition (pharmaceutical composition B) containing cabotevir at a concentration of about 150 mg / mL to about 230 mg / mL. b. Administering a second loading dose to a person, wherein the second loading dose comprises pharmaceutical composition B; c. Administering a third loading dose to a person, wherein the third loading dose comprises a pharmaceutical composition (pharmaceutical composition A) containing cabotevir at a concentration of about 300 mg / mL to about 650 mg / mL. d. Administer a fourth loading dose to the person, wherein the fourth loading dose comprises pharmaceutical composition A; e. Administering a maintenance dose of pharmaceutical composition A to a human; and f. Thereafter, a maintenance dose of pharmaceutical composition A shall be administered every 15-24 weeks.

[0360] Implementation Scheme 82: The method of Implementation Scheme 81 or Cabotvir for the stated purpose, wherein step (b) occurs 2-6 weeks after step (a); step (c) occurs 6-11 weeks after step (b); step (d) occurs 6-11 weeks after step (c); step (e) occurs 15-19 weeks after step (d); and step (f) begins 15-19 weeks after step (e) and is performed thereafter every 15-19 weeks.

[0361] Implementation Scheme 83: The method of Implementation Scheme 81 or Cabotvir for the stated purpose, wherein step (b) is performed 3-5 weeks after step (a); step (c) occurs 7-10 weeks after step (b); step (d) occurs 7-10 weeks after step (c); step (e) occurs 16-18 weeks after step (d); and step (f) begins 16-18 weeks after step (e) and is performed every 16-18 weeks thereafter.

[0362] Implementation Scheme 84: A method for preventing or treating HIV infection in humans, or cabotevir for preventing or treating HIV infection in humans, wherein said method or use includes: a. Administering a first loading dose to a person, wherein the first loading dose comprises a pharmaceutical composition (pharmaceutical composition A) containing cabotevir at a concentration of about 300 mg / mL to about 650 mg / mL. b. Administering a maintenance dose of pharmaceutical composition A to a human; and c. Administer a maintenance dose of pharmaceutical composition A every 15-24 weeks.

[0363] Implementation Scheme 85: The method of Implementation Scheme 84 or Cabotvir for the stated purpose, wherein step (b) is performed 6-11 weeks after step (a); and step (c) begins 15-19 weeks after step (b) and is performed every 15-19 weeks thereafter.

[0364] Implementation Scheme 86: The method of Implementation Scheme 84 or Cabotvir for the stated purpose, wherein step (b) is performed 7-10 weeks after step (a); and step (c) begins 16-18 weeks after step (b) and is performed every 16-18 weeks thereafter.

[0365] Implementation Scheme 87: The method of any one of Implementation Schemes 67-86 or cabotevir for the stated purpose, wherein the first loading dose comprises at least about 600 mg of cabotevir.

[0366] Implementation Scheme 88: The method of Implementation Scheme 70 or cabotevir for the stated purpose, wherein the first loading dose contains about 1600 mg of cabotevir, the second loading dose contains about 1600 mg of cabotevir, the third loading dose contains about 1600 mg of cabotevir, and each maintenance dose contains about 1600 mg of cabotevir.

[0367] Implementation Scheme 89: The method of Implementation Scheme 70 or 88 or cabotevir for the stated purpose, wherein the first loading dose contains 1600 mg of cabotevir, the second loading dose contains 1600 mg of cabotevir, the third loading dose contains 1600 mg of cabotevir, and each maintenance dose contains 1600 mg of cabotevir.

[0368] Implementation Scheme 90: The method of Implementation Scheme 71 or cabotevir for the stated purpose, wherein the first loading dose contains about 600 mg of cabotevir, the second loading dose contains about 1600 mg of cabotevir, the third loading dose contains about 1600 mg of cabotevir, and each maintenance dose contains about 1600 mg of cabotevir.

[0369] Implementation Scheme 91: The method of Implementation Scheme 71 or 90 or cabotevir for the stated purpose, wherein the first loading dose contains 600 mg of cabotevir, the second loading dose contains 1600 mg of cabotevir, the third loading dose contains 1600 mg of cabotevir, and each maintenance dose contains 1600 mg of cabotevir.

[0370] Implementation Scheme 92: The method of any one of Implementation Schemes 72-74 or cabotevir for the stated purpose, wherein the first loading dose comprises about 3200 mg of cabotevir, the second loading dose comprises about 1600 mg of cabotevir, and each maintenance dose comprises about 1600 mg of cabotevir.

[0371] Implementation Scheme 93: The method of any one of Implementation Schemes 72-74 and 92 or cabotevir for the stated purpose, wherein the first loading dose comprises 3200 mg of cabotevir, the second loading dose comprises 1600 mg of cabotevir, and each maintenance dose comprises 1600 mg of cabotevir.

[0372] Implementation Scheme 94: The method of any one of Implementation Schemes 75-77 or cabotevir for the stated purpose, wherein the first loading dose contains about 2400 mg of cabotevir, the second loading dose contains about 1600 mg of cabotevir, and each maintenance dose contains about 1600 mg of cabotevir.

[0373] Implementation Scheme 95: The method of any one of Implementation Schemes 75-77 and 94 or cabotevir for the stated purpose, wherein the first loading dose comprises 2400 mg of cabotevir, the second loading dose comprises 1600 mg of cabotevir, and each maintenance dose comprises 1600 mg of cabotevir.

[0374] Implementation Scheme 96: The method of any one of Implementation Schemes 78-80 or cabobotevir for the stated purpose, wherein the first loading dose comprises pharmaceutical composition A containing about 1600 mg of cabobotevir and pharmaceutical composition B containing about 600 mg of cabobotevir, the second loading dose comprises about 1600 mg of cabobotevir, the third loading dose comprises about 1600 mg of cabobotevir, and each maintenance dose comprises about 1600 mg of cabobotevir.

[0375] Implementation Scheme 97: The method of any one of Implementation Schemes 78-80 and 96 or cabotevir for the stated purpose, wherein the first loading dose comprises pharmaceutical composition A containing 1600 mg of cabotevir and pharmaceutical composition B containing 600 mg of cabotevir, the second loading dose comprises 1600 mg of cabotevir, the third loading dose comprises 1600 mg of cabotevir, and each maintenance dose comprises 1600 mg of cabotevir.

[0376] Implementation Scheme 98: The method of any one of Implementation Schemes 81-83 or cabotabvir for the stated purpose, wherein the first loading dose contains about 600 mg of cabotabvir, the second loading dose contains about 600 mg of cabotabvir, the third loading dose contains about 1600 mg of cabotabvir, the fourth loading dose contains about 1600 mg of cabotabvir, and each maintenance dose contains about 1600 mg of cabotabvir.

[0377] Implementation Scheme 99: The method of any one of Implementation Schemes 81-83 and 98 or cabotevir for the stated purpose, wherein the first loading dose contains 600 mg of cabotevir, the second loading dose contains 600 mg of cabotevir, the third loading dose contains 1600 mg of cabotevir, the fourth loading dose contains 1600 mg of cabotevir, and each maintenance dose contains 1600 mg of cabotevir.

[0378] Implementation Scheme 100: The method of any one of Implementation Schemes 84-86 or cabotevir for the stated purpose, wherein the first loading dose comprises about 1600 mg of cabotevir and each maintenance dose comprises about 1600 mg of cabotevir.

[0379] Implementation Scheme 101: The method of any one of Implementation Schemes 84-86 and 100 or cabotevir for the stated purpose, wherein the first loading dose comprises 1600 mg of cabotevir and each maintenance dose comprises 1600 mg of cabotevir.

[0380] Implementation Scheme 102: Cabotevir according to any one of Implementation Schemes 67-69, 71, 78-83, 90, 91 and 98-101 or for the purpose described herein, wherein the pharmaceutical composition B comprises cabotevir at a concentration of about 200 mg / mL.

[0381] Implementation Scheme 103: Cabotevir according to any one of Implementation Schemes 67-69, 71, 78-83, 90, 91 and 98-102 or for the purpose described herein, wherein the pharmaceutical composition B comprises cabotevir at a concentration of 200 mg / mL.

[0382] Implementation Scheme 104: Cabotevir according to any one of Implementation Schemes 67-103 or for the purpose described herein, wherein the pharmaceutical composition A comprises cabotevir at a concentration of about 400 mg / mL to about 550 mg / mL.

[0383] Implementation Scheme 105: Cabotevir according to any one of Implementation Schemes 67-104 or for the purpose described herein, wherein the pharmaceutical composition A comprises cabotevir at a concentration of about 400 mg / mL.

[0384] Implementation Scheme 106: Cabotevir according to any one of Implementation Schemes 67-105 or for the purpose described herein, wherein the pharmaceutical composition A comprises cabotevir at a concentration of 400 mg / mL.

[0385] Implementation Scheme 107: Cabotevir according to any one of Implementation Schemes 67-104 or for the purpose described herein, wherein the pharmaceutical composition A comprises cabotevir at a concentration of about 533 mg / mL.

[0386] Implementation Scheme 108: Cabotevir according to any one of Implementation Schemes 67-104 and 107 or for the purpose described herein, wherein the pharmaceutical composition A comprises cabotevir at a concentration of 533 mg / mL.

[0387] Implementation Scheme 109: Cabotevir according to any one of Implementation Schemes 67-108 or for the purposes described herein, wherein the pharmaceutical composition A further comprises polysorbate 80.

[0388] Implementation Scheme 110: Cabotevir according to any one of Implementation Schemes 67-109 or for the purposes described herein, wherein the pharmaceutical composition A further comprises sodium carboxymethyl cellulose.

[0389] Implementation Scheme 111: The method of any one of Implementation Schemes 67-110 or cabotevir for the stated purpose, wherein the pharmaceutical composition A further comprises mannitol.

[0390] Implementation Scheme 112: Cabotevir according to any one of Implementation Schemes 67-111 or for the purpose described herein, wherein the cabotevir in pharmaceutical composition A is present in particulate form with an X90 value greater than or equal to 5 μm and less than or equal to 25 μm.

[0391] Implementation Scheme 113: Cabotevir according to any one of Implementation Schemes 67-112 or for the purpose described herein, wherein the cabotevir in pharmaceutical composition A is in particulate form with an X50 value between 2.5 μm and 10 μm (including 2.5 μm and 10 μm).

[0392] Implementation Scheme 114: Cabotevir according to the method of Implementation Scheme 112 or 113 or for the purpose thereof, wherein the X50 value of the cabotevir particles in pharmaceutical composition A is greater than or equal to 3 μm and less than or equal to 8.5 μm, and wherein the X90 value of the cabotevir particles in pharmaceutical composition A is greater than or equal to 6 μm and less than or equal to 20 μm.

[0393] Implementation Scheme 115: The method of any one of Implementation Schemes 112-114 or the cabotevir used for the said purpose, wherein the X50 value of the cabotevir particles is greater than or equal to 3.5 μm and less than or equal to 8.0 μm.

[0394] Implementation Scheme 116: The method of Implementation Scheme 115 or the cabotevir used for the stated purpose, wherein the X50 value of the cabotevir particles is greater than or equal to 3.5 μm and less than or equal to 8.0 μm, and wherein the X90 value of the cabotevir particles is greater than or equal to 7.0 μm and less than or equal to 18.0 μm.

[0395] Implementation Scheme 117: Cabotevir according to any one of Implementation Schemes 67-116 or for the purposes described herein, wherein pharmaceutical composition A comprises polysorbate 80, sodium carboxymethyl cellulose and mannitol, and wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 100:1:1.25:8.75.

[0396] Implementation Scheme 118: Cabotevir according to any one of Implementation Schemes 67-116 or for the purposes described herein, wherein pharmaceutical composition A comprises polysorbate 80, sodium carboxymethyl cellulose and mannitol, and wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 400:3:3.7:25.9.

[0397] Implementation Scheme 119: The method of any one of Implementation Schemes 67-118 or Cabotevir for the stated purpose, wherein the pharmaceutical composition A has been reconstituted from lyophilized powder with a suitable liquid.

[0398] Implementation Scheme 120: The method of any one of Implementation Schemes 67-119 or cabotevir for the stated purpose, wherein the pharmaceutical composition A is administered by intramuscular or subcutaneous injection, and, if present, the pharmaceutical composition B is administered by intramuscular or subcutaneous injection.

[0399] Implementation Scheme 121: The method of Implementation Scheme 120 or cabotevir for the stated purpose, wherein the pharmaceutical composition A is administered intramuscularly, and, if present, the pharmaceutical composition B is administered intramuscularly.

[0400] Implementation Scheme 122: The method of Implementation Scheme 121 or cabotevir for the stated purpose, wherein the pharmaceutical composition A is administered to the gluteus medius, and, if present, the pharmaceutical composition B is administered to the gluteus medius.

[0401] Implementation Scheme 123: The method of Implementation Scheme 120 or cabotevir for the stated purpose, wherein the pharmaceutical composition A is administered subcutaneously, and, if present, the pharmaceutical composition B is administered subcutaneously.

[0402] Implementation Scheme 124: The method or cabotevir used for the stated purpose according to any one of Implementation Schemes 67-123, wherein the person is screened for HIV before the administration of the first loading dose.

[0403] Implementation Scheme 125: The method of any one of Implementation Schemes 67-124 or the cabotevir used for the stated purpose, wherein the cabotevir provides at least 1 μg / mL of Ctau.

[0404] Implementation Scheme 126: The method of any one of Implementation Schemes 67-125 or the cabotevir used for the said purpose, wherein the person was designated as female at birth and the cabotevir provides at least about 1.39 μg / mL of Ctau; or wherein the person was designated as male at birth and the cabotevir provides at least about 1.05 μg / mL of Ctau.

[0405] Implementation scheme 127: The method according to any one of implementation schemes 67-126, wherein the Ctau provided by cabotevir is higher than the Ctau achieved in the APRETUDE® dosing regimen.

[0406] Implementation Scheme 128: The method according to any one of Implementation Schemes 67-127, wherein the method is used to prevent HIV infection in humans.

[0407] Implementation Scheme 129: The method according to any one of Implementation Schemes 67-127, wherein the method is used to treat HIV infection in a person.

[0408] Implementation Scheme 130: Cabotevir for the stated purpose according to any one of Implementation Schemes 67-127, wherein the cabotevir used is for the prevention of HIV infection in humans.

[0409] Implementation Scheme 131: Cabotevir for the stated purpose according to any one of Implementation Schemes 67-127, wherein the cabotevir used is for the treatment of HIV infection in humans.

[0410] Implementation Scheme 132: The method of claim 30, wherein when two separate injections are administered at a loading dose or a maintenance dose, one of the separate injections is administered intramuscularly, and the other of the injections is administered subcutaneously.

[0411] Implementation Scheme 133: The method of claim 30, wherein when two separate injections are administered at a loading dose or a maintenance dose, both separate injections are administered intramuscularly.

[0412] Implementation Scheme 134: The method of claim 30, wherein when two separate injections are administered at a loading dose or a maintenance dose, both separate injections are administered subcutaneously.

[0413] Implementation Scheme 135: The method according to any one of Implementation Schemes 32 and 132-134, wherein when two separate injections are administered, the separate injections are administered to different sites at least 2 cm apart.

[0414] Implementation Scheme 136: The method according to Implementation Scheme 31, wherein the pharmaceutical composition is applied to the gluteus medius, gluteus maximus, or both the gluteus medius and gluteus maximus.

[0415] Implementation Scheme 137: The method according to Implementation Scheme 136, wherein the pharmaceutical composition is applied to the gluteus maximus muscle.

[0416] Implementation Scheme 138: The method according to Implementation Scheme 137, wherein when two separate injections are administered, one of the separate injections is administered to the left gluteus maximus and the other of the separate injections is administered to the right gluteus maximus.

[0417] Implementation Scheme 139: The method according to Implementation Scheme 32, wherein when two separate injections are administered, one of the separate injections is administered to the left gluteus medius and the other of the separate injections is administered to the right gluteus medius.

[0418] Implementation Scheme 140: Use of a pharmaceutical composition in the preparation of a medicament for treating HIV infection, wherein the pharmaceutical composition comprises cabotevir.

[0419] Implementation Scheme 141: Use of a pharmaceutical composition in the preparation of a medicament for the prevention of HIV infection, wherein the pharmaceutical composition comprises cabotevir.

[0420] The following non-limiting embodiments illustrate the present invention.

[0421] Example

[0422] Specific embodiments are described in the following description of the examples. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of this disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure.

[0423] Comparative example (Example 8 of WO 2021 / 116872A1): A long-acting suspension containing 200 mg / mL cabotevir, 20 mg / mL PS20, and 20 mg / mL PEG3350 was investigated to test its stability when the cabotevir concentration was increased to 400 mg / mL.

[0424] Suspensions were prepared in 250 mL batches using Netzsch miniCer and 0.3 mm YTZ grinding beads. A range of excipient concentrations were explored.

[0425] The formulation mediator was prepared by dissolving polysorbate 20 (Croda), polyethylene glycol 3350 (Clariant), and mannitol (Roquette Freres) in water for injection (WFI) and filtering the solution through a 0.2 μm filter. The formulation mediator was then added to cabotevir (free acid) to prepare a 400 mg / mL crude suspension. While stirring, the crude suspension was circulated at 73–145 mL / min through a wet bead mill (Netzsch MiniCer) containing 0.30 mm YTZ grinding beads (Nikkato Corp) set to 29.7 Hz until the desired median particle size of less than 0.25 μm, as measured by laser diffraction, was achieved. The wet bead mill was cooled to maintain a temperature of 1–25°C. The suspension was then filled into Type I glass vials, rinsed with nitrogen, plugged (FM457 stopper), and sealed. The filled suspension was then terminally sterilized by gamma radiation at a minimum dose of 25 kGy.

[0426] 30 mg / mL PS20, 20 mg / mL PEG3350, and 19 mg / mL mannitol were prepared with 400 mg / mL cabotevir. The gamma-irradiated suspensions in vials were placed upright and stored at 40°C / 75%RH. The suitability of the suspensions was tested after 1 month and 3 months of storage. Table 3 shows the particle size (μm) of the 400 mg / mL cabotevir formulation with 30 mg / mL PS20, 30 mg / mL PEG3350, and 19 mg / mL mannitol after preparation and after 1 month of storage at 40°C / 75%RH. At 1 month, the particle size increased compared to the initial time point (Table 3). At 3 months, the suspension became an irreversible gel that could not be removed from the vial with a syringe.

[0427] Table 3

[0428] Other suspensions containing cabotevir, PS20, and PEG3350 were prepared at the concentrations shown in Table 4. Experiments 1, 2, and 5 were prepared using the method described above for 20 mg / mL PS20 and PEG3350. In Experiment 3, the suspension was first ground with PS20 (without PEG3350), then PEG3350 was added, with 400 mg / mL cabotevir ground with 30 mg / mL PS20. After grinding, a concentrated solution of PEG3350 (400 mg / mL) was added to dilute the 400 mg / mL suspension to 360 mg / mL cabotevir, 27 mg / mL PS20, and 27 mg / mL mannitol. All compositions were prepared in 250 mL batches using a NetzschminiCer with 0.3 mm YTZ grinding beads.

[0429] Table 4

[0430] 400 mg / mL diluted 10% yields 360 mg / mL cabotevir and 27 mg / mL PS20. In Experiments 1, 2, 4, and 5, the suspensions thickened into a paste and became unrecoverable during wet bead milling on a miniCer. In Experiment 3, the suspension thickened and could no longer be stirred within 5 minutes of adding a 400 mg / mL PEG3350 solution. The combination of PS20 and PEG3350 with 400 mg / mL cabotevir did not produce physically stable suspensions.

[0431] Experimental Examples

[0432] In the following description of embodiments, specific implementations are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of this disclosure. Other implementations may be utilized, and logical and other changes may be made without departing from the scope of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure.

[0433] The particle size of cabotevir in the microsuspension in the following examples was measured according to the following protocol.

[0434] Solution Description Laser diffraction measurement method for particle size (USP) <429> ).

[0435] Reconstitute the lyophilized product with water for injection (WFI) (the volume of WFI is determined by the required concentration of the reconstituted suspension). Clean and fill the Malvern Mastersizer 3000 laser diffractometer with MV instrumentation using deionized water.

[0436] The dispersion was stirred at 2000 rpm, the particle refractive index was 1.67, the particle absorption index (the imaginary part of the refractive index) was 0.01, and a general analysis mode with normal sensitivity was used. The refractive index of the dispersant (DI water) was 1.33. The measurement time and background time were both 10 seconds, and two measurements were obtained for each aliquot sample.

[0437] Alignment and background measurement are performed.

[0438] The suspension (generated in the examples below) is stirred to ensure that all particles are suspended in the drug product vial.

[0439] Draw ~0.2 mL of contents using a 1 mL syringe fitted with a needle (18G).

[0440] Add two drops of suspension to a microcentrifuge tube containing 0.5 ml of 6.6% w / v P338 aqueous solution.

[0441] Gently vortex to produce a uniform dispersion of the drug product in P338 dispersant.

[0442] Add an appropriate amount of the dispersion to the instrument until a 5%-7% shielding effect is achieved.

[0443] Before starting the measurement, allow the test suspension to circulate in the instrument for about 30 seconds.

[0444] Perform measurements and rinse the instrument with deionized water after each measurement.

[0445] The process was repeated three times with each new sample divided into equal parts, and the average value obtained from the volume distribution was calculated.

[0446] Example 1

[0447] Table 5

[0448] Table 5 shows exemplary pharmaceutical compositions of the present invention (the pharmaceutical compositions are also described as “suspensions” in these examples) which were prepared using the following methods.

[0449] The formulation medium was prepared by dissolving / diluting 24.0 g of polysorbate 80 (“PS80”) (Croda) in approximately 300 g of water. Separately, 30.0 g of sodium carboxymethyl cellulose (“NaCMC”) (Ashland, 7L2P) and 210.0 g of mannitol (Roquette Freres) were dissolved in 4.8 kg of water for injection (WFI). Once the NaCMC and mannitol were dissolved, the PS80 solution was added to the NaCMC-mannitol solution with stirring. The weighing and dilution containers were rinsed with additional water into the mixing container, and the mixed medium solution was brought to a final weight of 6.06 kg and filtered through a 0.2 μm filter. 1.6 kg of cabotevir micronized free acid (target x 50 = 5–6 μm particle size) was added to 3.0 kg of the filtered medium and mixed to form a homogeneous suspension. While stirring, the mixed suspension was degassed until it reached its target batch volume, and then the suspension was filled into vials. The product was lyophilized by freezing at -45°C for at least 2 hours, annealing at -18°C for at least 2 hours, refreezing at -45°C for at least 2 hours (each transition at a heating rate of + / -1°C / min), primary drying at approximately 150 mTorr at -10°C (heating rate: 0.15°C / min) for at least 23 hours, and secondary drying at approximately 150 mTorr at 25°C (heating rate: 0.58°C / min) for at least 6 hours. The lyophilized vials were backwashed with nitrogen to approximately 600 Torr, sealed, and sterilized by gamma radiation at a minimum dose of 25 kGy. The formulation was reconstituted with WFI and briefly agitated to resuspend before administration.

[0450] Example 2

[0451] Table 6

[0452] Table 6 shows exemplary pharmaceutical compositions of the present invention (the pharmaceutical compositions are also described as “suspensions” in these examples) which were prepared using the following methods.

[0453] The formulation medium was prepared by dissolving / diluting 24.0 g of polysorbate 80 (“PS80”) (Croda) in approximately 300 g of water. Separately, 30.0 g of sodium carboxymethyl cellulose (“NaCMC”) (Ashland, 7L2P) and 210.0 g of mannitol (Roquette Freres) were dissolved in 3.4 kg of water for injection (WFI). Once the NaCMC and mannitol were dissolved, the PS80 solution was added to the NaCMC-mannitol solution with stirring. The weighing and dilution containers were rinsed with additional water into the mixing container, and the mixed medium solution was brought to a final weight of 4.50 kg and filtered through a 0.2 μm filter. 1.6 kg of cabotevir micronized free acid (target x 50 = 5–6 μm particle size) was added to the 3.0 kg of filtered medium and mixed to form a homogeneous suspension. While stirring, the mixed suspension was degassed until it reached its target batch volume, and then the suspension was filled into vials. The product was lyophilized by freezing at -45°C for at least 2 hours, annealing at -10°C for at least 2 hours, refreezing at -45°C for at least 2 hours (each transition at a heating rate of + / -1°C / min), primary drying at approximately 150 mTorr at -5°C (heating rate: 1°C / min) for at least 20 hours, and secondary drying at approximately 150 mTorr at 40°C (heating rate: 1°C / min) for at least 6 hours. The lyophilized vials were backwashed with nitrogen to approximately 600 Torr, sealed, and sterilized by gamma radiation at a minimum dose of 25 kGy. The formulation was reconstituted with WFI and briefly shaken to resuspend before administration.

[0454] Example 3

[0455] Table 7

[0456] Table 7 shows exemplary pharmaceutical compositions of the present invention (the pharmaceutical compositions are also described as “suspensions” in these examples) prepared using the following methods.

[0457] The formulation medium was prepared by dissolving / diluting 24.0 g of polysorbate 80 (“PS80”) (Croda) in approximately 300 g of water. Separately, 30.0 g of sodium carboxymethyl cellulose (“NaCMC”) (Ashland, 7L2P) and 210.0 g of mannitol (Roquette Freres) were dissolved in 3.4 kg of water for injection (WFI). Once the NaCMC and mannitol were dissolved, the PS80 solution was added to the NaCMC-mannitol solution with stirring. The weighing and dilution containers were rinsed with additional water into the mixing container, and the mixed medium solution was brought to a final weight of 4.50 kg and filtered through a 0.2 μm filter. 1.6 kg of cabotevir micronized free acid (target x 50 = 3–4 μm particle size) was added to the 3.0 kg of filtered medium and mixed to form a homogeneous suspension. While stirring, the mixed suspension was degassed until it reached its target batch volume, and then the suspension was filled into vials. The product was lyophilized by freezing at -45°C for at least 2 hours, annealing at -10°C for at least 2 hours, refreezing at -45°C for at least 2 hours (each transition at a heating rate of + / -1°C / min), primary drying at approximately 150 mTorr at -5°C (heating rate: 1°C / min) for at least 20 hours, and secondary drying at approximately 150 mTorr at 40°C (heating rate: 1°C / min) for at least 6 hours. The lyophilized vials were backwashed with nitrogen to approximately 600 Torr, sealed, and sterilized by gamma radiation at a minimum dose of 25 kGy. The formulation was reconstituted with WFI and briefly shaken to resuspend before administration.

[0458] Table 8 below applies to Examples 4-6.

[0459] Table 8

[0460] Example 4: Stability of a composition comprising cabotevir, sodium carboxymethyl cellulose, polysorbate 80, and mannitol

[0461] A formulation carrier was prepared by dissolving 2.10 g PS80 (Croda), 2.63 g NaCMC (Ashland), and 18.38 g mannitol (Roquette Freres) in 369.6 g WFI and filtering the solution through a 0.2 μm filter. The formulation carrier was added to 210 g cabotevir (free acid) to prepare a crude suspension of 400 mg / mL. The suspension was covered and stirred for 2 hours. The suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3. The lyophilized suspension was reconstituted to a cabotevir concentration of 400 mg / mL.

[0462] Table 9: Batch #1 (400 mg / mL Cabotevir; 0.4 w / v% PS80; 0.5 w / v% NaCMC; 3.5 w / v% Mannitol)

[0463] Note: AmbH ambient humidity RH (Relative Humidity) - This indicates that no testing was scheduled for these time points. NGT = not greater than NLT = not less than Example 5: Stability of a composition comprising cabotevir, sodium carboxymethyl cellulose, polysorbate 20, and mannitol A formulation carrier was prepared by dissolving 2.10 g of polysorbate 20 (Croda), 2.63 g of sodium CMC (Ashland), and 18.38 g of mannitol (Roquette Freres) in 550.9 g of WFI and filtering the solution through a 0.2 μm filter. The formulation carrier was added to 210 g of cabotevir (free acid) to prepare a crude suspension of 300 mg / mL. The suspension was covered and stirred for 2 hours. The suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3. The lyophilized suspension was reconstituted to a cabotevir concentration of 400 mg / mL.

[0464] Table 10: Batch #2 (400 mg / mL Cabotevir; 0.4 w / v% PS20; 0.5 w / v% NaCMC; 3.5 w / v% Mannitol)

[0465] Note: AmbH ambient humidity RH (Relative Humidity) - This indicates that no testing was scheduled for these time points. NGT = not greater than NLT = not less than Example 6: Stability of a composition comprising cabotevir, sodium carboxymethyl cellulose, poloxamer 338, and mannitol A formulation carrier was prepared by dissolving 2.10 g poloxamer 338 (BASF), 2.63 g sodium CMC (Ashland), and 18.38 g mannitol (Roquette Freres) in 369.6 g WFI and filtering the solution through a 0.2 μm filter. The formulation carrier was added to 210 g cabotevir (free acid) to prepare a crude suspension of 400 mg / mL. The suspension was covered and stirred for 2 hours. The suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3. The lyophilized suspension was reconstituted to a cabotevir concentration of 400 mg / mL.

[0466] Table 11: Batch #3 (400 mg / mL Cabotevir; 0.4 w / v% P338; 0.5 w / v% NaCMC; 3.5 w / v% Mannitol)

[0467] Note: AmbH ambient humidity RH (Relative Humidity) - This indicates that no testing was scheduled for these time points. NGT = not greater than NLT = not less than Example 7: Stability of a composition comprising cabotevir, sodium carboxymethyl cellulose, polysorbate 80, and mannitol A formulation medium was prepared by dissolving 1.04 g PS80 (Croda), 1.30 g NaCMC (Ashland; 7LF), and 9.1 g mannitol (Roquette Freres) in 183.4 g WFI. 195.0 mL of the formulation medium was added to 104.0 g cabotevir (free acid) to prepare a crude suspension of 400 mg / mL. The suspension was covered and stirred for 2 hours. The suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3. The lyophilized suspension was reconstituted to a cabotevir concentration of 533 mg / mL.

[0468] Table 12: Batch #1 (533 mg / mL Cabotevir; 0.53 w / v % PS80; 0.67 w / v % NaCMC; 4.66 w / v % Mannitol)

[0469] Note: AmbH ambient humidity RH relative humidity - Indicates that no testing was scheduled at these times. NGT = not greater than NLT = not less than Example 8: In vivo pharmacokinetic study in rats of a composition comprising cabotevir, sodium carboxymethyl cellulose, mannitol, and polysorbate 80 or poloxamer 338: The preparation of the compositions is described in Examples 4 and 6. Nine male Sprague Dawley rats were administered the formulations at 30 mg / kg subcutaneously in the intrascapular region. Briefly, two nanosuspension formulations of cabotevir, with different excipient compositions, were administered subcutaneously in each rat at a target dose of 30 mg / kg via a single injection: 200 mg / mL (Group 1) and 400 mg / mL (Group 2). Similarly, two lyophilized powder formulations of cabotevir with different excipient compositions and micron-sized components were reconstituted with WFI to a concentration of 400 mg / mL and administered subcutaneously in each rat at a target dose of 30 mg / kg via a single injection. Details of the formulations are described in Table 13.

[0470] Table 13: Details of suspension formulations of test articles administered in animal PK studies

[0471] Table 14 shows the plasma pharmacokinetics of cabotevir in preclinical studies and the statistical analysis of t-tests for several pharmacokinetic parameters. Compared with the nanosuspension formulation from group 1, the lyophilized formulation from group 3 highlighted a significantly reduced Cmax (1.8-fold) and prolonged t-test. 1 / 2 (1.5 times). Furthermore, compared to the formulation in group 4, the lyophilized formulation in group 3 showed improved t... 1 / 2 .

[0472] Table 14: Pharmacokinetic parameters of cabotevir and statistical analysis by t-test in the PK study of Example 8

[0473] #Data from 8 animals (1 animal was excluded as an outlier)

[0474] p-value calculated from a one-tailed unpaired t-test for significance: =0.01 <p<0.05; =0.001 <p<0.01; =0.0001 <p<0.001;p<0.0001

[0475] As part of the study, tolerability was assessed, with particular attention to injection site reactions, and the results are summarized in Table 15. The occurrence of edema and crusting was minimized and observed in a small number of animals over a short period. Nevertheless, minor differences were recorded between the four groups, with lower frequencies of edema observed in groups 3 and 4, particularly group 3.

[0476] Table 15: Observation of Injection Site Reactions

[0477] Example 9

[0478] Example 9 evaluated the safety, tolerability, and pharmacokinetics of a single-dose administration of the pharmaceutical composition of the present invention in 64 healthy adult participants. The lyophilized formulation of Example 9 is provided in Tables 16a and 16b below: Table 16a

[0479] Water is removed during the manufacturing process.

[0480] Nitrogen gas was used as a processing aid during the stoppering process of the vials.

[0481] Table 16b

[0482] Water is removed during the manufacturing process.

[0483] Nitrogen gas was used as a processing aid during the stoppering process of the vials.

[0484] Table 17 below describes the Cabotewe particle size (micrometers) obtained by diffraction: Table 17

[0485] The vials containing the formulation of Table 16a were reconstituted with 1.7 mL of water to obtain a suspension of cabotevir at a concentration of 400 mg / mL. The dosage of the formulation of Table 16a was administered in two groups: 800 mg (2 mL of 400 mg / mL suspension), via the subcutaneous (SC) abdominal route (group C1; 8 participants) and via the intramuscular (IM) (gluteus medius) route (group C2; 8 participants).

[0486] The vials containing the formulation in Table 16b were reconstituted with 1.7 mL of water to obtain a suspension of cabotevir at a concentration of 400 mg / mL, or with 1.1 mL of water to obtain a suspension of cabotevir at a concentration of 533 mg / mL. The dosages of the formulations in Table 16b were administered in five groups: 1200 mg (3 mL of 400 mg / mL suspension) via subcutaneous (SC) abdominal route (Group C3; 8 participants), 1200 mg (3 mL of 400 mg / mL suspension) via intramuscular (IM) (gluteus medius) route (Group C4; 8 participants), 1600 mg (3 mL of 533 mg / mL suspension) via intramuscular (IM) (gluteus medius) route (Group C5; 16 participants), 2400 mg (2.25 mL of 533 mg / mL suspension twice) via intramuscular (IM) (gluteus medius) route (Group C6; 9 participants), and 3200 mg (3 mL of 533 mg / mL suspension twice) via intramuscular (IM) (gluteus medius) route (Group C7; 7 participants).

[0487] Safety and tolerability

[0488] The safety and tolerability characteristics of the pharmaceutical compositions of Tables 16a and 16b administered in Example 9 were acceptable. Adverse events (AEs) occurred in 63–100% of participants (Table 18). Injection site reactions (ISRs) were the most common AEs, and most were Grade 1 (Table 19). Overall, fewer ISRs were reported after IM administration compared to SC administration; however, ISRs were predominantly Grade 1 (Table 19). No Grade 4 or serious AEs were reported in groups C1 through C7.

[0489] Table 18: Summary of the most frequent AEs (ISR and non-ISR) by group (all groups ≥2 participants)

[0490] Table 19: Overview of ISR

[0491]

[0492] Example 10. PK and Simulation

[0493] The plasma Cmax of cabotevir after a single SC (abdomen) or IM (gluteal muscle) injection of the pharmaceutical compositions (groups C1-C7) described in Example 9 was lower than that after a single IM injection of APRETUDE®. However, the plasma Cmax after bilateral 2.25 mL IM gluteal injections (total 4.5 mL) was comparable to that after a single IM injection of APRETUDE®.

[0494] Based on the PK data of groups C1 to C7 observed in Example 9, the predicted t1 / 2 after SC and IM injections for these groups is greater than 6 times (SC injection) and 2 times (IM injection) of APRETUDE® (Q2M cabotevir 200 mg / mL), respectively.

[0495] Table 20. Plasma pharmacokinetic and safety results in healthy adult participants (groups C1-C7)

[0496] a The value is reported as the geometric mean (%CVb).

[0497] simulation

[0498] In the first set of simulations, a population pharmacokinetic (PopPK) model of cabotevir (CAB) was established based on PK data collected from 16 historical studies following intramuscular (IM) administration of 200 mg / mL CAB. The model aimed to establish population pharmacokinetics of cabotevir following administration of oral tablets and long-acting intramuscular injections in adult HIV-1 infected and uninfected subjects. Han K, Baker M, Lovern M, Paul P, Xiong Y, Patel P, Moore KP, Seal CS, Cutrell AG, D'Amico RD, Benn PD, Landovitz RJ, Marzinke MA, Spreen WR, Ford SL. Br J ClinPharmacol. Oct 2022; 88(10):4607-4622. doi: 10.1111 / bcp.15439. Epub 2022 Jul 4. PMID: 35695476), and updated based on PK data from 19 studies: LAI116585, LAI117010, LAI117011, LAI117020, 201741, 201479, 201480, 205696, LAI116482 (LATTE), LAI115428, LAI116815, 200056 (LATTE-2), 201120 (ECLAIR), 201103 (HPTN077), 201584 (FLAIR), 201585 (ATLAS), 207966 (ATLAS-2M), 201738 (HPTN 083), and 201739 (HPTN 084). A total of 34,850 CAB plasma concentrations collected from 2,694 participants at different time points were used to construct the PopPK model. Findings: The long-term intramuscular gluteal resorption rate constant (KA2) of people designated as female at birth was 46.5% lower than that of people designated as male at birth.

[0499] If the injection is administered separately in individuals designated as male at birth, the KA2 level is 50.8% higher, but the KA2 level is independent of the separate injection in individuals designated as female at birth.

[0500] KA2 decreases with increasing BMI, and for the same amount of increase in BMI, people designated as male at birth decrease more than those designated as female at birth.

[0501] The longer the needle, the lower the KA2.

[0502] After adjusting for all covariates, KA2 in study 201120 (ECLAIR) was 22.8% higher than in other studies.

[0503] The apparent center clearance rate (CL / F) is 16.4% higher among current smokers.

[0504] Based on the PK data observed in the study discussed in Example 9, the PopPK model was modified to simulate the cabotevir formulation used in Example 9, with the typical half-life (t½) of the 533 mg / mL formulation set to 25 weeks, and doubled for the APRETUDE® 400 mg / mL formulation. Assumptions: The half-life (t1 / 2) after intramuscular injection of cabotevir in Example 9 at a concentration of 533 mg / mL was 25 weeks. For a formulation with a concentration of 400 mg / mL, the half-life (t1 / 2) after intramuscular injection of the formulation in Example 9 was twice that of APRETUDE®. The effects of body weight, BMI, and smoking status on PK, all variability (e.g., inter-individual variability and residual variability), and bioavailability were the same as those of 200 mg / mL IM intramuscular injection in the buttock.

[0505] The pharmacokinetic (PK) after a single IM gluteal injection of the formulation of Example 9 into both sides of the body is the same as that after a single IM gluteal injection of the formulation of Example 9.

[0506] The simulation was conducted as follows: Covariates including weight, BMI, and smoking status were resampled 5000 times from the distributions of these covariates for both men and women, generating 5000 virtual male subjects and 5000 virtual female subjects. Individual PK parameters for the virtual subjects were calculated using subject-specific covariates and subject-specific non-MEM inter-individual errors (ETAs) sampled from the distributions, which were determined by the variance-covariate matrix of estimated inter-individual variability from the final population PK model. Concentration-time curves for the virtual subjects were calculated using the individual PK parameters. Residual variability (EPS) was included in the simulation. The median and 10th and 90th percentiles (80% prediction intervals) of the simulated concentration-time curves for the virtual men and women were calculated.

[0507] Adequate doses are defined as doses that meet these criteria: 1. Among those designated male at birth and those designated female at birth, those who maintained a median and 10th percentile trough CAB plasma concentration (Ctau) higher than those from an approved Q2M regimen of 200 mg / mL CAB IM via intramuscular gluteal injection, or 2. Ctau levels remained above the sex-specific PrEP benchmark in over 90% of participants. The sex-specific PrEP benchmark was the 10th percentile of Ctau observed in phase 3 studies 201738 (HPTN 083) for those designated as male at birth (1.05 μg / mL) and 201739 (HPTN 084) for those designated as female at birth (1.39 μg / mL).

[0508] Simulations showed that in individuals designated as male or female at birth, 1.5 mL of 533 mg / mL cabotevir (799.5 mg cabotevir)... Figure 3 and 4 ) or 3 mL of 400 mg / mL cabotevir (1200 mg cabotevir) Figure 5 and 6 The maintenance dose of IM intramuscular injection in the Q4M regimen will not maintain CAB plasma concentrations higher than those of the approved Q2M regimen of CAB intramuscular injection at 200 mg / mL IM intramuscular injection.

[0509] A Q4M regimen consisting of an intramuscular gluteal injection of at least 2132 mg (4 mL) as a loading dose and a maintenance dose of at least 1066 mg (2 mL) as a starting Q4M administration 1 month after the loading dose will meet criterion 1, i.e., a person designated as male at birth. Figure 9 ) and those designated as female at birth ( Figure 10 In the approved Q2M regimen, CAB plasma concentrations will be maintained above CAB200 IM via intramuscular gluteal injection.

[0510] A Q4M regimen consisting of an intramuscular gluteal injection of at least 3200 mg (3 mL + 3 mL) as a loading dose and a maintenance dose of at least 1600 mg (3 mL) starting Q4M administration one month after the loading dose will meet two criteria: 1. A person designated as male at birth ( Figure 1 ) and those designated as female at birth ( Figure 2 In the approved Q2M regimen, CAB plasma concentrations are maintained above CAB200 IM via intramuscular gluteal injection.

[0511] 2. People who were designated as male in over 90% of their births ( Figure 7 ) and those designated as female at birth ( Figure 8Ctau levels were maintained above 1.05 μg / mL and 1.39 μg / mL, respectively. Figure 7 and Figure 8 As shown, the lower boundary of the gray band (the 10th percentile of the simulated CAB-ULA) is above the horizontal dashed line (the baseline).

[0512] In the second set of simulations, a cabotevir population pharmacokinetic (PopPK) model for CAB LA (APRETUDE®) was constructed and updated based on PK data collected from 19 historical studies following CAB 200 mg / mL IM. The CAB LA model served as the starting point for the development of the CAB ULA (CAB 533 mg / mL Q4M) model. Systemic cabotevir parameters (clearance and volume) independent of formulation and their inter-individual variability (IIV) were fixed to the CAB LA PopPK model parameter estimates. Following single-dose administration of 800 to 3200 mg of CAB ULA via the intramuscular (gluteal medius) route in a total of 48 healthy participants, parameters potentially affected by the formulation, such as absorption parameters and their IIV, were re-estimated based on CAB ULA plasma concentration data from the study shown in Example 9.

[0513] The CAB ULA PopPK model was used to simulate the concentration-time curves of virtual subjects as follows: Covariates including weight, BMI, and age were resampled 5000 times from the distributions of these covariates for males and females, generating 5000 virtual male subjects and 5000 virtual female subjects. Individual PK parameters for the virtual subjects were calculated using subject-specific covariates and population parameter estimates, along with subject-specific non-MEM inter-individual errors (ETAs) sampled from the distributions determined by the variance-covariate matrix of estimated inter-individual variability from the final population PK model. The concentration-time curves for the virtual subjects were calculated using the individual PK parameters. Residual variability (EPS) was included in the simulation. Calculate the median and corresponding 80% and / or 90% prediction intervals of the simulated concentration-time curves for virtual men and women, and the percentage of trough concentrations above (1) the PrEP PK baseline of 1.39 ug / mL for women (study HPTN 084), the PrEP PK baseline of 1.05 ug / mL for men (study HPTN083), and the 3-phase baseline of 0.45 ug / mL for men and women (studies 201584 [FLAIR], 201585 [ATLAS], and 207966 [ATLAS-2M]).

[0514] Updated simulations from a second set of simulations based on the CAB ULA PopPK model indicate that a regimen of 1600 mg CAB ULA (3 mL of 533 mg / mL cabotevir) IM intramuscular injection in the gluteal region (loading dose), followed by a maintenance regimen of 1600 mg CAB ULA (3 mL of 533 mg / mL cabotevir) IM intramuscular injection in the gluteal region starting 2 months after the loading dose, will be effective for individuals designated as male at birth. Figure 11 ) and those designated as female at birth ( Figure 12 The approved Q2M regimen maintains CAB plasma concentrations above 200 IM CAB intramuscular injection and above relevant PK benchmarks for treatment and pre-exposure prophylaxis.

[0515] It should be understood that the invention has been described by way of example only, and modifications to the details are possible within the scope of the invention. Each feature disclosed in the specification and, where appropriate, in the claims and drawings may be provided independently or in any suitable combination.

Claims

1. A method of preventing HIV in a person, comprising administering a pharmaceutical composition containing cabotevir to the person once every 15 to 24 weeks.

2. A method of treating HIV in a person in need, comprising administering a pharmaceutical composition comprising cabotevir to the person every 15 to 24 weeks.

3. The method of claim 1 or claim 2, wherein cabotevir provides at least 1 μg / mL of Ctau.

4. The method of claim 3, wherein the person was designated female at birth and the cabotevir provides at least about 1.39 μg / mL of Ctau; or wherein the person was designated male at birth and the cabotevir provides at least about 1.05 μg / mL of Ctau.

5. The method of claim 1 or claim 2, wherein cabotevir provides a higher Ctau than the Ctau achieved in the APRETUDE® dosing regimen.

6. The method according to any one of the preceding claims, wherein the method comprises: a. First, administer a loading dose of the pharmaceutical composition to the person; b. Two to six weeks after administering the loading dose, administer a maintenance dose of the pharmaceutical composition to the person; Then c. Thereafter administer the maintenance dose every 15 to 24 weeks.

7. The method of claim 6, wherein the loading dose of the pharmaceutical composition comprises about 600 mg to about 4000 mg of cabotevir.

8. The method according to claim 6 or claim 7, wherein the maintenance dose of the pharmaceutical composition comprises about 1300 to about 1700 mg of cabotevir.

9. The method according to any one of the preceding claims, wherein the pharmaceutical composition further comprises polysorbate 80, sodium carboxymethyl cellulose, and mannitol.

10. The method according to any one of the preceding claims, wherein the cabotevir in the pharmaceutical composition is in particulate form with an X50 value of 2.5 μm to 10 μm (including 2.5 μm and 10 μm).

11. The method according to any one of the preceding claims, wherein the concentration of cabotevir in the pharmaceutical composition is from about 300 mg / mL to about 650 mg / mL.

12. The method according to any one of the preceding claims, wherein the pharmaceutical composition has been reconstituted from lyophilized powder with a suitable liquid.

13. A pharmaceutical composition for treating HIV, wherein the pharmaceutical composition comprises cabotevir and the treatment comprises administering the pharmaceutical composition to a person once every 15-24 weeks.

14. A pharmaceutical composition for the prevention of HIV, wherein the pharmaceutical composition comprises cabotevir, and the prevention comprises administering the pharmaceutical composition to a person once every 15-24 weeks.

15. A pharmaceutical composition for use according to claim 13 or claim 14, wherein the cabotevir provides at least 1 μg / mL of Ctau.

16. The pharmaceutical composition for use according to claim 15, wherein the person is designated as female at birth and the cabotevir provides at least about 1.39 μg / mL of Ctau; or wherein the person is designated as male at birth and the cabotevir provides at least about 1.05 μg / mL of Ctau.

17. The pharmaceutical composition for use according to claim 13 or claim 14, wherein the Ctau provided by said cabotevir is higher than the Ctau achieved in the APRETUDE® dosing regimen.

18. The pharmaceutical composition for use according to claim 13 or 14, wherein the use includes: a. First, administer a loading dose of the pharmaceutical composition to the person; b. Two to six weeks after administering the loading dose, administer a maintenance dose of the pharmaceutical composition to the person; Then c. Thereafter administer the maintenance dose every 15 to 24 weeks.

19. The pharmaceutical composition for use according to claim 18, wherein the loading dose of said pharmaceutical composition comprises about 600 mg to about 4000 mg of cabotevir.

20. A pharmaceutical composition for use according to any one of claims 13-19, wherein the maintenance dose of said pharmaceutical composition comprises about 1300 to about 1800 mg of cabotevir.

21. The pharmaceutical composition for use according to any one of claims 13 to 20, wherein the maintenance dose is administered once every 15 to 20 weeks.

22. A pharmaceutical composition for use according to any one of claims 14 to 21, wherein the pharmaceutical composition further comprises polysorbate 80, sodium carboxymethyl cellulose, and mannitol.

23. A pharmaceutical composition for use according to any one of claims 13-22, wherein the cabotevir in the pharmaceutical composition is in particulate form with an X50 value greater than 2.5 μm to 10 μm (and including 2.5 μm and 10 μm).

24. A pharmaceutical composition for use according to any one of claims 13-23, wherein the concentration of cabotevir in the pharmaceutical composition ranges from about 300 mg / mL to about 650 mg / mL.

25. A pharmaceutical composition for use according to any one of claims 13 to 24, wherein the pharmaceutical composition has been reconstituted from lyophilized powder with a suitable liquid.

26. Use of a pharmaceutical composition in the preparation of a medicament for treating HIV infection, wherein the pharmaceutical composition comprises cabotevir.

27. Use of a pharmaceutical composition in the preparation of a medicament for the prevention of HIV infection, wherein the pharmaceutical composition comprises cabotevir.

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