Methods for treating HIV with dolutegravir and lamivudine

Abstract

To provide methods for treating HIV.SOLUTION: Methods for treating HIV in a human in need thereof are provided which comprise administering to such a human a therapeutically effective amount of a combination of dolutegravir or a pharmaceutically acceptable salt thereof and lamivudine or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method of treating HIV in humans by the in vivo administration of dolutegravir or a pharma- ceutically acceptable salt thereof in combination with lamivudine or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] The current standard of care for first-line treatment of HIV-1 infection in antiretroviral therapy (ART)-naive adults is a regimen of ≥ 3 antiretroviral drugs, including two nucleoside reverse transcriptase inhibitors (NRTIs) and one boosted protease inhibitor (PI), integrase inhibitor (INSTI), or other drug from the non-nucleoside reverse transcriptase inhibitor (NNRTI) class. However, concerns exist regarding the need for lifelong treatment with drugs that have diverse safety and resistance profiles. Therefore, a two-drug regimen (2DR) that can induce and / or maintain virologic suppression while reducing lifetime cumulative drug exposure and potential long-term toxicity would be an alternative treatment option for people living with HIV-1 infection.

[0003] Early (2000-2014) trials evaluating 2DRs yielded inconclusive results, likely due in part to small sample sizes, short treatment durations, and limitations in available treatments. The AIDS Clinical Trials Group Study A5142 team found that the virologic efficacy of a 2DR containing efavirenz + ritonavir-boosted lopinavir (n=250) was similar to efavirenz + 2 NRTIs (n=250) during 96 weeks of treatment in ART-naive participants. However, this 2DR was associated with increased emergence of drug resistance. Similarly, the PROGRESS study showed that ritonavir-boosted lopinavir + raltegravir 2DR (n=101) exerted similar antiviral efficacy through 96 weeks in ART-naive participants compared with ritonavir-boosted lopinavir + tenofovir disoproxil fumarate / emtricitabine triple-drug regimen (3DR) (n=105), although the study produced a majority of participants with viral loads <100,000 copies / mL and CD4+ cell counts ≥200 cells / mm. The GARDEL study showed noninferior virologic efficacy of open-label ritonavir-boosted lopinavir + lamivudine (n=214) compared with ritonavir-boosted lopinavir + 2NRTIs (n=202) after 48 weeks of treatment in ART-naive participants. However, these 2DRs contain ritonavir-boosted PIs, which are associated with a variety of metabolic syndrome and cardiovascular diseases, which may negate the expected benefits in terms of reduced drug exposure and cumulative toxicity. These studies demonstrate both the potential of 2DRs as an option to ART and the importance of selecting agents with appropriate and complementary virologic and clinical properties.

[0004] The INSTI dolutegravir has emerged as a strong candidate for a 2DR core agent. Phase III clinical development of dolutegravir has provided extensive evidence, with follow-up data up to 144 weeks supporting virologic efficacy, a favorable resistance profile, and high barriers to resistance as a first-line 3DR core agent in ART-naive individuals. In the SWORD-1 and SWORD-2 studies, dolutegravir plus rilpivirine demonstrated non-inferior virologic efficacy for maintaining virologic suppression and acceptable resistance compared with continuation of current ART through week 48. Analysis at 100 weeks showed that a high proportion of virologic suppression was maintained with a low discontinuation rate.

[0005] Lamivudine is an NRTI included in several standard-of-care regimens for the first-line treatment of HIV-1 infection. Studies evaluating lamivudine have demonstrated a well-established efficacy, safety, and resistance profile. One challenge associated with lamivudine is the rapid emergence of drug resistance as a result of selection for the M184V reverse transcriptase mutation when used as monotherapy. However, results from in vitro studies suggest that lamivudine retains some of its antiviral efficacy after selection for the M184V variant when combined with other agents. The 2DR of dolutegravir plus lamivudine was evaluated in the 48-week pilot study PADDLE for the treatment of ART-naive participants. By week 8, all 20 participants had achieved a viral load of <50 copies / mL, including 4 with baseline HIV-1 RNA ≥100,000 copies / mL, and 90% (n=18) maintained virologic suppression at week 48, and all of these 18 participants maintained virologic suppression at week 96. In addition, the phase II, single-arm ACTG A5353 study, which treated 120 treatment-naive participants with HIV-1 RNA <500,000 copies / mL with dolutegravir plus lamivudine, showed that 90% (n=108) achieved HIV-1 RNA <50 copies / mL at week 24. Thus, dolutegravir plus lamivudine may constitute a viable combination as a novel 2DR used for early suppression of HIV-1 infection in ART-naive patients. Cahn et al., "Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomized, non-inferiority, phase 3 trials.", Volume 393, Issue 10167, January 12, 2019: 143-155. Summary of the Invention [Means for solving the problem]

[0006] The present invention includes a method of treating HIV in a human in need thereof comprising the in vivo administration of a therapeutically effective amount of a combination of dolutegravir, or a pharma- ceutically acceptable salt thereof, and lamivudine, or a pharma- ceutically acceptable salt thereof.

[0007] According to another embodiment, the present invention comprises dolutegravir, or a pharma- ceutically acceptable salt thereof, and lamivudine, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0008] According to another embodiment, the present invention comprises dolutegravir, or a pharma- ceutically acceptable salt thereof, and lamivudine, or a pharma- ceutically acceptable salt thereof, for use in the treatment of HIV.

[0009] According to another embodiment, the invention comprises the use of dolutegravir, or a pharma- ceutically acceptable salt thereof, and lamivudine, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of HIV.

[0010] The present invention consists essentially of a method of treating HIV in a human in need thereof comprising the in vivo administration of a therapeutically effective amount of a combination of dolutegravir, or a pharma- ceutically acceptable salt thereof, and lamivudine, or a pharma-ceutically acceptable salt thereof.

[0011] According to another embodiment, the invention consists essentially of dolutegravir, or a pharma- ceutically acceptable salt thereof, and lamivudine, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0012] According to another embodiment, the invention consists essentially of dolutegravir, or a pharma- ceutically acceptable salt thereof, and lamivudine, or a pharma- ceutically acceptable salt thereof, for use in the treatment of HIV.

[0013] According to another embodiment, the invention consists essentially of the use of dolutegravir, or a pharma- ceutically acceptable salt thereof, and lamivudine, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of HIV. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The two-drug combination of dolutegravir (an integrase inhibitor [INSTI]) and lamivudine (a nucleoside reverse transcriptase inhibitor [NRTI]) is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with no known substitutions associated with resistance to the individual components of the combination.

[0015] 1. Indications and Usage The combination is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with no known substitutions associated with resistance to the individual components of the combination.

[0016] 2 Dosage and Administration 2.1 Pregnancy testing before starting the combination Perform a pregnancy test in adolescents and adults of childbearing potential prior to initiating this combination [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1 and 8.3)].

[0017] 2.2 Recommended Dosage The combination is a fixed-dose combination product containing 50 mg of dolutegravir and 300 mg of lamivudine. The recommended adult dosage regimen for the combination is one tablet taken orally once daily with or without food.

[0018] 2.3 Dosage recommendations when using specific concomitant medications The dolutegravir dose (50 mg) in this combination is insufficient when administered concomitantly with drugs listed in Table 1 that may reduce dolutegravir concentrations. The following dolutegravir dosing regimen is recommended:

[0019] [Table 1]

[0020] 2.4 Not recommended due to lack of dose titration Because the combination is a fixed-dose tablet and cannot be titrated, the combination is not recommended in patients with creatinine clearance less than 50 mL / min [see Use in Specific Populations (8.6)].

[0021] 3. Dosage form and strength The combination tablets are oval, biconvex, white, film-coated tablets embossed with "SV 137" on one side. Each tablet contains dolutegravir sodium equivalent to 50 mg of dolutegravir and 300 mg of lamivudine [see Description (11)].

[0022] 4 Contraindications This combination is contraindicated in patients with a previous hypersensitivity reaction to dolutegravir [see Warnings and Precautions (5.2)] or lamivudine, or in patients receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk of serious and / or life-threatening events with concurrent use of dolutegravir [see Drug-Drug Interactions (7)].

[0023] 5. Warnings and Precautions 5.1 Post-treatment exacerbation of hepatitis in patients with hepatitis B coinfection Clinical and laboratory evidence of exacerbation of hepatitis occurred following discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be monitored closely with both clinical and laboratory follow-up for at least several months after discontinuing treatment.

[0024] 5.2 Hypersensitivity reactions Hypersensitivity reactions have been reported with the use of dolutegravir, a component of the combination, and were characterized by rash, constitutional findings, and occasionally organ dysfunction, e.g., liver damage. These events were reported in <1% of subjects receiving dolutegravir in Phase 3 clinical trials. Immediately discontinue the combination if signs or symptoms of a hypersensitivity reaction occur (e.g., but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint pain, skin blistering or peeling, oral blistering or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, dyspnea). Clinical status, including hepatic aminotransferases, should be monitored, and appropriate treatment should be initiated. Delay in discontinuing treatment with the combination or other suspected agents after the onset of hypersensitivity may result in fatal reactions.

[0025] 5.3 Emergence of lamivudine-resistant HBV The safety and efficacy of lamivudine for the treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV have not been established. Emergence of hepatitis B virus mutants with resistance to lamivudine has been reported in HIV-1-infected subjects receiving antiretroviral regimens containing lamivudine in the presence of coinfection with hepatitis B virus. See full prescribing information for EPIVIR-HBV (lamivudine).

[0026] 5.4 Liver toxicity Hepatic adverse events have been reported in patients receiving dolutegravir-containing regimens [see Adverse Reactions (6.1)]. Patients with underlying hepatitis B or C may be at increased risk of exacerbation or development of transaminase elevations with the use of this combination [see Adverse Reactions (6.1)]. In some cases, transaminase elevations have been consistent with immune reconstitution inflammatory syndrome or hepatitis B reactivation, especially in the setting of cessation of antihepatitis treatment. Cases of hepatic toxicity, including elevated serum liver biochemistry, hepatitis, and acute liver failure have also been reported in patients receiving dolutegravir-containing regimens who did not have preexisting liver disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplantation has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

[0027] 5.5 Severe hepatomegaly with lactic acidosis and steatosis Severe hepatomegaly with lactic acidosis and steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine (a component of the combination). The majority of these cases have been women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for EPIVIR (lamivudine). Treatment with the combination should be temporarily interrupted in any patient who develops clinical or laboratory findings suggestive of overt liver toxicity, which may include hepatomegaly and steatosis even in the absence of lactic acidosis or significant transaminase elevations.

[0028] 5.6 Embryo-fetal toxicity Preliminary data from observational studies have indicated that dolutegravir, a component of the combination, is associated with an increased risk of neural tube defects when administered at the time of conception and early in pregnancy. Because there is limited understanding of the reported types of neural tube defects associated with dolutegravir use and the date of conception cannot be precisely determined, avoid use of the combination from the time of conception through the first trimester of pregnancy [see Use in Specific Populations (8.1)].

[0029] If pregnancy is planned or confirmed within the first trimester while on this combination, switch to an alternative regimen, if possible.

[0030] A pregnancy test should be performed in adolescents and adults of childbearing potential prior to initiating this combination to preclude use of this combination during the first trimester of pregnancy [see Dosage and Administration (2.1)].

[0031] Advise adolescents and adults of childbearing age to use effective contraception consistently [see Use in specific populations (8.1, 8.3)].

[0032] 5.7 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug-Drug Interactions Concurrent use of this combination with other medications may result in known or potentially serious drug-drug interactions, some of which are [see Contraindications (4) and Drug-Drug Interactions (7.4)]. The possibility of loss of therapeutic efficacy and development of resistance to the combination Possible clinically significant adverse reactions from greater exposure to concomitant medications This may cause.

[0033] See Table 5 for e.g., dosing recommendations to prevent or manage these possible known serious drug-drug interactions. Consider the potential for drug-drug interactions prior to and during treatment with this combination, review concomitant medications during treatment with this combination, and monitor for adverse reactions associated with the concomitant medications.

[0034] 5.8 Immune reconstitution syndrome Immune reconstitution inflammatory syndromes have been reported in patients treated with combination antiretroviral therapy, including combinations. During the initial phase of combination antiretroviral therapy, patients with a responsive immune system may develop inflammatory responses to indolent or residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may require further evaluation and treatment.

[0035] Autoimmune diseases (e.g., Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however the time to onset is more variable and can occur many months after initiation of treatment.

[0036] 6 Adverse Reactions 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and do not reflect rates observed in clinical practice.

[0037] The safety evaluation of this combination in HIV-1-infected, treatment-naive adult subjects with viral loads ≤500,000 HIV-1 RNA copies / mL is based on a primary analysis of 48 weeks of pooled data from two identical multicenter, double-blind, controlled trials, GEMINI-1 and GEMINI-2. A total of 1,433 adult HIV-1-infected, treatment-naive subjects were randomized to receive dolutegravir (TIVICAY) 50 mg + lamivudine (EPIVIR) 300 mg as a complete once-daily regimen, or TIVICAY 50 mg once-daily + fixed-dose combination tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC) (TRUVADA).

[0038] In the pooled analysis, the rate of adverse events leading to discontinuation was 2% of subjects in both treatment arms. The most common adverse event leading to discontinuation was psychiatric disorders, occurring in <1% of subjects in both treatment arms.

[0039] Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm in the pooled analysis at week 48 from the GEMINI-1 and GEMINI-2 trials are provided in Table 2.

[0040] In a 48-week analysis of pooled data from GEMINI-1 and GEMINI-2, adverse reactions observed with TIVICAY + EPIVIR were generally consistent with the adverse reaction profile and severity for the individual components when administered with other antiretroviral agents.

[0041] [Table 2]

[0042] Less common adverse reactions The following adverse reactions occurred in <2% of subjects receiving dolutegravir + lamivudine or were from studies that are described in the prescribing information for the individual components TIVICAY (dolutegravir) and EPIVIR (lamivudine). Some events were included for evaluation of their severity and potential causality. Blood and lymphatic system disorders: Anemia, neutropenia, thrombocytopenia. Gastrointestinal disease: Abdominal discomfort, abdominal pain, flatulence, epigastric pain, vomiting. General: Malaise, fever, discomfort. Hepatobiliary diseases: Hepatitis. Immune system disorders: hypersensitivity, immune reconstitution syndrome. Musculoskeletal disorders: Myositis. Nervous system disorders: Somnolence. Psychiatric disorders: abnormal dreams, depression, suicidal thoughts, attempts, actions, or completion; these events were observed primarily in subjects with a history of depression or other psychiatric illness. Renal and urinary disorders: Renal dysfunction. Skin and subcutaneous tissue disorders: Pruritus, rash.

[0043] Abnormal test findings Selected laboratory abnormalities that had a worsening grade from baseline and represented worst-grade toxicity in ≥2% of subjects are shown in Table 3. The mean changes from baseline observed for selected lipid values ​​are shown in Table 4.

[0044] [Table 3]

[0045] [Table 4]

[0046] Changes in serum creatinine. Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without any effect on renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first 4 weeks of treatment in both arms and remained stable through Week 48. Mean changes from baseline of 0.116 mg / dL and 0.154 mg / dL were observed after 48 weeks of treatment with TIVICAY + EPIVIR and TIVICAY + TRUVADA, respectively. These changes are not considered clinically relevant.

[0047] 6.2 Post-market experience In addition to the adverse reactions reported from clinical trials, the following adverse reactions have been identified in patients receiving dolutegravir- or lamivudine-containing regimens during postmarketing experience. Because these reactions are reported spontaneously from a population of indeterminate size, it is not always possible to reliably assess their frequency or establish a causal relationship to drug exposure: body fat redistribution / accumulation, hyperglycemia, weakness, anemia (e.g. pure red cell aplasia and severe anemia that progresses during treatment), lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.5)], pancreatitis, post-treatment exacerbation of hepatitis B [see Warnings and Precautions (5.1)], acute hepatic failure, hepatotoxicity, anaphylaxis, urticaria, weight gain, arthralgia, CPK elevated, muscle weakness, myalgia, rhabdomyolysis, paresthesia, peripheral neuropathy, anxiety, alopecia, and pruritus.

[0048] 7 Drug-drug interactions 7.1 Concomitant use of other antiretroviral drugs Because this combination is a complete regimen, coadministration with other antiretroviral agents for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1)]. No information on potential drug-drug interactions with other antiretroviral agents is provided [see Contraindications (4), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)].

[0049] 7.2 Potential for this combination to affect other medications Dolutegravir, a component of the combination, inhibits the renal organic cation transporter (OCT)2 and the multidrug and toxin extrusion transporter (MATE)1 and may therefore increase plasma concentrations of drugs that are excreted via OCT2 or MATE1, such as dofetilide and metformin [see Contraindications (4), Drug-Drug Interactions (7.4), and Clinical Pharmacology (12.3)].

[0050] 7.3 Other drugs may affect the components of this combination Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 with some contribution from cytochrome P450 (CYP) 3A. Dolutegravir is also a substrate for UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce these enzymes and transporters may decrease plasma concentrations of dolutegravir and reduce the therapeutic efficacy of dolutegravir [see Drug-Drug Interactions (7.4) and Clinical Pharmacology (12.3)]. Concomitant administration of dolutegravir with other drugs that inhibit these enzymes may increase plasma concentrations of dolutegravir.

[0051] Coadministration of dolutegravir with products containing polyvalent cations may result in decreased absorption of dolutegravir [see Drug-Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

[0052] 7.4 Established and Other Potentially Significant Drug-Drug Interactions No drug-drug interaction studies have been conducted with the fixed-dose combination tablet of dolutegravir and lamivudine.

[0053] Information on potential drug-drug interactions with dolutegravir is provided in Table 5. These recommendations are based on either drug-drug interaction studies or are anticipated due to the anticipated magnitude of the interaction and the potential for serious adverse events or loss of efficacy [see Contraindications (4) and Clinical Pharmacology (12.3)].

[0054] [Table 5]

[0055] Sorbitol Lamivudine: Coadministration of a single dose of lamivudine and sorbitol solution resulted in a sorbitol dose-dependent reduction in lamivudine exposure. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology (12.3)].

[0056] 8 Use in specific populations 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the combination during pregnancy. Healthcare providers are encouraged to enroll their patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

[0057] Risk Overview Preliminary data from observational studies have confirmed a possible increased risk of neural tube defects when dolutegravir, a component of the combination, is administered at the time of conception compared with non-dolutegravir-containing antiretroviral regimens. Because defects related to neural tube closure occur from conception to the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are potentially at risk. In addition, two of the four birth defects observed with dolutegravir use (encephalocele and porencephalocele), often referred to as neural tube defects, can occur after neural tube closure and may occur later than 6 weeks of gestation, but within the first trimester. Because of the limited understanding of the types of reported neural tube defects associated with dolutegravir use, and because the date of conception cannot be precisely determined, avoid use of the combination from the time of conception through the first trimester of pregnancy. Neural tube defects have not been reported in children born to mothers who initiated dolutegravir after the first trimester of pregnancy (see Data).

[0058] If pregnancy is planned or confirmed during this combination during the first trimester, switch to an alternative regimen, if possible. Inform pregnant adolescents and adults of the potential risk to the embryo exposed to this combination from the time of conception through the first trimester of pregnancy.

[0059] Human data regarding the use of this combination during pregnancy are insufficient to definitively assess the drug-associated risk of birth defects and miscarriage. The background risk for major birth defects in the applicable population is not known. In the general U.S. population, estimated background rates for major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

[0060] In animal reproduction studies, no evidence of adverse developmental outcomes was observed at systemic exposures (AUC) of dolutegravir less (rabbits) and 38-fold (rats) higher than human exposure at the recommended human dose (RHD) (see Data). In pre- / postnatal development studies in rats, maternal systemic exposure (AUC) of dolutegravir was approximately 32-fold higher than human exposure at the RHD. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in fetal lethality at systemic exposures (AUC) similar to those at the RHD. However, plasma concentrations (C) of lamivudine 32-fold higher than those at the RHD in pregnant rats during organogenesis were not observed. max No adverse growth effects were observed with oral administration of lamivudine in mice (see data).

[0061] data Human data: Dolutegravir: As of May 2018, an ongoing observational birth outcomes study in Botswana has reported four cases of neural tube defects (0.94%) among 426 births to mothers exposed to dolutegravir-containing regimens at conception. In comparison, neural tube defect prevalence was 0.12% (14 / 11,300) in the non-dolutegravir arm and 0.09% (61 / 66,057) in the HIV-uninfected arm. The four cases reported with dolutegravir included one case each of encephalocele, anencephaly, myelomeningocele, and porencephalocele. No infants born to women who initiated dolutegravir during pregnancy had neural tube defects (n=2,812).

[0062] Data analyzed to date from APR, clinical trials, and other sources, including postmarketing data, are insufficient to address the risk of neural tube defects with dolutegravir.

[0063] Lamivudine: Based on the prospective report of APRs for >11,000 exposures to lamivudine during pregnancy that resulted in a live birth (including >4,500 exposures during the first trimester), there was no difference in the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the MACDP U.S. reference population. The prevalence of defects in live births was 3.1% (95% CI: 2.6% to 3.6%) after first-trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5%, 3.3%) after second- / third-trimester exposure to lamivudine-containing regimens.

[0064] Lamivudine pharmacokinetics was studied in pregnant women during two clinical trials conducted in South Africa. The trials evaluated the pharmacokinetics of 150 mg lamivudine twice daily with zidovudine in 16 women at 36 weeks' gestation, 150 mg lamivudine twice daily with zidovudine in 10 women at 38 weeks' gestation, and 300 mg lamivudine twice daily without other antiretroviral medication in 10 women at 38 weeks' gestation. These studies were not designed to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected after natural rupture of the membranes to confirm that lamivudine crosses the placenta in humans. Based on limited data at the time of delivery, the median (range) amniotic fluid concentration of lamivudine was 3.9-fold (1.2-12.8-fold) greater than paired maternal serum concentrations (n=8).

[0065] Animal data: Dolutegravir: Dolutegravir was administered orally up to 1,000 mg / kg daily to pregnant rats and rabbits on gestation days 6-17 and 6-18, respectively, and to rats from gestation day 6 to lactation / postpartum day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre- / postnatal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposure (AUC) to dolutegravir in rabbits was less than in humans with RHD, and in rats it was approximately 38-fold higher than in humans with RHD. In a rat pre- / postnatal development study, reduced body weight of developing pups was observed during lactation at maternally toxic doses (approximately 32-fold higher than human exposure with RHD).

[0066] Lamivudine: Lamivudine was administered orally to pregnant rats (90, 600, and 4,000 mg / kg / day) and rabbits (90, 300, and 1,000 mg / kg / day and 15, 40, and 90 mg / kg / day) during organogenesis (gestational days 7-16 [rats] and 8-20 [rabbits]). Evidence of lamivudine-attributable fetal malformations was observed at plasma concentrations (C) approximately 32-fold higher than human exposure during RHD. max No evidence of early fetal lethal effects was observed in rats or rabbits at doses that produced 100 mg / kg of naphthalene. Evidence of early fetal lethal effects was seen in rabbits at systemic exposures (AUC) similar to those observed in humans, but at plasma concentrations (C) 32-fold higher than human exposure at the RHD. max ) rats, there was no indication of this effect. A study in pregnant rats showed that lamivudine is transferred to the fetus across the placenta. In a fertility / pre- and postnatal development study in rats, lamivudine was administered orally (from premating through postnatal day 20) at doses of 180, 900, and 4,000 mg / kg / day. In this study, fertility and offspring development, including reproductive performance, were not affected by maternal administration of lamivudine.

[0067] 8.2 Breastfeeding Risk Overview The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breast-feed their infants to avoid risking postnatal transmission of HIV-1 infection.

[0068] Lamivudine, a component of this combination, is present in human breast milk. It is not known whether dolutegravir, a component of this combination, is present in human breast milk. When administered to lactating rats, dolutegravir was present in breast milk (see Data). There is no information on the effects of this combination or the components of this combination (dolutegravir and lamivudine) on breast-fed infants or the effect of these drugs on breast milk secretion.

[0069] Instruct mothers not to breast-feed if this combination is administered due to: (1) HIV-1 transmission (in HIV-negative infants), (2) development of viral resistance (in HIV-positive infants), and (3) the potential for adverse reactions in breast-fed infants similar to those observed in adults.

[0070] data Animal Data: Dolutegravir was the predominant drug-related moiety secreted in the milk of lactating rats after a single oral dose of 50 mg / kg on day 10 of lactation, with milk concentrations up to approximately 1.3-fold the maternal plasma concentrations observed 8 hours after dosing.

[0071] 8.3 Reproductive males and females Pregnancy test A pregnancy test should be performed in adolescents and adults of childbearing potential prior to initiating this combination.

[0072] contraception Adolescents and adults of childbearing age should avoid use of this combination from the time of conception through the first trimester of pregnancy due to the potential risk of neural tube defects [see Use in Specific Populations (8.1)].

[0073] Advise adolescents and adults of childbearing age taking this combination to use effective contraception consistently.

[0074] 8.4 Pediatric Use The safety and effectiveness of this combination has not been established in pediatric patients.

[0075] 8.5 Elderly Use Clinical trials of this combination did not include sufficient numbers of elderly subjects to determine whether subjects 65 years of age or older respond differently from younger subjects. In general, caution should be used when administering this combination to elderly patients, reflecting a higher incidence of impaired hepatic, renal, or cardiac function, and comorbid conditions or other drug treatments [see Clinical Pharmacology (12.3)].

[0076] 8.6 Renal dysfunction Because this is a fixed-dose combination and the doses of the individual components cannot be adjusted, the combination is not recommended for patients with a creatinine clearance <50 mL / min. If a reduced dose of lamivudine, a component of the combination, is necessary for patients with a creatinine clearance <50 mL / min, the individual components should be used [see Clinical Pharmacology (12.3)].

[0077] 8.7 Liver disorders No dose adjustment of the combination is necessary in patients with mild or moderate (Child-Pugh score A or B) hepatic impairment. Dolutegravir has not been studied in patients with severe hepatic impairment (Child-Pugh score C). Therefore, the combination is not recommended for patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

[0078] 10 Overdose There is no known specific treatment for overdose with this combination. If an overdose occurs, the patient should be monitored and standard supportive care applied if necessary.

[0079] Dolutegravir Dolutegravir is highly bound to plasma proteins and is therefore unlikely to be significantly removed by dialysis.

[0080] Lamivudine Because negligible amounts of lamivudine were removed by (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known whether continuous hemodialysis provides a clinical benefit in the event of lamivudine overdosage.

[0081] 11 Explanation The combination is a fixed-dose combination tablet containing dolutegravir (as dolutegravir sodium) (INSTI) and lamivudine (also known as 3TC), a nucleoside analogue.

[0082] The combination tablets are for oral administration. Each film-coated tablet contains 50 mg of dolutegravir (equivalent to 52.6 mg of dolutegravir sodium) and 300 mg of lamivudine as active ingredients, and magnesium stearate, mannitol, microcrystalline cellulose, povidone K29 / 32, sodium starch glycolate, and sodium stearyl fumarate as inactive ingredients. The tablet film coating contains the inactive ingredients hypromellose, polyethylene glycol, and titanium dioxide.

[0083] Dolutegravir The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-oleate. Its empirical formula is C 20 H 18 F 2 N 3 NaO 5 It has a molecular weight of 441.36 g / mol and the following structural formula:

[0084] [ka] Dolutegravir sodium is a white to pale yellow powder and is poorly soluble in water.

[0085] Lamivudine The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-) enantiomer of the dideoxy analogue of cytidine. Lamivudine is also known as (-)2',3'-dideoxy,3'-thiacytidine and is 8 H 11 N 3 O 3 S and a molecular weight of 229.3 g / mol, and has the following structural formula:

[0086] [ka] Lamivudine is a white to off-white crystalline solid and is soluble in water.

[0087] 12 Clinical Pharmacology 12.1 Mechanism of action This combination is a fixed-dose combination of the HIV-1 antiretrovirals dolutegravir and lamivudine [see Microbiology (12.4)].

[0088] 12.2 Pharmacology Cardiac Electrophysiology The effect of this combination on the QT interval has not been studied.

[0089] Extensive QT studies have been performed for dolutegravir. The effect of lamivudine on the QT interval has not been evaluated.

[0090] In a randomized, placebo-controlled crossover study, 42 healthy subjects received single oral doses of placebo, dolutegravir 250 mg suspension (approximately three times the exposure of a 50 mg dose once daily at steady state), and moxifloxacin 400 mg (active control) in a randomized sequence. After baseline and placebo adjustment, the maximum mean QTc change (QTcF) based on the Fridericia correction method for dolutegravir was 2.4 msec (one-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours after dosing.

[0091] Effect on renal function The effect of dolutegravir on renal function was evaluated in an open-label, randomized, three-arm, parallel, placebo-controlled study in healthy subjects (n=37) receiving dolutegravir 50 mg once daily (n=12), dolutegravir 50 mg twice daily (n=13), or placebo once daily (n=12) for 14 days. Reductions in creatinine clearance, as determined by 24-hour urine collection, were observed with both doses of dolutegravir after 14 days of treatment in subjects receiving 50 mg once daily (9% reduction) and 50 mg twice daily (13% reduction). Neither dose of dolutegravir demonstrated a significant effect on actual glomerular filtration rate (determined by clearance of the probe drug iohexol) or effective renal plasma flow (determined by clearance of the probe drug para-aminohippurate) compared with placebo.

[0092] 12.3 Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of the components of this combination are shown in Table 6. Multiple dose pharmacokinetic parameters are shown in Table 7.

[0093] [Table 6]

[0094] [Table 7]

[0095] Specific populations Pediatric Patients: The pharmacokinetics of this combination have not been studied in pediatric subjects [see Use in Specific Populations (8.4)].

[0096] Elderly Patients: Population pharmacokinetic analyses have demonstrated that age has no clinically relevant effect on the pharmacokinetics of dolutegravir. There are limited pharmacokinetic data for dolutegravir and lamivudine in subjects 65 years of age and older [see Use in Specific Populations (8.5)].

[0097] Patients with renal impairment: The effect on this combination of dolutegravir and lamivudine has not been evaluated. See full prescribing information for TIVICAY (dolutegravir) and EPIVIR (lamivudine).

[0098] Patients with Hepatic Impairment: The effect of hepatic impairment on the combination of dolutegravir and lamivudine has not been evaluated. See full prescribing information for TIVICAY (dolutegravir) and EPIVIR (lamivudine).

[0099] Gender and Race: Population pharmacokinetic analyses from individual component studies revealed that gender and race had no clinically relevant effects on the pharmacokinetics of dolutegravir or lamivudine.

[0100] Drug-Drug Interaction Research The drug-drug interaction studies described were performed with dolutegravir and / or lamivudine as single entities. No drug-drug interaction studies were performed using the combination of dolutegravir and lamivudine. No clinically significant drug-drug interactions are expected between dolutegravir and lamivudine.

[0101] In vitro, dolutegravir did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP) 1B1, OATP1B3, OCT1, multidrug resistance protein (MRP) 2, or MRP4 (IC 50 >50 μM). In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4.

[0102] In vitro, dolutegravir inhibited renal OCT2 (IC 50 = 1.93 μM) and MATE1 (IC 50 = 6.34 μM). In vivo, dolutegravir inhibits renal tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs that are excreted via OCT2 or MATE1, such as dofetilide and metformin [see Contraindications (4) and Drug-Drug Interactions (7.4)].

[0103] In vitro, dolutegravir inhibits the basolateral renal transporter, organic anion transporter (OAT) 1 (IC 50 = 2.12 μM) and OAT3 (IC 50 = 1.97 μM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or paraaminohippurate, which are substrates of OAT1 and OAT3.

[0104] Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate for UGT1A3, UGT1A9, BCRP, and P-gp in vitro. In vitro, dolutegravir was not a substrate for OATP1B1 or OATP1B3.

[0105] Dosing recommendations as a result of established and other potentially significant drug-drug interactions with the individual components of the combination are provided in Section 7.4 [See Drug-Drug Interactions (7)].

[0106] [Table 8]

[0107] [Table 9]

[0108] Lamivudine: The drug-drug interactions described are based on studies performed with lamivudine as a single entity.

[0109] Effect of Lamivudine on the Pharmacokinetics of Other Drugs: Based on the results of in vitro studies, lamivudine during therapeutic drug exposure is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: OATP1B1 / 3, BCRP, P-gp, MATE1, MATE2-K, OCT1, OCT2, or OCT3.

[0110] Effect of other drugs on lamivudine pharmacokinetics: Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim, an inhibitor of these drug transporters, has been shown to increase lamivudine plasma concentrations. This interaction is not expected to be clinically significant as no dose adjustment of lamivudine is necessary.

[0111] Lamivudine is a substrate for P-gp and BCRP, but considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in lamivudine absorption. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect lamivudine pharmacokinetics and excretion.

[0112] Interferon-alpha: There was no significant pharmacokinetic interaction between lamivudine and interferon-alpha in a study of 19 healthy male subjects.

[0113] Ribavirin: In vitro data indicate that ribavirin reduces the phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentration or intracellular concentration of triphosphorylated active metabolite) or pharmacodynamic (e.g., loss of HIV-1 / HCV virologic suppression) interactions were observed when ribavirin was coadministered with lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) as part of a multidrug regimen to HIV-1 / HCV coinfected subjects.

[0114] Sorbitol (excipient): Lamivudine and sorbitol solution were co-administered to 16 healthy adult subjects in an open-label, randomized-sequence, four-period crossover study. Each subject received a single 300 mg dose of lamivudine oral solution alone or co-administered a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in the solution. Co-administration of lamivudine and sorbitol increased the AUC (0-24) 20%, 39%, and 44% for AUC (∞) 14%, 32%, and 36% in C max produced dose-dependent reductions in lamivudine of 28%, 52%, and 55%.

[0115] The effect of other concomitant medications on lamivudine is shown in Table 10.

[0116] [Table 10]

[0117] 12.4 Microbiology Mechanism of action Dolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand-transfer step of retroviral DNA integration, which is essential for the HIV replication cycle. It has an IC of 2.7 nM and 12.6 nM in strand-transfer biochemical assays using purified recombinant HIV-1 integrase and pretreated substrate DNA. 50 values ​​were obtained.

[0118] Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The primary mode of action of 3TC-TP is the inhibition of reverse transcriptase (RT) via DNA chain termination following incorporation of the nucleotide analogue.

[0119] Antiviral activity in cell culture Dolutegravir: Dolutegravir has antiviral activity against laboratory strains of wild-type HIV-1, with the average concentration of drug needed to achieve 50 percent viral replication (EC 50 ) values ​​ranged from 0.5 nM (0.21 ng / mL) to 2.1 nM (0.85 ng / mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells.

[0120] Dolutegravir had a mean EC value of 0.52 nM against 13 clinically distinct clade B isolates in a viral integrase susceptibility assay using integrase coding regions derived from clinical isolates. 50 Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (three from each group of M [clades AG] and three from group O), with EC values ​​ranging from 0.02 nM to 2.14 nM for HIV-1. 50 Antiviral activity was demonstrated in EC values ​​of 0.01–0.05 and 0.01–0.05 in PBMC assays against three clinical HIV-2 isolates. 50 The values ​​ranged from 0.09 nM to 0.61 nM.

[0121] Lamivudine: The antiviral activity of lamivudine against HIV-1 was evaluated in several cell lines, including monocytes and PBMCs, using standard susceptibility assays. EC 50 The values ​​ranged from 0.003 to 15 μM (1 μM = 0.23 mcg / mL). The EC50 values ​​of lamivudine against various HIV-1 clade (AG) and group O viruses ranged from 0.001 to 0.120 μM, and against HIV-2 isolates ranged from 0.003 to 0.120 μM in PBMCs.

[0122] Antiviral activity in combination with other antiviral drugs Neither dolutegravir nor lamivudine was antagonistic to all anti-HIV drugs tested. See full prescribing information for TIVICAY (dolutegravir) and EPIVIR (lamivudine).

[0123] Resistance Cell culture: Dolutegravir: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions emerged in different ways, with the appearance of G118R conferring a 10-fold reduced susceptibility to dolutegravir, whereas substitutions E92Q, S153F or Y, G193E, or R263K conferred up to a 4-fold reduced susceptibility to dolutegravir.

[0124] Lamivudine: HIV-1 resistance to lamivudine involves the development of the M184I or M184V amino acid changes close to the active site of the viral RT. This mutation occurs both in vitro and in patients infected with HIV-1 and treated with antiretroviral therapy containing lamivudine. The M184V mutant displays greatly reduced susceptibility to lamivudine and reduced viral replicative capacity in vitro.

[0125] Clinical Subjects: None of the six subjects in the dolutegravir + lamivudine group or the four subjects in the dolutegravir + TDF / FTC group who met protocol-defined confirmed virologic discontinuation (CVW) criteria during the pooled GEMINI-1 and GEMINI-2 studies over 48 weeks had emerged INSTI or NRTI resistance substitutions.

[0126] Cross-resistance Dolutegravir: Dolutegravir susceptibility was tested against 60 INSTI-resistant site-specific mutant HIV-1 viruses (28 single substitutions and 32 ≥2 substitutions). Single INSTI resistance substitutions T66K, I151L, and S153Y conferred a >2-fold (range: 2.3-fold to 3.6-fold) decrease in dolutegravir susceptibility. Multiple substitution combinations T66K / L74M, E92Q / N155H, G140C / Q148R, G140S / Q148H, R or K, Q148R / N155H, T97A / G140S / Q148, and E138 / G140 / Q148 substitutions showed a >2-fold (range: 2.5-fold to 21-fold) decrease in dolutegravir susceptibility.

[0127] Lamivudine: Cross-resistance conferred by M184V RT is limited within the nucleoside inhibitor class of antiretrovirals. Zidovudine maintains its antiretroviral activity against lamivudine-resistant HIV-1. Abacavir and tenofovir maintain antiretroviral activity against lamivudine-resistant HIV-1 with only the M184V substitution. Cross-resistance is expected with emtricitabine, which also selects for the M184V substitution, and abacavir, which selects for M184V plus additional RT mutations K65R, L74V, and Y115F.

[0128] 13 Non-clinical toxicity 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenicity Dolutegravir: A 2-year carcinogenicity study was conducted with dolutegravir in mice and rats. Mice were dosed up to 500 mg / kg and rats were dosed up to 50 mg / kg. In mice, no significant increase in the incidence of drug-related neoplasms was observed at the highest dose tested, resulting in a dolutegravir AUC exposure approximately 20-fold higher than in humans at the recommended 50 mg once daily dose. In rats, no significant increase in the incidence of drug-related neoplasms was observed at the highest dose tested, resulting in a dolutegravir AUC exposure 17-fold higher than in humans at the recommended 50 mg once daily dose.

[0129] Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenicity at exposures up to 12 times (mice) and 72 times (rats) the recommended human exposure at a dose of 300 mg.

[0130] Mutagenicity Dolutegravir: Dolutegravir was not genotoxic in microbial reverse mutation assays, mouse lymphoma assays, or in vivo rodent micronucleus assays.

[0131] Lamivudine: Lamivudine was mutagenic in the L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assays, in vitro cell transformation assays, rat bone marrow cytogenetic assays, and assays for unscheduled DNA synthesis in rat liver.

[0132] Impaired fertility Dolutegravir or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 33 or 112 times higher than those at doses of 50 mg and 300 mg, respectively, in humans.

[0133] 14 Clinical research 14.1 Clinical Trials in Adults The efficacy of this combination is supported by data from two randomized, double-blind, controlled trials (GEMINI-1 [NCT204861] and GEMINI-2 [NCT205543]) in antiretroviral treatment-naive adults.

[0134] GEMINI-1 and GEMINI-2 are identical, 148-week, phase 3, randomized, multicenter, parallel-group, non-inferiority trials. A total of 1,433 HIV-1-infected, antiretroviral treatment-naive adult subjects were treated in the studies. Subjects with screening plasma HIV-1 RNA of 1,000 to ≤500,000 copies / mL and no evidence of major resistance-associated mutations were included. Subjects were randomized to receive a two-drug regimen of TIVICAY plus EPIVIR once daily or TIVICAY 50 mg once daily plus fixed-dose TRUVADA. The primary efficacy endpoint for each GEMINI trial was the proportion of subjects with plasma HIV-1 RNA <50 copies / mL at week 48 (snapshot algorithm for the ITT-E population).

[0135] At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% were female, 68% were white, 9% were CDC stage 3 (AIDS), and the median plasma HIV-1 RNA was 4.4 log 10 copies / mL, 20% had HIV-1 RNA >100,000 copies / mL, and a median CD4+ cell count of 432 cells / mm 3 and 8% had a CD4+ cell count ≤ 200 cells / mm 3 These characteristics were similar across studies and treatment arms.

[0136] The primary endpoint and other results for the pooled GEMINI-1 and GEMINI-2 studies, including results by important baseline covariates, are shown in Table 11. Virological results for GEMINI-1 and GEMINI-2 were similar to the pooled GEMINI-1 and GEMINI-2 virologic results.

[0137] [Table 11]

[0138] At week 48, the adjusted mean change from baseline in CD4+ cell counts based on a pooled analysis was 224 cells / mm3 in patients receiving TIVICAY + EPIVIR 3 , 217 cells / mm in the group receiving TIVICAY + TRUVADA 3 It was.

[0139] 16 Supply form / storage and handling Each combination tablet contains 50 mg of dolutegravir as dolutegravir sodium and 300 mg of lamivudine and is an oval, biconvex, white, film-coated tablet embossed with "SV 137" on one side. Child resistant bottle containing 30 tablets NDC 49702-246-13. Store below 30°C (86°F).

Claims

1. A therapeutically effective amount dolutegravir or a pharma- ceutically acceptable salt thereof, and Lamivudine or a pharma- ceutically acceptable salt thereof 4. A method of treating HIV in a human in need thereof comprising the in vivo administration of a combination of

2. A therapeutically effective amount dolutegravir sodium, and Lamivudine or a pharma- ceutically acceptable salt thereof The method of claim 1, comprising in vivo administration of a combination of

3. The method of claim 1, taking into account adverse reactions of the combination.

4. The method of claim 1, taking into account drug-drug interactions of the combination.

5. The method of claim 1, taking into account the clinical pharmacology of the combination.

6. The method of claim 1, taking into account the toxicity of the combination.

7. 13. The method of claim 1, wherein the combination is co-administered with carbamazepine or rifampin and an additional 50 mg of dolutegravir or a pharma- ceutically acceptable salt thereof is administered 12 hours apart.

8. 13. The method of claim 1, wherein the combination is co-administered with metformin, and the total amount of metformin per day is limited to 1000 mg when either metformin or the combination is initiated.

9. 13. The method of claim 1, wherein the combination is administered 2 hours before or 6 hours after taking the drug containing a multivalent cation.

10. 10. The method of claim 9, wherein the drug containing a multivalent cation contains magnesium or aluminum.

11. 10. The method of claim 9, wherein the multivalent cation-containing drug is a cation-containing antacid or laxative, sucralfate or a buffering drug.

12. 10. The method of claim 1, wherein the drug is administered 2 hours before or 6 hours after taking a nutritional supplement containing calcium or iron.

13. 10. The method of claim 1, wherein the drug is co-administered with food and a nutritional supplement containing calcium or iron.

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