Pharmacology: Pharmacodynamics: Mechanism of Action:
TIVICAY inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. In vitro
, dolutegravir dissociates slowly from the active site of the wild type integrase-DNA complex (t½
: In a randomized, dose-ranging trial, HIV 1–infected subjects treated with TIVICAY monotherapy demonstrated rapid and dose-dependent antiviral activity, with mean declines from baseline to day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group.
Antiviral Activity in Cell Culture: Peripheral blood mononuclear cells (PBMC) infected with HIV-1 strain BaL or HIV-1 strain NL432 gave DTG IC50s of 0.51 nM and 0.53 nM, respectively. MT-4 cells infected with HIV-1 strain IIIB and incubated with dolutegravir for 4 or 5 days resulted in IC50s of 0.71 and 2.1 nM. Two in vitro
strand transfer biochemical assay formats using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50s of 2.7 nM and 12.6 nM.
In a viral integrase susceptibility assay using the integrase coding region from 13 clinically diverse clade B isolates, dolutegravir demonstrated antiviral potency similar to laboratory strains, with a mean IC50 of 0.52 nM. When tested in PBMC assays against a panel consisting of 24 HIV-1 clinical isolates [group M (clade A, B, C, D, E, F and G) and group O] and 3 HIV-2 clinical isolates, the geometric mean IC50 was 0.20 nM and IC50 values ranged from 0.02 to 2.14 nM for HIV-1, while the geometric mean IC50 was 0.18 nM and IC50 values ranged from 0.09 to 0.61 nM for HIV-2 isolates.
Antiviral Activity in Combination with Other Antiviral Agents: No drugs with inherent anti-HIV activity were antagonistic with dolutegravir (in vitro
assessments were conducted in checkerboard format in combination with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir). In addition, antivirals without inherent anti-HIV activity (ribavirin) had no apparent effect on dolutegravir activity.
Effect of Human Serum and Serum Proteins: In vitro
studies suggested a 75-fold shift in IC50 of dolutegravir in the presence of 100% human serum (by method of extrapolation), and the protein adjusted IC90 (PA-IC90) in PBMCs was estimated to be 64 ng/mL. Dolutegravir trough concentration for a single 50 mg dose in integrase inhibitor naïve subjects was 1.20 μg/mL and therefore 19 times higher than the estimated PA-IC90.
Resistance in vitro
: Isolation from wild type HIV-1: Viruses highly resistant to dolutegravir were not observed during the 112 day passage of strain IIIB, with a 4.1-fold maximum fold change (FC) observed for the passaged resistant virus populations with substitutions at the conserved IN positions S153Y and S153F.
Passage of the wild type HIV-1 strain NL432 in the presence of dolutegravir selected for E92Q (passage population virus FC=3.1) and G193E (passage population virus FC=3.2) substitutions on Day 56. Additional passage of wildtype subtype B, C, and A/G viruses in the presence of DTG selected for R263K, G118R, and S153T.
Anti-HIV Activity Against Resistant Strains: Reverse Transcriptase Inhibitor- and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent potency against 2 non-nucleoside (NN)-RTI-resistant, 3 nucleoside (N)-RTI-resistant, and 2 PI-resistant HIV-1 mutant clones (1 triple and 1 sextuple) compared to the wildtype strain.
Integrase Inhibitor-Resistant HIV-1 Strains: Sixty integrase inhibitor-resistant mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions) were produced from wild-type virus NL-432 using site-directed mutagenesis. Dolutegravir showed anti-HIV activity (susceptibility) with FC <5 against 27 of 28 integrase inhibitor-resistant mutant viruses with single substitutions including T66A/I/K, E92Q/V, Y143C/H/R Q148H/K/R, and N155H, while for raltegravir and elvitegravir there were 17/28 and 11/21 tested mutant viruses with FC <5, respectively. In addition, of the 32 integrase inhibitor-resistant mutant viruses with 2 or more substitutions, 23 of 32 showed FC <5 to dolutegravir compared with FC <5 for 4 of 32 for raltegravir and FC <5 for 2 of 25 tested for elvitegravir.
Integrase Inhibitor-Resistant HIV-2 Strains: Site directed mutant HIV-2 viruses were constructed based on subjects infected with HIV-2 and treated with raltegravir who showed virologic failure. Overall the HIV-2 FCs observed were similar to HIV-1 FCs observed for similar pathway mutations. Dolutegravir FC was <5 against 4 HIV-2 viruses (S163D, G140A/Q148R, A153G/N155H/S163G and E92Q/T97A/N155H/S163D); for E92Q/N155H, dolutegravir FC was 8.5, and for G140S/Q148R dolutegravir FC was 17. Dolutegravir, raltegravir and elvitegravir all had had the same activity against site directed mutant HIV-2 with S163D as wildtype, and for the remaining mutant HIV-2 virus raltegravir FC ranges were 6.4 to 420 and elvitegravir FC ranges were 22 to 640.
Clinical Isolates From Raltegravir Treatment Virologic Failure Subjects: Thirty clinical isolate samples with genotypic and phenotypic resistance to raltegravir (median FC >81) were examined for susceptibility to dolutegravir (median FC 1.5) using Monogram Biosciences PhenoSense assay. The median FC to dolutegravir for isolates containing changes at G140S + Q148H was 3.75; G140S + Q148R was 13.3; T97A + Y143R was 1.05 and N155H was 1.37.
Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed for susceptibility to dolutegravir using the Monogram Biosciences PhenoSense assay. Dolutegravir has a <10 FC against 93.9% of the 705 clinical isolates.
Resistance in vivo
: Integrase inhibitor naïve patients: No INI-resistant mutations or treatment emergent resistance to the NRTI backbone therapy were isolated with TIVICAY 50 mg once daily in treatment–naive studies (SPRING-1, SPRING-2 and SINGLE studies). In the SAILING study for treatment experienced (and integrase naïve) patients (n=354 in the dolutegravir arm), treatment emergent integrase resistance was observed at Week 48 in 4 of 17 subjects receiving dolutegravir with virologic failure. Of these four, 2 subjects had a unique R263K integrase substitution, with a maximum FC of 1.93, 1 subject had a polymorphic V151V/I integrase substitution, with maximum FC of 0.92, and 1 subject had pre-existing integrase mutations and is assumed to have been integrase experienced or infected with integrase resistant virus by transmission (see Clinical Studies in the following text).
Resistance in vivo:
integrase inhibitor resistant patients: The VIKING-3 study examined TIVICAY (plus optimized background therapy) in subjects with pre-existing INI resistance. Thirty six subjects (36/183) experienced protocol defined virologic failure through to Week 24. Of these, 31 had paired baseline and PDVF resistance data for analysis and 16/31 (52%) had treatment emergent mutations. Treatment-emergent mutations or mixtures of mutations observed were L74L/M (n=1), E92Q (n=2), T97A (n=8), E138K/A (n=7), G140S (n=2), Y143H (n=1), S147G (n=1), Q148H/K/R (n=4), N155H (n=1) and E157E/Q (n=1). Fourteen of the 16 subjects with virus exhibiting treatment-emergent mutations harboured Q148 pathway virus present at baseline or historically.
Effects on Electrocardiogram: In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single dose oral administrations of placebo, DTG 250 mg suspension (exposures approximately 3-fold of the 50 mg once-daily dose at steady state), and moxifloxacin (400 mg, active control) in random sequence. Dolutegravir did not prolong the QTc interval for 24 hours post dose. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) was 1.99 msec (1-sided 95% upper CI: 4.53 msec).
Effects on Renal Function: The effect of TIVICAY on serum creatinine clearance (CrCl), glomerular filtration rate (GFR) using iohexol as the probe and effective renal plasma flow (ERPF) using para-aminohippurate (PAH) as the probe was evaluated in an open-label, randomized, 3 arm, parallel, placebo-controlled study in 37 healthy subjects, who were administered TIVICAY 50 mg once daily (n=12), 50 mg twice daily (n=13) or placebo once daily (n=12) for 14 days. A modest decrease in CrCl was observed with dolutegravir within the first week of treatment, consistent with that seen in clinical studies. Dolutegravir at both doses had no significant effect on GFR or ERPF. These data support in vitro studies which suggest that the small increases in creatinine observed in clinical studies are due to the nonpathologic inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.
Antiretroviral naïve subjects: The efficacy of dolutegravir in HIV-infected, therapy naive subjects is based on data from two randomized, international, double-blind, active-controlled trials, 96 week data from SPRING-2 (ING113086) and 48 week data from SINGLE (ING114467).
In SPRING, 822 HIV-1 infected, antiretroviral therapy (ART)-naïve adults were randomized and received at least one dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both administered with fixed-dose dual NRTI therapy (either ABC/3TC or TDF/FTC). At baseline, median patient age was 36 years, 14% were female, 15% non-white, and 12% had hepatitis B and/or C co-infection and 2% were CDC Class C, these characteristics were similar between treatment groups.
In SINGLE, 833 subjects were randomized and received at least one dose of either TIVICAY 50 mg once daily with fixed-dose abacavir-lamivudine (TIVICAY + ABC/3TC) or fixed-dose efavirenz-tenofovir-emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% non-white, 7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics were similar between treatment groups.
Week 48 outcomes (including outcomes by key baseline covariates) for SPRING-2 and SINGLE are shown in Table 1. (see Table 1.)
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In the SPRING-2 study through 96 weeks, virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir group (81%) was non-inferior to the raltegravir group (76%). The median change in CD4+ T cell count from baseline were 230 cells/mm3
in the group receiving TIVICAY and the raltegravir group at 48 weeks and 276 cells/mm3
in the group receiving dolutegravir compared to 264 cells/mm3
the raltegravir group at 96 weeks.
In the SINGLE study, virologic suppression (HIV-1 RNA <50 copies/mL) in the TIVICAY + ABC/3TC arm was 88%, which was superior to the EFV/TDF/FTC arm (81%) based on the primary analysis (p=0.003). The adjusted mean change in CD4+ T cell count from baseline were 267 cells/mm3
in the group receiving TIVICAY + ABC/3TC and 208 cells/mm3
for the EFV/TDF/FTC arm in SINGLE at 48 weeks. The adjusted difference and 95% CI was 58.9 (33.4, 84.4), p<0.001 (repeated measure model adjusting for the baseline stratification factors: baseline HIV-1 RNA and baseline CD4+ T cell count, among other factors). This analysis was pre-specified and adjusted for multiplicity. The median time to viral suppression was 28 days in the group receiving TIVICAY + ABC/3TC and 84 days in the EFV/TDF/FTC arm in SINGLE at 48 weeks (p<0.0001). This analysis was pre-specified and adjusted for multiplicity.
In both SPRING-2 and SINGLE studies virologic suppression (HIV-1 RNA <50 copies/mL) treatment differences were comparable across baseline characteristics (gender, race and age).
Through 48 weeks in SINGLE and 96 weeks SPRING-2, no INI-resistant mutations or treatment emergent resistance in background therapy were isolated on the dolutegravir-containing arms. In SPRING-2, four subjects on the raltegravir arm failed with major NRTI mutations and one subject developed raltegravir resistance; in SINGLE, four subjects on the EFV/TDF/FTC arm failed with mutations associated with NNRTI resistance and one developed a major NRTI mutation.
Sustained virological response was demonstrated in the SPRING-1 study (ING112276), in which 88% of patients receiving TIVICAY 50 mg (n=51) once daily) had HIV-1 RNA <50 copies/mL, compared to 72% of patients in the efavirenz group (n=50) at 96 weeks. No INI-resistant mutations or treatment emergent resistance in background therapy were isolated with TIVICAY 50 mg once daily through 96 weeks.
Antiretroviral experienced (and integrase inhibitor naïve) subjects: In the international, multicentre, double-blind SAILING study (ING111762), 719 HIV-1 infected, ART-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator selected background regimen (BR) consisting of up to 2 agents (including at least one fully active agent). At baseline, median patient age was 43 years, 32% were female, 49% non-white, 16% had hepatitis B and/or C co-infection, and 46% were CDC Class C. All subjects had at least two class ART resistance, and 49% of subjects had at least 3-class ART resistance at baseline.
Week 48 outcomes (including outcomes by key baseline covariates) for SAILING are shown in Table 2. (see Table 2.)
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In the SAILING study, virologic suppression (HIV-1 RNA <50 copies/mL) in the TIVICAY arm (71%) was statistically superior to the raltegravir arm (64%), at Week 48 (p=0.030). Virologic suppression (HIV-1 RNA <50 copies/mL) treatment differences were comparable across the baseline characteristics of gender, race, and HIV sub type. The mean changes in CD4+ T cell count from baseline were 113 cells/mm3 at week 24 and 162 cells/mm3
at week 48 in the group receiving TIVICAY and 106 cells/mm3
at week 24 and 153 cells/mm3
at week 48 for the raltegravir group.
Statistically fewer subjects failed therapy with treatment-emergent resistance in the IN gene on TIVICAY (4/354, 1%) than on raltegravir (17/361, 5%) (p=0.003).
Integrase inhibitor resistant subjects: In the Phase IIb, international, multicentre, open-label, single arm sequential cohort VIKING pilot study (ING112961), two sequential cohorts of subjects with multiclass resistance including resistance to HIV integrase inhibitors were enrolled to examine the antiviral activity of TIVICAY 50 mg once daily (n=27) vs. 50 mg twice daily (n=24) after 10 days of functional monotherapy. Responses were greater with twice daily (1.8 log10 change from baseline in HIV RNA) than with once daily dosing (1.5 log10 change from baseline, adjusted difference 0.3log10, p=0.017). Higher response rates with twice daily dosing were maintained with continued TIVICAY dosing and optimization of the background regimen through 48 weeks of therapy (33% vs. 71% <50 c/mL, ITT-E TLOVR analysis). A comparable safety profile was observed across doses. Subsequently, VIKING-3 examined the effect of TIVICAY 50 mg twice daily over 7 days of functional monotherapy, followed by optimized background therapy and continued TIVICAY twice daily treatment.
In the multicentre, open-label, single arm VIKING-3 study (ING112574), HIV-1 infected, ART-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days but with optimised background ART from Day 8. One hundred and eighty-three subjects enrolled, 133 with INI-resistance at Screening and 50 with only historical evidence of resistance (and not at Screening) resistance. At baseline, median patient age was 48 years, 23% were female, 29% non-white, and 20% had hepatitis B and/or C co-infection. Median baseline CD4+ was 140 cells/mm3
, median duration of prior ART was 13 years, and 56% were CDC Class C. Subjects showed multiple class ART resistance at baseline: 79% had ≥2 NRTI, 75% ≥1 NNRTI, and 71% ≥2 PI major mutations; 62% had non-R5 virus.
Mean change from baseline in HIV RNA at day 8 (primary endpoint) was 1.4log10 (95% CI -1.3, -1.5log10, p<0.001). Response was associated with baseline INI mutation pathway, as shown in Table 3. (See Table 3.)
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After the monotherapy phase, subjects had the opportunity to optimize their background regimen when possible.
Of the 183 subjects who completed 24 weeks on study or discontinued before data cut-off, 126 (69%) had <50 copies/mL RNA at Week 24 (Snapshot algorithm). Subjects harbouring virus with Q148 with additional Q148-associated secondary mutations had a lower response at Week 24. Background overall susceptibility score (OSS) was not associated with Week 24 response. (See Table 4.)
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Virologic suppression (HIV-1 RNA <50 copies/mL) was comparable across baseline characteristics (gender, race and age). At Week 24 the median change in CD4+ T cell count from baseline was 61 cells/mm3
for VIKING-3 based on observed data.
In the multicentre, double blind, placebo controlled VIKING-4 study (ING116529), 30 HIV-1 infected, ART-experienced adults with current virological failure on an integrase inhibitor containing regimen and primary genotypic resistance to INIs at Screening, were randomized to receive either dolutegravir 50 mg twice daily or placebo with the current failing regimen for 7 days with all subjects receiving open label dolutegravir plus optimised background regimen from Day 8. The primary endpoint treatment comparison at Day 8, showed that dolutegravir 50 mg twice daily was superior to placebo, with an adjusted mean treatment difference for the change from Baseline in Plasma HIV-1 RNA at Day 8 of -1.2 log10 copies/mL (95% CI -1.5, -0.8 log10 copies/mL, p<0.001).
Children: In a Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of TIVICAY was evaluated in combination regimens in HIV-1 infected infants, children and adolescents.
At 24 weeks, 16 of 23 (70%) children and adolescents (12 to less than 18 years of age) treated with TIVICAY once daily (35 mg n=4, 50 mg n=19) plus OBR achieved viral load less than 50 copies/mL. Twenty out of 23 children and adolescents (87%) had >1 log10 copies/mL decrease from Baseline in HIV-1 RNA or HIV-1 RNA <400 copies/mL at Week 24.
Four subjects had virologic failure none of which had INI resistance at the time of virologic failure.
Dolutegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is between low to moderate. In Phase 1 studies in healthy subjects, between-subject CVb% for AUC and Cmax ranged from ~20 to 40% and CΤ
from 30 to 65% across studies. The between-subject PK variability of DTG was higher in HIV-infected subjects than healthy subjects. Within-subject variability (CVw%) is lower than between-subject variability.
: Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for tablet formulation. The linearity of dolutegravir pharmacokinetics is dependent of dose and formulation. Following oral administration of tablet formulations, in general, TIVICAY exhibited nonlinear pharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; however increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg.
TIVICAY may be administered with or without food. Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC(0-∞)
by 33%, 41%, and 66%, increased Cmax
by 46%, 52%, and 67%, prolonged Tmax
to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. These increases are not clinically significant.
The absolute bioavailability of dolutegravir has not been established.
: Dolutegravir is highly bound (approximately 99.3%) to human plasma proteins based on in vitro
data. The apparent volume of distribution (following oral administration of suspension formulation, Vd/F) is estimated at 12.5 L. Binding of dolutegravir to plasma proteins was independent of concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. Free fraction of DTG in plasma is estimated at approximately 0.2 to 1.1% in healthy subjects, approximately 0.4 to 0.5% in subjects with moderate hepatic impairment, and 0.8 to 1.0% in subjects with severe renal impairment, and 0.5% in HIV-1 infected patients.
Dolutegravir is present in cerebrospinal fluid (CSF). In 12 treatment-naïve subjects receiving a regimen of dolutegravir plus abacavir/lamivudine (3TC) for 16 weeks, dolutegravir concentration in CSF averaged 15.4 ng/mL at Week 2 and 12.6 ng/mL at Week 16, ranging from 3.7 to 23.2 ng/mL (comparable to unbound plasma concentration). CSF:plasma concentration ratio of DTG ranged from 0.11 to 2.04%. Dolutegravir concentrations in CSF exceeded the IC50, supporting the median reduction from baseline in CSF HIV-1 RNA of 2.2 log after 2 weeks of therapy and 3.4 log after 16 weeks (see Pharmacology: Pharmacodynamics in the previous text).
Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue, and vaginal tissue were 6 to 10% of that in corresponding plasma at steady-state. AUC was 7% in semen and 17% in rectal tissue, of those in corresponding plasma at steady-state.
: Dolutegravir is primarily metabolized via UGT1A1 with a minor CYP3A component (9.7% of total dose administered in a human mass balance study). Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged drug is low (<1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the feces. It is unknown if all or part of this is due to unabsorbed drug or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-one percent of the total oral dose is excreted in the urine, represented by ether glucuronide of DTG (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).
: Dolutegravir has a terminal half-life of ~14 hours and an apparent clearance (CL/F) of 0.56 L/hr.
Special Patient Populations
: Children: In a paediatric study including 23 antiretroviral treatment-experienced HIV-1 infected children and adolescents aged 12 to 18 years of age, the pharmacokinetics of dolutegravir was evaluated in 10 children and showed that TIVICAY 50 mg once daily dosage resulted in dolutegravir exposure in paediatric subjects comparable to that observed in adults who received TIVICAY 50 mg once daily (see Table 5).
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Elderly: Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure. Pharmacokinetic data for dolutegravir in subjects of >65 years old are limited.
Renal Impairment: Renal clearance of unchanged drug is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CrCl <30 mL/min). No clinically important pharmacokinetic differences between subjects with severe renal impairment (CrCl <30 mL/min) and matching healthy subjects were observed. No dosage adjustment is necessary for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.
Hepatic Impairment: Dolutegravir is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with moderate hepatic impairment (Child-Pugh category B) to 8 matched healthy adult controls, the single 50 mg dose exposure of dolutegravir was similar between the two groups. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.
Polymorphisms in Drug Metabolising Enzymes: There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n=41). Polymorphisms in CYP3A4, CYP3A5, and NR1I2 were not associated with differences in the pharmacokinetics of dolutegravir.
Gender: The dolutegravir exposure in healthy subjects appear to be slightly higher (~20%) in women than men based on data obtained in a healthy subject study (males n=17, females n=24). Population PK analyses using pooled pharmacokinetic data from Phase 2b and Phase 3 adult trials revealed no clinically relevant effect of gender on the exposure of dolutegravir.
Race: Population PK analyses using pooled pharmacokinetic data from Phase 2b and Phase 3 adult trials revealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese subjects appear similar to observed parameters in Western (US) subjects.
Co-infection with Hepatitis B or C: Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited data on subjects with hepatitis B co-infection.
Toxicology: Pre-Clinical Safety Data:
Carcinogenesis/Mutagenesis: Dolutegravir was not mutagenic or clastogenic using in vitro
tests in bacteria and cultured mammalian cells, and an in vivo
rodent micronucleus assay. Dolutegravir was not carcinogenic in long term studies in the mouse and rat.
Reproductive Toxicology: Fertility: Dolutegravir did not affect male or female fertility in rats at doses up to 1000 mg/kg/day, the highest dose treated (33 times the 50 mg human clinical exposure based on AUC)
Pregnancy: Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (37.9 times the 50 mg human clinical exposure based on AUC).
Oral administration of dolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity (0.56 times the 50 mg human clinical exposure based on AUC). In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.56 times the 50 mg human clinical exposure based on AUC).
Animal Toxicology and/or Pharmacology: The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oral dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primary effect of dolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemic exposures approximately 32 and 1.2 times the 50 mg human clinical exposure based on AUC, respectively. Because gastrointestinal (GI) intolerance is considered to be due to local drug administration, mg/kg or mg/m2
metrics are appropriate determinates of safety cover for this toxicity. GI intolerance in monkeys occurred at 30 times the human mg/kg equivalent dose (based on 50 kg human), and 11 times the human mg/m2
equivalent dose for a total daily clinical dose of 50 mg.