Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands
Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, combinations
ATC code: J05AR25
Dolutegravir 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.
Lamivudine, via its active metabolite 5'-triphosphates (TP) (an analogue for cytidine), inhibits reverse transcriptase of HIV-1 and HIV-2 through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine triphosphate shows significantly less affinity for host cell DNA polymerases.
Dolutegravir and lamivudine have been shown to inhibit replication of lab-strains and clinical isolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage derived lines and primary cultures of activated peripheral blood mononuclear cells (PMBCs) and monocyte/macrophages. The concentration of active substance necessary to effect viral replication by 50% (IC50-half maximal inhibitory concentration) varied according to virus and host cell type.
The IC50 for dolutegravir in various lab-strains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 value was 0.2 nM (range 0.02-2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61).
The median or mean IC50 values for lamivudine against lab-strains of HIV-1 ranged from 0.007 to 2.3 M. The mean IC50 against lab-strains of HIV-2 (LAV2 and EHO) ranged from 0.16 to 0.51 μM for lamivudine. The IC50 values of lamivudine against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 μM, against Group O from 0.030 to 0.160 M and against HIV-2 isolates from 0.002 to 0.120 M in peripheral blood mononuclear cells.
HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37 untreated patients in Africa and Asia were susceptible to lamivudine (IC50 fold changes <3.0). Group O isolates from antiviral naïve patients tested for lamivudine activity were highly sensitive.
In 100% human serum, the mean fold shift for dolutegravir activity was 75 fold, resulting in protein adjusted IC90 of 0.064 g/mL. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).
Dovato is indicated in the absence of documented or suspected resistance to the integrase inhibitor class and to lamivudine (see section 4.1). For information around in vitro resistance, and cross resistance to other agents of the integrase- and NRTI class, please refer to the SmPCs of dolutegravir and lamivudine.
None of the twelve subjects in the dolutegravir plus lamivudine group or the nine subjects in the dolutegravir plus tenofovir disoproxil/emtricitabine FDC group that met virological withdrawal criteria through Week 144 across the GEMINI-1 (204861) and GEMINI-2 (205543) studies had treatment emergent integrase inhibitor or NRTI class resistance.
In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase inhibitor class, or to the NRTI class was seen (n=1118 follow-up of 48-96 weeks).
No relevant effects were seen with dolutegravir on the QTc interval, with doses exceeding the clinical dose by approximately three fold. A similar study was not conducted with lamivudine.
The efficacy of Dovato is supported by data from 2 identical 148-week, Phase III, randomised, double-blind, multicentre, parallel-group, non-inferiority controlled trials GEMINI-1 (204861) and GEMINI-2 (205543). A total of 1433 HIV-1 infected antiretroviral treatment-naïve adult subjects received treatment in the trials. Subjects were enrolled with a screening plasma HIV-1 RNA of 1000 c/mL to ≤500,000 c/mL. Subjects were randomised to a two-drug regimen of dolutegravir 50 mg plus lamivudine 300 mg once daily or dolutegravir 50 mg plus tenofovir disoproxil/emtricitabine 245/200 mg once daily. 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). Double blind therapy will continue up to week 96, followed by open label therapy up to week 148.
At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% were female, 69% were white, 9% were CDC Stage 3 (AIDS), 20% had HIV-1 RNA >100,000 copies/mL, and 8% had CD4+ cell count less than 200 cells per mm³; these characteristics were similar between studies and treatment arms.
In the primary week 48 analysis, dolutegravir plus lamivudine was non-inferior to dolutegravir plus tenofovir disoproxil/emtricitabine FDC in GEMINI-1 and GEMINI-2 studies. This was supported by the pooled analysis, see Table 3.
Table 3. Virologic Outcomes of Randomised Treatment of GEMINI at Week 48 (Snapshot algorithm):
| GEMINI-1 and GEMINI-2 Pooled Data** | ||
|---|---|---|
| DTG + 3TC N=716 | DTG + TDF/FTC N=717 | |
| HIV-1 RNA <50 copies/mL | 91% | 93% |
| Treatment Difference† (95% confidence intervals) | -1.7 (-4.4, 1.1) | |
| Virologic non response | 3% | 2% |
| Reasons: | ||
| Data in window and ≥50 copies/mL | 1% | <1% |
| Discontinued for lack of efficacy | <1% | <1% |
| Discontinued for other reasons and ≥50 copies/mL | <1% | <1% |
| Change in ART | <1% | <1% |
| No virologic data at Week 48 window | 6% | 5% |
| Reasons: | ||
| Discontinued study due to adverse event or death | 1% | 2% |
| Discontinued study for other reasons | 4% | 3% |
| Missing data during window but on study | <1% | 0% |
| HIV-1 RNA <50 copies/mL by baseline covariates n/N (%) n/N (%) | ||
| Baseline Plasma Viral Load (copies/mL) | ||
| ≤100,000 | 526/576 (91%) | 531/564 (94%) |
| >100,000 | 129/140 (92%) | 138/153 (90%) |
| Baseline CD4+ (cells/mm³) | ||
| ≤200 | 50/63 (79%) | 51/55 (93%) |
| >200 | 605/653 (93%) | 618/662 (93%) |
| HIV-1 subtype | ||
| B | 424/467 (91%) | 452/488 (93%) |
| A | 84/86 (98%) | 74/78 (95%) |
| Other | 147/163 (90%) | 143/151 (95%) |
| Gender | ||
| Male | 555/603 (92%) | 580/619 (94%) |
| Female | 100/113 (88%) | 89/98 (91%) |
| Race | ||
| White | 451/484 (93%) | 473/499 (95%) |
| African-American/African Heritage/Other | 204/232 (88%) | 196/218 (90%) |
* The results of the pooled analysis are in line with those of the individual studies, for which the primary endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at Week 48 based on the Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil/emtricitabine FDC) was met. The adjusted difference was -2.6 (95% CI: -6.7; 1.5) for GEMINI-1 and -0.7 (95% CI: -4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 10%.
† Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1 RNA (≤100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (≤200 cells/mm³ vs. >200 cells/mm³). Pooled analysis also stratified by study. Assessed using a non-inferiority margin of 10%.
N = Number of subjects in each treatment group
At 96 weeks and at 144 weeks in the GEMINI studies, the lower bound of the 95% confidence interval for the adjusted treatment difference of proportion of subjects with HIV-1 RNA <50 copies/mL (Snapshot) was greater than the non-inferiority margin of -10%, for the individual studies as well as pooled analysis, see Table 4.
Table 4. Virologic Outcomes of Randomised Treatment of GEMINI at Weeks 96 and 144 (Snapshot algorithm):
| 32_. | GEMINI-1 and GEMINI-2 Pooled Data* | |||
|---|---|---|---|---|
| DTG + 3TC N=716 | DTG + TDF/FTC N=717 | DTG + 3TC N=716 | DTG + TDF/FTC N=717 | |
| Week 96 | Week 144 | |||
| HIV-1 RNA <50 copies/mL | 86% | 90% | 82% | 84% |
| Treatment Difference† (95% confidence intervals) | -3.4% (-6.7, 0.0) | -1.8% (-5.8; 2.1) | ||
| Virologic non response | 3% | 2% | 3% | 3% |
| Reasons | ||||
| Data in window, ≥50 cps/mL | <1% | <1% | <1% | <1% |
| Discontinued, lack of efficacy | 1% | <1% | 1% | <1% |
| Discontinued, other reasons, ≥50 cps/mL | <1% | <1% | <1% | 2% |
| Change in ART | <1% | <1% | <1% | <1% |
| No virologic data at Week 96/Week 144 window | 11% | 9% | 15% | 14% |
| Reasons | ||||
| Discontinued study due to AE or death | 3% | 3% | 4% | 4% |
| Discontinued study for other reasons | 8% | 5% | 11% | 9% |
| Loss to follow-up | 3% | 1% | 3% | 3% |
| Withdrew consent | 3% | 2% | 4% | 3% |
| Protocol deviations | 1% | 1% | 2% | 1% |
| Physicians decision | 1% | <1% | 2% | 1% |
| Missing data in window, on study | 0% | <1% | <1% | <1% |
* The results of the pooled analysis are in line with those of the individual studies.
† Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1 RNA (≤100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (≤200 cells/mm³ vs. >200 cells/mm³). Pooled analysis also stratified by study. Assessed using a non-inferiority margin of 10%.
N = Number of subjects in each treatment group
The mean increase in CD4+ T-cell counts through week 144 was 302 cells/mm³ in the dolutegravir plus lamivudine arm and 300 cells/mm³ in the dolutegravir plus tenofovir/emtricitabine arm.
The efficacy of dolutegravir/lamivudine in virologically suppressed subjects is supported by data from a randomised, open-label, trial (TANGO 204862). A total of 741 adult HIV-1 infected subjects, without any evidence of resistance to the NRTI or integrase inhibitor (INSTI) class and who were on a stable suppressive tenofovir alafenamide based regimen (TBR) received treatment in the studies. Subjects were randomised in a 1:1 ratio to receive dolutegravir/lamivudine FDC or continue with TBR for up to 200 weeks. Randomisation was stratified by baseline core agent class (protease inhibitor [PI], INSTI, or non-nucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA ≥50 c/mL (virologic non-response) as per the FDA Snapshot category at Week 48 (adjusted for randomisation stratification factor).
At baseline the median age of subjects was 39 years, 8% were female and 21% non-white, 5% were CDC Class C (AIDS) and 98% subjects had Baseline CD4+ cell count ≥200 cells/mm³; these characteristics were similar between treatment arms. Subjects had been on ART for a median of around 3 years prior to Day 1 Around 80% were on INSTI-based TBR (mainly elvitegravir/c) at baseline.
The primary analysis demonstrated that dolutegravir/lamivudine is non-inferior to TBR, with <1% of subjects in both arms experiencing virologic failure (HIV-1 RNA ≥50 c/mL) at Week 48 (Table 5).
Table 5. Virologic Outcomes of Randomised Treatment of TANGO at Week 48 (Snapshot algorithm):
| DTG/3TC N=369 | TBR N=372 | |
|---|---|---|
| HIV-1 RNA <50 copies/mL* | 93% | 93% |
| Virologic non response (≥50 copies/mL)** | <1% | <1% |
| Treatment Difference† (95% confidence intervals) | -0.3 (-1.2, 0.7) | |
| Reasons for virologic non response: | ||
| Data in window and ≥50 copies/mL | 0% | 0% |
| Discontinued for lack of efficacy | 0% | <1% |
| Discontinued for other reasons and ≥50 copies/mL | <1% | 0% |
| Change in ART | 0% | 0% |
| No virologic data at Week 48 window | 7% | 6% |
| Reasons: | ||
| Discontinued study due to adverse event or death | 3% | <1% |
| Discontinued study for other reasons | 3% | 6% |
| Missing data during window but on study | 0% | <1% |
* Based on an 8% non-inferiority margin, DTG/3TC is non-inferior to TBR at Week 48 in the secondary analysis (proportion of subjects achieving <50 copies/mL plasma HIV-1 RNA).
** Based on a 4% non-inferiority margin, DTG/3TC is non-inferior to TBR at Week 48 in the primary analysis (proportion of subjects with plasma HIV-1 RNA ≥50 c/mL).
† Based on CMH-stratified analysis adjusting for Baseline third agent class (PI, NNRTI, INSTI).
N = Number of subjects in each treatment group; TBR = tenofovir alafenamide based regimen.
Treatment outcomes between treatment arms at week 48 were similar across the stratification factor, baseline third agent class and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage, and countries. The median change from baseline in CD4+ count at Week 48 was 22.5 cells per mm³ in subjects who switched to dolutegravir/lamivudine and 11.0 cells per mm³ in subjects who stayed on TBR.
At 96 weeks in the TANGO study, the proportion of subjects with HIV-1 RNA ≥50 c/mL (Snapshot) was 0.3% and 1.1% in the dolutegravir/lamivudine and TBR groups, respectively. Based on a non-inferiority margin of 4%, dolutegravir/lamivudine remained non-inferior to TBR, as the upper bound of the 95% CI for the adjusted treatment difference (-2.0%; 0.4%) was less than 4% for the ITT E Population.
The median change from baseline in CD4+ T-cell counts at week 96 was 61 cells/mm³ in the dolutegravir/lamivudine arm and 45 cells/mm³ in the TBR arm.
At 144 weeks, the proportion of subjects with HIV-1 RNA ≥50 c/mL (Snapshot) was 0.3% and 1.3% in the dolutegravir/lamivudine and TBR groups, respectively. Based on a non-inferiority margin of 4%, dolutegravir/lamivudine remained non-inferior to TBR, as the upper bound of the 95% CI for the adjusted treatment difference (-2.4%, 0.2%) was less than 4% for the ITT E Population.
The median change from baseline in CD4+ T-cell counts at Week 144 was 36 cells/mm³ in the dolutegravir/lamivudine arm and 35 cells/mm³ in the TBR arm.
The efficacy of Dovato, or the dual combination of dolutegravir plus lamivudine (as single entities) has not been studied in children or adolescents.
The European Medicines Agency has deferred the obligation to submit the results of studies with Dovato in one or more subsets of the paediatric population in the treatment of HIV infection.
When administered in fasted state, bioequivalence regarding Cmax was achieved for dolutegravir, when comparing Dovato to dolutegravir 50 mg co-administered with lamivudine 300 mg. Dolutegravir AUC0-t was 16% higher for Dovato than for dolutegravir 50 mg co-administered with lamivudine 300 mg. This increase is not considered clinically relevant.
When administered in fasted state, bioequivalence was achieved for lamivudine AUC, when comparing Dovato to lamivudine 300 mg co-administered with dolutegravir 50 mg. Lamivudine Cmax for Dovato was 32% higher than lamivudine 300 mg co-administered with dolutegravir 50 mg. The higher lamivudine Cmax, is not considered clinically relevant.
Dolutegravir and lamivudine are rapidly absorbed following oral administration. The absolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oral lamivudine in adults is approximately 80-85%. For Dovato, the median time to maximal plasma concentration (tmax) is 2.5 hours for dolutegravir and 1.0 hour for lamivudine, when dosed under fasted conditions.
Exposure to dolutegravir was generally similar between healthy subjects and HIV-1–infected subjects. In HIV-1–infected adult subjects following dolutegravir 50 mg once daily, the steady-state pharmacokinetic parameters (geometric mean [CV]) based on population pharmacokinetic analyses were AUC(0-24) = 53.6 (27) g.h/mL, Cmax = 3.67 (20) g/mL, and Cmin = 1.11 (46) g/mL. Following multipledose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 µg/mL (26) and the mean (CV) AUC(0-24) is 8.87 µg.h/mL (21%).
Administration of a single Dovato tablet with a high fat meal increased dolutegravir AUC(0-∞) and Cmax by 33% and 21%, respectively, and decreased the lamivudine Cmax by 30% compared to fasted conditions. The lamivudine AUC(0-∞) was not affected by a high fat meal. These changes are not clinically significant. Dovato may be administered with or without food.
The apparent volume of distribution of dolutegravir (Vd/F) is 17-20 L. Intravenous studies with lamivudine showed that the mean apparent volume of distribution is 1.3 L/kg.
Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data. Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood and plasma drugrelated radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma is increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding in vitro (<16%-36% to serum albumin).
Dolutegravir and lamivudine are present in cerebrospinal fluid (CSF). In 13 treatment-naïve subjects on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the IC50). The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% 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 active substance is low (<1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (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).
Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by renal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%).
In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, UGT1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OCT1, MATE2-K, multidrug resistance-associated protein (MRP) 2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Based on this data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters (see section 4.5).
In vitro, dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.
In vitro, lamivudine did not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or CYP2D6) and demonstrated no or weak inhibition of OATP1B1, OAT1B3, OCT3, BCRP, P-gp, MATE1 or MATE2-K. Lamivudine is therefore not expected to affect the plasma concentrations of medicinal products that are substrates of these enzymes or transporters.
Lamivudine was not significantly metabolised by CYP enzymes.
Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1 L/hr in HIV-infected patients based on a population pharmacokinetic analysis.
The observed lamivudine half-life of elimination is 18 to 19 hours. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was 16 to 19 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance (>70%) via the organic cationic transport system. Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction is required for patients with creatinine clearance <50 mL/min (see section 4.2).
In a randomized, dose-ranging trial, HIV-1–infected subjects treated with dolutegravir monotherapy (ING111521) demonstrated rapid and dose-dependent antiviral activity, with mean decline in HIV-1 RNA of 2.5 log10 at day 11 for 50 mg dose. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group.
The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to 17 years) showed that dolutegravir 50 mg once daily dosage resulted in dolutegravir exposure comparable to that observed in adults who received dolutegravir 50 mg once daily.
Limited data are available in adolescents receiving a daily dose of 300 mg of lamivudine. Pharmacokinetic parameters are comparable to those reported in adults.
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 and lamivudine in subjects >65 years of age are limited.
Pharmacokinetic data have been obtained for dolutegravir and lamivudine separately.
Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min). No clinically important pharmacokinetic differences between subjects with severe renal impairment (CLcr <30 mL/min) and matching healthy subjects were observed. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.
Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance.
Based on the lamivudine data, Dovato is not recommended for patients with creatinine clearance of <50 mL/min.
Pharmacokinetic data has been obtained for dolutegravir and lamivudine separately.
Dolutegravir is primarily metabolized and eliminated by the liver. A single dose of 50 mg of dolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5 to 2 fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairment compared to healthy controls. No dosage adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.
Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.
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).
Population PK analyses using pooled pharmacokinetic data from clinical studies where dolutegravir or lamivudine was administered to adults in combination with other ARVs revealed no clinically relevant effect of gender on the exposure of dolutegravir or lamivudine. There is no evidence that a dose adjustment of dolutegravir or lamivudine would be required based on the effects of gender on PK parameters.
Population PK analyses using pooled pharmacokinetic data from clinical studies where dolutegravir was administered to adults in combination with other ARVs 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. There is no evidence that a dose adjustment of dolutegravir or lamivudine would be required based on the effects of race on PK parameters.
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited pharmacokinetic data on subjects with hepatitis B co-infection (see section 4.4).
There are no data available on the effects of the combination of dolutegravir and lamivudine in animals.
Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay. Lamivudine was not mutagenic in bacterial tests, but consistent with other nucleoside analogues, inhibits cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma assay. The results from two in vivo rat micronucleus tests with lamivudine were negative. Lamivudine has not shown any genotoxic activity in the in vivo studies.
The carcinogenic potential of a combination of dolutegravir and lamivudine has not been tested. Dolutegravir was not carcinogenic in long term studies in the mouse and rat. In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential.
In reproductive toxicity studies in animals, dolutegravir and lamivudine were shown to cross the placenta.
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 (37.2 times the 50 mg human clinical exposure, based on AUC following single dose in the fasted state). 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 (0.55 times the 50 mg human clinical exposure, based on AUC following single dose in the fasted state). In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.55 times the 50 mg human clinical exposure, based on AUC following single dose in the fasted state).
Lamivudine was not teratogenic in animal studies but there were indications of an increase in early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. A similar effect was not seen in rats even at very high systemic exposure.
Fertility studies in rats have shown that dolutegravir or lamivudine have no effect on male or female fertility.
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 28.5 and 1.1 times the 50 mg human clinical exposure following single dose in the fasted state based on AUC, respectively. Because gastrointestinal (GI) intolerance is considered to be due to local active substance 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.
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