Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Mylan (Pty) Ltd, 4 Brewery Street, Isando, Johannesburg, 1609, Republic of South Africa
Pharmacological Classification: A 20.2.8 Antimicrobial (Chemotherapeutic) Agents. Antiviral Agents
Pharmacotherapeutic group: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors
ATC code: J05AF13
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. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC~50~ values of 2,7 nM and 12,6 nM.
3TC is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.
Lamivudine, a nucleoside reverse transcriptase inhibitor (NRTI), is a selective inhibitor of HIV-1 and HIV-2 replication in vitro.
Lamivudine is metabolised intracellularly to the 5'-triphosphate which has an intracellular half-life of 16-19 hours. Lamivudine 5'-triphosphate is a weak inhibitor of the RNA and DNA dependent activities of HIV reverse transcriptase, its mode of action is a chain terminator of HIV reverse transcription.
Reduced in vitro sensitivity to lamivudine has been reported for HIV isolates from patients who have received lamivudine therapy.
Lamivudine-resistant HIV-1 mutants are cross-resistant to didanosine and zalcitabine. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.
Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondrial DNA content.
TAF is a phosphonoamidate prodrug of tenofovir (2' deoxyadenosine monophosphate analogue). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate.
Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination.
Tenofovir has activity that is specific to hepatitis B virus and human immunodeficiency virus (HIV-1 and HIV-2). Cell culture studies have shown that both tenofovir and FTC can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.
Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC50 values of 0,5 nM (0,21 ng per mL to 2,1 nM (0,85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells.
Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0,52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M clades A, B, C, D, E, F and G, and 3 in group O) with EC50 values ranging from 0,02 nM to 2,14 nM for HIV-1.
Dolutegravir EC50 values against 3 HIV-2 clinical isolates in PBMC assays ranged from 0,09 nM to 0,61 nM.
The antiviral activity of 3TC against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0,003 to 15 microM (1 microM = 0,23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0,003 to 0,120 microM in PBMCs. 3TC was not antagonistic to all tested anti-HIV agents. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3,5-fold in MT-4 cells.
The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophate cells and CD4-T lymphocytes. The EC50 values for TAF ranged from 2,0 to 14,7 nM.
TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F and G (EC50 values ranged from 0,10 to 12,0 nM) and strain specific activity against HIV-2 (EC50 values ranged from 0,91 to 2,63 nM).
In a study of TAF with a broad panel of representatives from the major classes of approved anti-HIV medicines (NRTIs, NNRTIs, INSTIs, and PIs) no antagonism was observed for these combinations.
The antiviral activity of dolutegravir was not antagonistic when combined with the INSTI, raltegravir; nonnucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz or nevirapine; the nucleoside reverse transcriptase inhibitors (NRTIs), abacavir or stavudine; the protease inhibitors (PIs), amprenavir or lopinavir; the CCR5 co-receptor antagonist, maraviroc; or the fusion inhibitor, enfuvirtide. Dolutegravir antiviral activity was not antagonistic when combined with the HBV reverse transcriptase inhibitor, adefovir or inhibited by the antiviral, ribavirin.
Neither dolutegravir nor 3TC were antagonistic to all tested anti-HIV agents. See full prescribing information for dolutegravir and 3TC.
Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Passage of mutant viruses containing the Q148R or Q148H substitutions selected for additional substitutions in integrase that conferred decreased susceptibility to dolutegravir (fold-change increase of 13 to 46). The additional integrase substitutions included T97A, E138K, G140S, and M154I. Passage of mutant viruses containing both G140S and Q148H selected for L74M, E92Q, and N155H.
3TC-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that the resistance was predominantly due to a methionine to valine or isoleucine (M184V/I).
HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT was observed.
HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT was observed.
Viruses highly resistant to dolutegravir have not been observed during HIV-1 passage. During wilde type HIV-1 passage in the presence of dolutegravir integrase substitutions observed were S153Y and S153F with FCs ≤4,1 for strain IIIB, or E92Q with FC = 3,1 and G193E with FC = 3,2 for strain NL432. Additional passage of wildtype subtype B, C and A/G viruses in the presence of dolutegravir selected for R263K, G118R and S153T.
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: Dolutegravir showed anti-HIV activity (susceptibility) with FC < 5 against 27 and 28 integrase inhibitor -resistant mutant viruses with single substitutions including T66A/I/K, E92Q/V, Y143C/H/R, Q148H/K/R, and N155H
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.
Integrase inhibitor naϊve patients: No integrase inhibitor (INI) resistant mutations or treatment emergent resistance to the NRTI backbone therapy were isolated with dolutegravir 50 mg once daily in treatment -naϊve studies.
In a pooled analysis of patients receiving ENVUTEG, sequence analysis was performed on paired baseline and on treatment HBV isolates for patients who either experienced virologic breakthrough (2 consecutive visits with HBV DNA ≥69 IU/mL after having been <69 IU/mL, or 1,0 log 10 or greater increase in HBV DNA from nadir) or patients with HBV DNA ≥69 IU/mL at Week 96 or at early discontinuation at or after Week 24. In analyses at Week 48 (N = 20) and Week 96 (N = 72), no amino acid substitutions associated with resistance to ENVUTEG were identified in these isolates (genotypic and phenotypic analyses).
No subjects in the treatment arm receiving dolutegravir + fixed-dose abacavir sulfate and lamivudine in SINGLE (treatment-naïve trial) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 11 with HIV-1 RNA greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies per mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had a corresponding decrease in dolutegravir susceptibility.
The resistance profile of TAF in combination with other antiretroviral medicines for the treatment of HIV-1 infection is based on studies of FTC + TAF with EVG + COBI in the treatment of HIV-1 infection. In a pooled analysis of antiretroviral-naïve subjects, genotyping was performed on plasma HIV-1 isolates from all subjects with HIV-1 RNA greater than 400 copies per mL at confirmed virologic failure, at Week 48, or at time of early study medicine discontinuation. Genotypic resistance developed in 7 of 14 evaluable subjects. The resistance associated substitutions that emerged were M184V/I (N = 7) and K65R (N = 1). Three subjects had virus with emergent R, H, or E at the polymorphic Q207 residue in reverse transcriptase.
The antiviral activity of tenofovir alafenamide was evaluated against a panel of isolates containing nucleos(t)ide reverse transcriptase inhibitor mutations in HepG2 cells. HBV isolates expressing the rtV173L, rtL180M, and rtM204V/l substitutions associated with resistance to lamivudine remained susceptible to tenofovir alafenamide (<2 fold change in EC50). HBV isolates expressing the rtL180M. rtM204V plus rtT184G, rtS202G, or rtM250V substitutions associated with resistance to entecavir remained susceptible to tenofovir alafenamide. HBV isolates expressing the rtA181T, rtA181V, or rtN236T single substitutions associated with resistance to adefovir remained susceptible to tenofovir alafenamide; however, the HBV isolate expressing rtA181V plus rtN236T exhibited reduced susceptibility to tenofovir alafenamide (3,7 fold change in EC50). The clinical relevance of these substitutions is not known.
Cross-resistance among certain reverse transcriptase inhibitors has been observed. 3TCresistant HIV-1 isolate were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.
Tenofovir resistance substitutions K65R and K70E result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir.
HIV-1 with multiple thymidine analog substitutions (M41L,D67N, K70R, L210W, T215F/Y, K219Q/E/N/R), or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M substitution complex including K65R, showed reduced susceptibility to TAF in cell culture.
The mean systemic exposures of dolutegravir, lamivudine and tenofovir alafenamide from the combination tablets (50 mg/300 mg/25 mg) were comparable to that from TIVICAY tablets of ViiV U.S.A. (containing dolutegravir 50 mg), EPIVIR tablets of ViiV U.S.A. (containing lamivudine 300 mg), and DESCOVY tablets of Gilead Sciences, Inc. U.S.A. (containing emtricitabine and tenofovir alafenamide 200 mg/25 mg), respectively, when single doses were administered to healthy subjects under fasted conditions. The mean systemic exposures of dolutegravir and lamivudine from the combination tablets (50 mg/300 mg/25 mg) were comparable to that from TIVICAY tablets of ViiV U.S. A. (containing dolutegravir 50 mg), and EPIVIR tablets of ViiV U.S.A. (containing lamivudine 300 mg) under fed conditions. Based on cross trial comparison, under fed conditions, the effect of food on the systemic exposure of TAF from the combination tablets is comparable to the effect of food on the systemic exposure of TAF from DESCOVY.
Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours post dose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24h ranging from 1,2 to 1,5. Dolutegravir is a P-glycoprotein substrate in vitro. The absolute bioavailability of dolutegravir has not been established. Dolutegravir is highly bound (greater than or equal to 98,9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17,4 L based on a population pharmacokinetic analysis.
Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [14C] dolutegravir, 53% of the total oral dose is excreted unchanged in the faeces. Thirty-one percent of the total oral dose is excreted in the urine, represented by an ether glucuronide of dolutegravir (18,9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3,0% of total dose), and its hydrolytic N-dealkylation product (3,6% of total dose). Renal elimination of unchanged medicine was less than 1% of the dose. Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CLIF) of 1.0 L per hour based on population pharmacokinetic analyses. The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1-infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects (Table 5).
Table 5. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1- Infected Adults:
| Parameter | 50 mg Once Daily GeometricMean (% CV) |
| AUC(0-24) (mcg•h/mL) | 53,6 (27) |
| Cmax (mcg/mL) | 3,67 (20) |
| Cmin (mcg/mL) | 1,11 (46) |
In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13,2 ng per mL (range: 3,74 ng per mL to 18,3 ng per mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established.
In a meta-analysis of healthy subject trials, 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).
Following oral administration, 3TC is rapidly absorbed and extensively distributed. After multiple dose oral administration of 3TC 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2,04 ± 0,54 meg per mL (mean± SD) and the 24 hour steady state AUC (AUC24,ss) was 8,87 ± 1,83 mcg•hour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of 3TC is recovered as unchanged medicine in the urine. Metabolism of 3TC is a minor route of elimination. In humans, the only known metabolite is the trans sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (ty2) ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was 398,5 ± 69,1 mL per min (mean ± SD).
The pharmacokinetic (PK) properties of the components of TAF are provided in Table 6. The multiple dose PK parameters of TAF and its metabolite tenofovir are provided in Table 7.
Table 6. Pharmacokinetic properties of the components of TAF:
| Tenofovir Alafenamide | |
|---|---|
| Absorption | |
| Tmax (h) | 1 |
| Effect of high fat meal (relative to fasting)a | AUC Ratio= 1,75 (1,64; 1,88) Cmax Ratio=0,85 (0,75; 0,95) |
| Distribution | |
| % Bound to human plasma proteins | 80 |
| Source of protein binding data | Ex vivo |
| Blood-to-plasma ratio | 1.0 |
| Metabolism | |
| Metabolism | Cathepsin Ab (PBMCs) CES1 (hepatocytes) CYP3A (minimal) |
| Elimination | |
| Major route of elimination | Metabolism (>80% of oral dose) |
| t1/2 (h)c | 0,51 |
| % Of dose excreted in urined | <1 |
| %Of dose excreted in faecesd | 31,7 |
PBMCs =peripheral blood mononuclear cells; CES1=carboxylesterase 1
a Values refer to geometric mean ratio [High-fat meal/fasting] in PK parameters and (90% confidence interval). High-calorie/high-fat meal=800 kcal, 50% fat.
b In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected.
c t1/2 values refer to median terminal plasma half-life. Note that the pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150-180 hours within PBMCs.
d Dosing in mass balance studies: TAF (single dose administration of C4C] tenofovir alafenamide).
Table 7. Multiple Dose PK Parameters of Tenofovir Alafenamide and its Metabolite:
Tenofovir Following Oral Administration with Food in HIV-Infected Adults:
| Parameter Mean (CV%) | Tenofovir Alafenamidea | Tenofovirb |
|---|---|---|
| Cmax (microgram per mL) | 0,16 (51,1) | 0,02 (26,1) |
| AUCtau (microgram•hour per mL) | 0,21 (71,8) | 0,29 (27,4) |
| Ctrough (microgram per mL) | NA | 0,01 (28,5) |
CV=Coefficient of Variation; NA=Not Applicable
a From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with FTC+ TAF with EVG + COBI (N=539).
b From Population PK analysis in two trials of treatment-naive adults with HIV-1 infection treated with FTC+ TAF with EVG + COBI (N=841).
The effect of food on dolutegravir, lamivudine and tenofovir alafenamide tablets has not been evaluated. Based on cross trial comparisons, the pharmacokinetics of dolutegravir, lamivudine and tenofovir alafenamide tablets is not anticipated to be significantly affected by food, hence dolutegravir, lamivudine and tenofovir alafenamide tablets can be administered with or without food.
Dolutegravir is primarily metabolized and eliminated by the liver. In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50 mg dose was similar between the 2 groups. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, dolutegravir is not recommended for use in patients with severe hepatic impairment.
The pharmacokinetic properties of 3TC have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function.
Safety and efficacy of 3TC have not been established in the presence of decompensated liver disease.
Clinically relevant changes in tenofovir pharmacokinetics in subjects with hepatic impairment were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment (see section 4.2)
Because dolutegravir, lamivudine and tenofovir alafenamide tablets is a fixed-dose formulation and cannot be dose adjusted, dolutegravir, lamivudine and tenofovir alafenamide tablets is not recommended in patients with creatinine clearance less than 50 mL per min or patients with end-stage renal disease (ESRD) requiring hemodialysis (see section 4.2).
Table 8. Pharmacokinetics of the Components of TAF and a Metabolite (Tenofovir) in HIV Infected Adults with Renal Impairment Compared to Subjects with Normal Renal Function:
| Creatinine | AUCtau (microgram·hour per mL) Mean (CV%) Clearance | ||
|---|---|---|---|
| ≥90mL per minute (N=18)b | 60-89mL per minute (N=11)c | 30-59 mL per minute (N=18) | |
| Tenofovir Alafenamide* | 0,23 (47,2) | 0,24 (45,6) | 0,26 (58,8) |
| Tenofovir | 0,32 (14,9) | 0,46 (31,5) | 0,61 (28,4) |
* AUClast
a Trial in HIV infected adults with renal impairment treated with FTC + TAF with EVG + COBI.
b From a phase 2 trial in HIV-infected adults with normal renal function treated with FTC + TAF with EVG + COBI.
c These subjects had an eGFR ranging from 60 to 69 mL per minute.
There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, lamivudine or tenofovir alafenamide) based on the available information that was analyzed for each of the individual components. *AUClast
There are no significant or clinically relevant racial differences in the pharmacokinetics of dolutegravir, 3TC, or TAF based on the available information that was analyzed for each of the individual components.
Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir.
The pharmacokinetics of 3TC have not been studied in subjects older than 65 years.
Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of TAF with FTC, EVG, and COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age (see section 4.2).
Dolutegravir, lamivudine and tenofovir alafenamide tablets should not be administered to pediatric patients weighing less than 40 kg.
The pharmacokinetics of the combination of dolutegravir and 3TC in pediatric subjects have not been established.
Mean exposures of TAF in 24 pediatric subjects aged 12 to less than 18 years who received TAF with FTC, EVG, and COBI were decreased (23% for AUC) compared to exposures achieved in treatment-naïve adults following administration of this dosage regimen. The TAF exposure differences are not thought to be clinically significant based on exposure response relationships (Table 9).
Table 9. Multiple Dose PK Parameters of Emtricitabine, Tenofovir Alafenamide and its Metabolite Tenofovir Following Oral Administration of FTC + TAF with EVG + COBI in HIV-Infected Paediatric Subjects Aged 12 to less than 18 Yearsa:
| Parameter Mean (CV%) | Emtricitabine | Tenofovir Alafenamide | Tenofovir |
|---|---|---|---|
| Cmax (microgram per mL) | 2,3 (22,5) | 0,17 (64,4) | 0,02 (23,7) |
| AUCtau (microgram•hour per mL) | 14,4 (23,9) | 0,20b (50,0) | 0,29b (18.8) |
| Ctrough (microgram per mL) | 0,10b (38,9) | NA | 0,01 (21,4) |
CV=Coefficient of Variation; NA=Not Applicable
a From Intensive PK analysis in a trial in treatment-naïve paediatric subjects with HIV-1 infection (N=24).
b N=23
The interaction trials described were conducted with dolutegravir, 3TC, and/or TDF as single entities; no medicine interaction trials have been conducted using the fixed-dose dolutegravir, lamivudine and tenofovir alafenamide tablets. No clinically significant medicine interactions are expected between dolutegravir and 3TC.
Dosing or regimens recommendations as a result of established and other potentially significant interactions with dolutegravir are provided in Table 1 (see section 4.5).
The effects of dolutegravir on the exposure of co-administered medicines are summarized in Table 10 and the effects of co-administered medicines on the exposure of dolutegravir are summarized in Table 11.
Table 10. Summary of Effect of Dolutegravir on the Pharmacokinetics of Co-administered Medicines:
| Co-administered Medicine(s) and Dose(s) | Dose of Dolutegravir | n | Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Co-administered Medicine with/without Dolutegravir No Effect=1.00 | ||
|---|---|---|---|---|---|
| Cmax | AUC | Cτ C24 | |||
| Daclatasvir 60 mg once daily | 50 mg once daily | 12 | 1,03 (0,84 to 1,25) | 0,98 (0,83 to 1,15) | 1,06 (0,88 to 1,29) |
| Elbasvir 50 mg once daily | 50 mg single dose | 12 | 0,97 (0,89' 1,05) | 0,98 (0,93, 1,04) | 0,98 (0,93, 1,03) |
| Ethinyl estradiol 0,035 mg | 50 mg twice daily | 15 | 0,99 (0,91 to 1,08) | 1,03 (0,96 to 1,11) | 1,02 (0,93 to 1,11) |
| Grazoprevir 200 mg once daily | 50 mg single dose | 12 | 0,64 (0,44, 0,93) | 0,81 (0,67, 0,97) | 0,86 (0,79; 0,93) |
| Metformin 500 mg twice daily | 50 mg once daily | 15a | 1,66 (1,53 to 1,81) | 1,79 (1,65 to 1,93) | - |
| Metformin 500 mg twice daily | 50 mg twice daily | 15a | 2,11 (1,91 to 2,33) | 2,45 (2,25 to 2,66) | - |
| Methadone 16 to 150 mg | 50 mg twice daily | 11 | 1,00 (0,94 to 1,06) | 0,98 (0,91 to 1,06) | 0,99 (0,91 to 1,07) |
| Midazolam 3 mg | 25 mg once daily | 10 | - | 0,95 (0,79 to 1,15) | - |
| Norelgestromin 0.25 mg | 50 mg twice daily | 15 | 0,89 (0,82 to 0,97) | 0,98 (0,91 to 1,04) | 0,93 (0,85 to 1,03) |
| Rilpivirine 25 mg once daily | 50mg once daily | 16 | 1,10 (0,99 to 1,22) | 1,06 (0,98 to 1,16) | 1,21 (1,07 to 1,38) |
| Sofosbuvir 400 mg once daily Metabolite (GS-331007) | 50 mg once daily | 24 | 0,88 (0,80, 0,98) 1,01 (0, 93, 1,10) | 0,92 (0,85, 0,99) 0,99 (0,97, 1,01) | NA 0,99 (0,97, 1,01) |
| Tenofovir disoproxil fumarate 300 mg once daily | 50 mg once daily | 15 | 1,09 (0,97 to 1,23) | 1,12 (1,01 to 1,24) | 1,19 (1,04 to 1,35) |
| Velpatasvir 100 mg once daily | 50 mg once daily | 24 | 0,94 (0,86; 1,02) | 0,91 (0,84, 0,98) | 0,88 (0,82, 0,94) |
a The number of subjects represents the maximum number of subjects that were evaluated.
Table 11. Summary of Effect of Co-administered Medicines on the Pharmacokinetics of Dolutegravir:
| Co-administered Medicine(s) and Dose(s) | Dose of Dolutegravir | n | Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Medicines No Effect=1.00 | ||
|---|---|---|---|---|---|
| Cmax | AUC | C or C24 | |||
| Atazanavir 400 mg once daily | 30mg once daily | 12 | 1,50 (1,40 to 1,59) | 1,91 (1,80 to 2,03) | 2,80 (2,52 to 3,11) |
| Atazanavir/ritonavir 300 mg/100 mg once daily | 30 mg once daily | 12 | 1,34 (1,25 to 1,42) | 1,62 (1,50 to 1,74) | 2,21 (1,97 to 2,47) |
| Darunavir/ritonavir 600 mg/100 mg twice daily | 30 mg once daily | 15 | 0,89 (0,83 to 0,97) | 0,78 (0,72 to 0,85) | 0,62 (0,56 to 0,69) |
| Efavirenz 600 mg once daily | 50 mg once daily | 12 | 0,61 (0,51 to 0,73) | 0,43 (0,35 to 0,54) | 0,25 (0,18 to 0,34) |
| Elbasvir/grazoprevir 50/200 mg once daily | 50 mg single dose | 12 | 1,22 (1,05; 1,40) | 1,16 (1,00; 1,34) | 1,14 (0,95, 1,36) |
| Etravirine 200 mg twice daily | 50 mg once daily | 16 | 0,48 (0,43 to 0,54) | 0,29 (0,26 to 0,34) | 0,12 (0,09 to 0,16) |
| Etravirine + darunavir/ritonavir 200 mg + 600 mg/100 mg twice daily | 50 mg once daily | 9 | 0,88 (0,78 to 1,00) | 0,75 (0,69 to 0,81) | 0,63 (0,52 to 0,76) |
| Etravirine + lopinavir/ritonavir 200 mg + 400 mg/100 !mg twice daily | 50 mg once daily | 8 | 1,07 (1,02 to 1,13) | 1,11 (1,02 to 1,20) | 1,28 (1,13 to 1,45) |
| Fosamprenavir/ritonavir 700 mg/100 mg twice daily | 50 mg once daily | 12 | 0,76 (0,63 to 0,92) | 0,65 (0,54 to 0,78) | 0,51 (0,41 to 0,63) |
| Lopinavir/ritonavir 400 mg/100 mg twice daily | 30 mg once daily | 15 | 1,00 (0,94 to 1,07) | 0,97 (0,91 to 1,04) | 0,94 (0,85 to 1,05) |
| Rilpivirine 25 mg once daily | 50 mg once daily | 16 | 1,13 (1,06 to 1,21) | 1,12 (1,05 to 1,19) | 1,22 (1,15 to 1,30) |
| Tenofovir 300 mg once daily | 50 mg once daily | 15 | 0,97 (0,87 to 1,08) | 1,01 (0,91 to 1,11) | 0,92 (0,82 to 1,04) |
| Tipranavir/ritonavir 500 mg/200 mg twice daily | 50 mg once daily | 14 | 0,54 (0,50 to 0,57) | 0,41 (0,38 to 0,44) | 0,24 (0,21 to 0,27) |
| Antacid (Maalox) simultaneous administration | 50 mg single dose | 16 | 0,28 (0,23 to 0,33) | 0,26 (0,22 to 0,32) | 0,26 (0,21 to 0,31) |
| Antacid (Maalox) 2h after dolutegravir | 50 mg single dose | 16 | 0,82 (0,69 to 0,98) | 0,74 (0,62 to 0,90) | 0,70 (0,58 to 0,85) |
| Calcium carbonate 1,200 g simultaneous administration (fasted) | 50 mg single dose | 12 | 0,63 (0,50 to 0,81) | 0,61 (0,47 to 0,80) | 0,61 (047 to 0,80) |
| Calcium carbonate 1,200 g simultaneous administration (fed) | 50 mg single dose | 11 | 1,07 (0,83 to 1,38) | 1,09 (0,84 to 1,43) | 1,08 (0,81 to 1,42) |
| Calcium carbonate 1,200 g 2h after dolutegravir | 50 mg single dose | 11 | 1,00 (0,78 to 1,29) | 0,94 (0,72 to 1,23) | 0,90 (0,68 to 1,19) |
| Carbamazepine 300 mg twice daily | 50 mg once daily | 16' | 0,67 (0,61 to 0,73) | 0,51 (0,48 to 0,55) | 0,27 (0,24 to 0,31) |
| Daclatasvir 60 mg once daily | 50mg once daily | 12 | 1,29 (1,07 to 1,57) | 1,33 (1,11 to 1,59) | 1,45 (1,25 to 1,68) |
| Ferrous fumarate 324 mg simultaneous administration (fasted) | 50 mg single dose | 11 | 0,43 (0,35 to 0,52) | 0,46 (0,38 to 0,56) | 0,44 (0,36 to 0,54) |
| Ferrous fumarate 324 mg simultaneous administration (fed) | 50 mg single dose | 11 | 1,03 (0,84 to 1,26) | 0,98 (0,81 to 1,20) | 1,00 (0,81 to 1,23) |
| Ferrous fumarate 324 mg 2h after dolutegravir | 50 mg single dose | 10 | 0,99 (0,81 to 1,21) | 0,95 (0,77 to 1,15) | 092 (0,74 to 1,13) |
| Multivitamin (One-A-Day) simultaneous administration | 50 mg single dose | 16 | 0,65 (0,54 to 0,77) | 0,67 (0,55 to 0,81) | 0,68 (0,56 to 0,82) |
| Omeprazole 40 mg once daily | 50 mg single dose | 12 | 0,92 (0,75 to 1,11) | 0,97 (0,78 to 1,20) | 0,95 (0,75 to 1,21) |
| Prednisone 60 mg once daily with taper | 50 mg once daily | 12 | 1,06 (0,99 to 1,14) | 1,11 (1,03 to 1,20) | 1,17 (1,06 to 1,28) |
| Rifampina 600 mg once daily | 50 mg twice daily | 11 | 0,57 (0,49 to 0,65) | 0,46 (0,38 to 0,55) | 0,28 (0,23 to 0,34) |
| Rifampinb 600 mg once daily | 50 mg twice daily | 11 | 1,18 (1,03 to 1,37) | 1,33 (1,15 to 1,53) | 1,22 (1,01 to 1,48) |
| Rifabutin 300 mg once daily | 50 mg once daily | 9 | 1,16 (0,98 to 1,37) | 0,95 (0,82 to 1,10) | 0,70 (0,57 to 0,87) |
a Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily.
b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.
c The number of subjects represents the maximum number of subjects that were evaluated.
Based on in vitro study results, 3TC at therapeutic medicines exposures is not expected to affect the pharmacokinetics of medicines that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K, organic cation transporter 1 (OCT1), OCT2, or OCT3.
3TC is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase 3TC plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of 3TC is needed. 3TC is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of 3TC. Therefore, coadministration of medicines that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of 3TC.
There was no significant pharmacokinetic interaction between 3TC and interferon alfa in a trial of 19 healthy male subjects.
In vitro data indicate ribavirin reduces phosphorylation of 3TC, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and 3TC (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.
3TC and sorbitol solutions were co-administered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of 3TC oral solution alone or co-administered with a single dose of 3,2 grams, 10.2 grams, or 13,4 grams of sorbitol in solution. Coadministration of 3TC with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24), 14%, 32%, and 36% in the AUC(∞), and 28%, 52%, and 55% in the Cmax of 3TC, respectively.
3TC and TMP/SMX were co-administered to 14 HIV-1-positive subjects in a single-centre, open-label, randomized, crossover trial. Each subject received treatment with a single 300 mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of 3TC 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with 3TC resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in 3TC renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. There is no information regarding the effect on 3TC pharmacokinetics of higher doses of TMP/SMX such as those used in treat PCP.
TAF: The effects of co-administered medicines on the exposure of TAF are shown in Table 12 and the effects of TAF on the exposure of co-administered medicines are shown in Table 13 (these studies were conducted with FTC and/or TAF. For information regarding clinical recommendations, see section 4.5)
Concentrations may be increased by ENVUTEG. Metformin is contraindicated in patients taking ENVUTEG (see section 4.3)
Table 12. Interactions: Changes in TAF Pharmacokinetic Parameters in the Presence of Co-administered Medicine(s)a:
| Co-administered Medicine | Co-administered Medicine(s) Dosage (once daily) (mg) | Tenofovir Alafenamide Dosage (once daily) (mg) | N | Mean Ratio of TAF PK Parameters (90% CI); No effect=1.00 | ||
|---|---|---|---|---|---|---|
| Cmax | AUC | Cmin | ||||
| Atazanavir | 300 (+ 100 ritonavir) | 10 | 10 | 1,77 (1,28, 2,44) | 1,91 (1,55, 2,35) | NC |
| Cobicistat | 150 | 8 | 12 | 2,83 (2,20, 3,65) | 2,65 (2,29, 3,07) | NC |
| Darunavir | 800 (+ 150 cobicistat) | 25b | 11 | 0,93 (0,72, 1,21) | 0,98 (0,80, 1,19) | NC |
| Darunavir | 800 (+ 100 ritonavir) | 10 | 10 | 1,42 (0,96, 2,09) | 1,06 (0,84, 1,35) | NC |
| Dolutegravir | 50 | 10 | 10 | 1,24 (0,88, 1,74) | 1,19 (0,96, 1,48) | NC |
| Efavirenz | 600 | 40b | 11 | 0,78 (0,58, 1,05) | 0,86 (0,72, 1,02) | NC |
| Lopinavir | 800 (+ 200 ritonavir) | 10 | 10 | 2,19 (1,72, 2,79) | 1,47 (1,17, 1,85) | NC |
| Rilpivirine | 25 | 25 | 17 | 1,01 (0,84, 1,22) | 1,01 (0,94, 1,09) | NC |
| Sertraline | 50 (dosed as a single dose) | 10c | 19 | 1,00 (0,86, 1,16) | 0,96 (0,89, 1,03) | NC |
NC=Not Calculated
a All interaction studies conducted in healthy volunteers.
b Study conducted with DESCOVY (FTC/TAF).
c Study conducted with FTC + TAF with EVG + COBI.
Table 13. Interactions: Changes in PK Parameters for Co-administered Medicine in the Presence of FTC and/or TAFa:
| Co-administered Medicine | Co-administered Medicine Dosage (once daily) (mg) | Tenofovir Alafenamide Dosage (once daily) (mg) | N | Mean Ratio of Co-administered Drug PK Parameters (90% CI); No effect=1.00 | ||
|---|---|---|---|---|---|---|
| Cmax | AUC | Cmin | ||||
| Atazanavir | 300 + 100 ritonavir | 10 | 10 | 0,98 (0,89, 1,07) | 0,99 (0,96, 1,01) | 1,00 (0,96, 1,04) |
| Darunavir | 800 + 150 cobicistat | 25b | 11 | 1,02 (0,96, 1,09) | 0,99 (0,92, 1,07) | 0,97 (0,82, 1,15) |
| Darunavir | 800 + 100 ritonavir | 10 | 10 | 0,99 (0,91, 1,08) | 1,01 (0,96, 1,06) | 1,13 (0,95, 1,34) |
| Dolutegravir | 50mg | 10 | 10 | 1,15 (1,04, 1,27) | 1,02 (0,97, 1,08) | 1,05 (0,97, 1,13) |
| Lopinavir | 800 + 200 ritonavir | 10 | 10 | 1,00 (0,95, 1,06) | 1,00 (0,92, 1,09) | 0,98 (0,85, 1,12) |
| Midazolamc | 2.5 (single dose, orally) | 25 | 18 | 1,02 (0,92, 1,13) | 1,13 (1,04, 1,23) | NC |
| 1 (single dose, intravenous) | 0,99 (0,89, 1,11) | 1,08 (1,04, 1,14) | NC | |||
| Rilpivirine | 25 | 25 | 16 | 0,93 (0,87, 0,99) | 1,01 (0,96, 1,06) | 1,13 (1,04, 1,23) |
| Sertraline | 50 (single dose) | 10d | 19 | 1,14 (0,94, 1,38) | 0,93 (0,77, 1,13) | NC |
NC=Not Calculated
a All interaction studies conducted in healthy volunteers.
b Study conducted with DESCOVY (FTC/TAF).
c A sensitive CYP3A4 substrate.
d Study conducted with FTC + TAF with EVG + COBI.
Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of medicine-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14 times higher than those in humans at the recommended dose of 50 mg twice daily. In rats, no increases in the incidence of medicine-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10 times and 15 times higher in males and females, respectively, than those in humans at the recommended dose of 50 mg twice daily.
Long-term carcinogenicity studies with 3TC in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.
Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 167 times (mice) and 55 times (rat) those observed in humans after administration of the daily recommended dose of TAF. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 167 times (TAF) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.
Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.
3TC was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. 3TC was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. 3TC showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2000 mg per kg, producing plasma levels of35 to 45 times those in humans at the recommended dose for HIV-1 infection.
TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
Dolutegravir or 3TC did not affect male or female fertility in rats at doses associated with exposures approximately 44 or 112 times (respectively) higher than the exposures in humans at the doses of 50 mg and 300 mg (respectively).
There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 62 times (25 mg TAF) the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.
Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three- and nine-month administration of TAF; reversibility was seen after a three-month recovery period. No eye toxicity was observed in the dog at systemic exposures of 5 (TAF) and 15 (tenofovir) times the exposure seen in humans with the recommended daily TAF dose.
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