Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: XIXIA PHARMACEUTICALS (PTY) LTD, Building 6, Greenstone Hill Office Park, Emerald Boulevard, MODDERFONTEIN, 1645, Republic of South Africa Telephone: 011 451 1300
Pharmacological classification: Category A, 20.2.8 Antiviral agents
MYLATAF tablets are a fixed-dose combination of antiretroviral medicines dolutegravir (DTG), emtricitabine (FTC) and tenofovir alafenamide (TAF).
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 IC50 values of 2,7 nM and 12,6 nM.
FTC, a synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'- triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.
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 chaintermination.
Tenofovir has activity against HIV-1. 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 FTC against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGICCR5 cell line, and primary peripheral blood mononuclear cells. The EC50 values for FTC were in the range of 0,0013 to 0,64 micromolar. FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0,007 to 0,075 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 0,007 to 1,5 micromolar).
In a study of FTC with a broad panel of representatives from the major classes of approved anti-HIV medicines (NRTIs, non-nucleoside reverse transcriptase inhibitors [NNRTIs], integrase strand transfer inhibitors [INSTIs], and PIs) no antagonism was observed for these combinations.
The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage 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.
Dolutegravir: 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.
Dolutegravir: 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 (foldchange 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.
Emtricitabine: HIV-1 isolates with reduced susceptibility to FTC were selected in cell culture and in subjects treated with FTC. Reduced susceptibility to FTC was associated with M184V or I substitutions in HIV-1 RT.
Tenofovir alafenamide: 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.
Emtricitabine and tenofovir alafenamide: The resistance profile of emtricitabine and tenofovir alafenamide 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.
One subject was identified with emergent resistance to FTC or TAF (M184M/I) out of 4 virologic failure subjects in a clinical study of virologically-suppressed subjects who switched from a regimen containing FTC + TDF to FTC + TAF with EVG + COBI (N=799).
The single integrase strand transfer inhibitor-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2,3-fold to 3,6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2,5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8,5-fold and 17-fold decreases in dolutegravir susceptibility, respectively.
FTC-resistant viruses with the M184V or I substitution were cross-resistant to lamivudine, but retained in vitro sensitivity to didanosine, stavudine, tenofovir, zidovudine and NNRTIs (delavirdine, efavirenz, and nevirapine).
Viruses harbouring substitutions conferring reduced susceptibility to stavudine and zidovudine-ethymidine analogue substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N substitution or other substitutions associated with resistance to NNRTIs was susceptible to FTC.
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.
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-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.
Dolutegravir may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.
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 has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1,0 L per hour based on population pharmacokinetic analyses.
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 was excreted unchanged in faeces. Thirty-one percent of the total oral dose was excreted in 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 Ndealkylation product (3,6% of total dose). Renal elimination of unchanged medicine was low (less than 1% of the dose).
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).
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. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV-1-infected subjects was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. Dolutegravir was administered without regard to food in these trials.
The pharmacokinetic (PK) properties of the components of emtricitabine and tenofovir alafenamide are provided in the table below.
| Emtricitabine | Tenofovir alafenamide | |
|---|---|---|
| Absorption | ||
| Tmax (h) | 3 | 1 |
| Effect of high fat meal (relative to fasting)a | AUC Ratio = 0,91 (0,89; 0,93) Cmax Ratio = 0,74 (0,69; 0,78) | AUC Ratio = 1,75 (1,64; 1,88) Cmax Ratio = 0,85 (0,75; 0,95) |
| Distribution | ||
| % Bound to human plasma proteins | <4 | ~80 |
| Source of protein binding data | In vitro | Ex vivo |
| Blood-to-plasma ratio | 0.6 | 1.0 |
| Metabolism | ||
| Metabolism | Not significantly metabolized | Cathepsin Ab (PBMCs) CES1 (hepatocytes) CYP3A (minimal) |
| Elimination | ||
| Major route of elimination | Glomerular filtration and active tubular secretion | Metabolism (>80% of oral dose) |
| t1/2 (h)c | 10 | 0,51 |
| % Of dose excreted in urined | 70 | <1,0 |
| % Of dose excreted in faecesd | 13,7 | 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 to 180 hours within PBMCs.
d Dosing in mass balance studies: FTC (single dose administration of [14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [14C] tenofovir alafenamide).
The multiple dose PK parameters of FTC and TAF and its metabolite tenofovir following oral administration with food in HIV-Infected adults are provided in the table below.
| Parameter Mean (CV %) | Emtricitabinea | Tenofovir Alafenamideb | Tenofovirc |
|---|---|---|---|
| Cmax (microgram per mL) | 2,1 (20,2) | 0,16 (51,1) | 0,02 (26,1) |
| AUCtau (microgram•hour per mL) | 11,7 (16,6) | 0,21 (71,8) | 0,29 (27,4) |
| Ctrough (microgram per mL) | 0,10 (46,7) | NA | 0,01 (28,5) |
CV = Coefficient of Variation; NA = Not Applicable
a From Intensive PK analysis in a phase 2 trial in HIV-infected adults treated with FTC + TAF and EVG + COBI.
b From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with FTC + TAF with EVG + COBI (N=539).
c From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with FTC + TAF with EVG + COBI (N=841).
The pharmacokinetics of dolutegravir, emtricitabine and tenofovir are not affected by food, hence MYLATAF tablets can be administered with or without food.
Dolutegravir: Dolutegravir is primarily metabolised and eliminated by the liver. In a study comparing 8 subjects with moderate hepatic impairment (Child-Pugh Class B) to 8 matched healthy adult controls, the single 50 mg dose exposure of dolutegravir was similar between the 2 groups. No dosage adjustment is necessary for patients with mild hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of dolutegravir has not been studied.
Emtricitabine: The pharmacokinetics of FTC has not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.
Tenofovir alafenamide: 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.
MYLATAF tablets are not recommended for patients with severe renal impairment (estimated creatinine clearance below 30 mL per min) because dolutegravir, emtricitabine and tenofovir alafenamide tablets are a fixeddose combination and the dosage of the individual components cannot be adjusted [see section 4.2].
Emtricitabine and tenofovir alafenamide: The pharmacokinetics of FTC and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.
Dolutegravir: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV coinfection.
Dolutegravir: Population analyses using pooled pharmacokinetic data from adult trials indicated gender or race had no clinically relevant effect on the exposure of dolutegravir.
Emtricitabine and tenofovir alafenamide: Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on gender or race.
Dolutegravir: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir.
Emtricitabine and tenofovir alafenamide: Pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of FTC + TAF and EVG + COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.
MYLATAF tablets should not be administered to paediatric patients weighing less than 40 kg.
Dolutegravir: The pharmacokinetics of dolutegravir in HIV-1-infected children (n=14) weighing at least 40 kg were similar to those observed in HIV-1-infected adults who received dolutegravir 50 mg once daily.
Emtricitabine and tenofovir alafenamide: Exposures of FTC and TAF in 24 paediatric subjects aged 12 to less than 18 years who received FTC + TAF and EVG + COBI were decreased (23% for AUC) compared to exposures achieved in treatment-naïve adults following administration of this dosage regimen. These exposure differences are not thought to be clinically significant based on exposure-response relationships.
The interaction trials described were conducted with dolutegravir, emtricitabine, and/or tenofovir alafenamide as single entities; no interaction trials have been conducted using the fixed-dose combination of dolutegravir, emtricitabine and tenofovir alafenamide.
Dolutegravir: Interaction trials were performed with dolutegravir and other medicines likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of dolutegravir on the exposure of coadministered medicines are summarized in the table below.
| Coadministered medicine(s) and dose(s) | Dose of dolutegravir | n | Geometric Mean Ratio (90% CI) of pharmacokinetic parameters of coadministered medicine with/without dolutegravir No Effect = 1.00 | ||
|---|---|---|---|---|---|
| Cmax | AUC | Cτ or 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) |
| Ethinyl estradiol 0,035 mg | 50 mg once daily | 15 | 0,99 (0,91 to 1,08) | 1,03 (0,96 to 1,11) | 1,02 (0,93 to 1,11) |
| 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 once daily | 15a | 2,11 (1,91 to 2,33) | 2,45 (2,25 to 2,66) | - |
| Methadone 16 to 150 mg | 50 mg once 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 | 50 mg once daily | 10 | - | 0,95 (0,79 to 1,15) | - |
| Norelgestromin 0,25 mg | 50 mg once 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 | 50 mg once daily | 16 | 1,10 (0,99 to 1,22) | 1,06 (0,98 to 1,16) | 1,21 (1,07 to 1,38) |
| 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) |
a The number of subjects represents the maximum number of subjects that were evaluated.
The effects of coadministered medicines on the pharmacokinetics of
dolutegravir are summarized below.
| Coadministered 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 | Cτ or C24 | |||
| Atazanavir 400 mg once daily | 30 mg 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) |
| 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) 2 h 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) |
| Boceprevir 800 mg every 8 hours | 50 mg once daily | 13 | 1,05 (0,96 to 1,15) | 1,07 (0,95 to 1,20) | 1,08 (0,91 to 1,28) |
| Calcium carbonate 1200 mg simultaneous administration (fasted) | 50 mg single dose | 12 | 0,63 (0,50 to 0,81) | 0,61 (0,47 to 0,80) | 0,61 (0,47 to 0,80) |
| Calcium carbonate 1200 mg 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 1200 mg 2 h 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 | 16c | 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 | 50 mg 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 2 h after dolutegravir | 50 mg single dose | 10 | 0,99 (0,81 to 1,21) | 0,95 (0,77 to 1,15) | 0,92 (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.
Emtricitabine and tenofovir alafenamide: The effects of coadministered medicines on the exposure of TAF are shown in the table below.
Interactions: Changes in TAF Pharmacokinetic Parameters in the Presence of Coadministered Medicine(s)a:
| Coadministered medicine | Coadministered 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 |
| 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) 1.03) | NC |
NC = Not Calculated
a All interaction studies conducted in healthy volunteers.
b Study conducted with emtricitabine and tenofovir alafenamide (FTC/TAF).
c Study conducted with FTC + TAF with EVG + COBI
The effects of emtricitabine and tenofovir alafenamide or its components on the exposure of coadministered medicines are shown in the table below [these studies were conducted with fixed-dose emtricitabine and tenofovir alafenamide or the components of fixed-dose emtricitabine and tenofovir alafenamide (FTC or TAF) administered alone]. For information regarding clinical recommendations, see section 4.5.
Interactions: Changes in PK Parameters for Coadministered Medicines in the Presence of Emtricitabine and Tenofovir Alafenamide or the Individual Componentsa:
| Coadministered medicine | Coadministered medicine(s) dosage (once daily) (mg) | Tenofovir alafenamide dosage (once daily) (mg) | N | Mean ratio of coadministered medicine 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 | 50 mg | 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) | ||||
| Rilpivirine | 25 | 25 | 16 | 0,93 (0,87; 0,99) | 1,01 (0,96; 1,06) | 1,13 (1,04; 1,23) |
| Sertraline | 50 (dosed as a 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 emtricitabine and tenofovir alafenamide (FTC/TAF).
c A sensitive CYP3A4 substrate.
d Study conducted with FTC + TAF with EVG + COBI.
Dosing or regimen recommendations as a result of established and other potentially significant interactions with dolutegravir are provided in section 4.5.
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