Pharmacokinetics in Adults

One TRIUMEQ tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n = 62).

TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension are bioequivalent for the abacavir and lamivudine components, but not for the dolutegravir component. The relative dolutegravir bioavailability of TRIUMEQ PD is approximately 1.7-fold higher than TRIUMEQ; therefore, the 2 dosage forms are not substitutable on a milligram-per-milligram basis [see Dosage and Administration (2.3), Warnings and Precautions (5.7)]. The relative dolutegravir bioavailability is expected to be similar between TRIUMEQ PD and TIVICAY PD.

Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour/mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug‑related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′‑carboxylic acid and glucuronyl transferase to form the 5′‑glucuronide. In single-dose trials, the observed elimination half-life (t½) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L/h/kg (mean ± SD).

Dolutegravir: Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h 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 is highly bound (≥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 feces. 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 drug was <1% of the dose. Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L/h 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.

Cerebrospinal Fluid (CSF): In 11 treatment-naive subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 18 ng/mL (range: 4 ng/mL to 23.2 ng/mL) 2 to 6 hours postdose after 2 weeks of treatment. The clinical relevance of this finding has not been established. 

Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple‑dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg/mL (mean ± SD) and the 24‑hour steady‑state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour/mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine 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 with plasma sampling up to 48 or 72 hours after dosing, the observed mean elimination half-life (t½) ranged from 13 to 19 hours. In HIV-1–infected subjects, total clearance was 398.5 ± 69.1 mL/min (mean ± SD).

Effect of Food on Oral Absorption

TRIUMEQ or TRIUMEQ PD may be taken with or without food. Overall, when compared with fasted conditions, administration of TRIUMEQ to healthy adult subjects with a high-fat meal (53% fat, 869 calories) resulted in decreased Cmax for abacavir and increased Cmax and AUC for dolutegravir. Lamivudine exposures were not affected by food. With a high-fat meal, the Cmax of abacavir decreased 23% and the Cmax and AUC of dolutegravir increased 37% and 48%, respectively. When compared with fasted conditions, administration of TRIUMEQ PD to healthy adult subjects with a high-fat meal (50% fat, 917 calories) resulted in decreased Cmax for abacavir (55%), dolutegravir (29%) and lamivudine (36%). AUCs for all 3 components were not affected by food.

Specific Populations

Patients with Renal Impairment: The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD have been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).

Patients with Hepatic Impairment: The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).

Pregnant women: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.

Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Pediatric Patients: The pharmacokinetics of TRIUMEQ, TRIUMEQ PD (abacavir, dolutegravir, and lamivudine) and their individual components have been evaluated in pediatric subjects.

Abacavir, Dolutegravir and Lamivudine: The pharmacokinetics of TRIUMEQ and TRIUMEQ PD were evaluated in the IMPAACT 2019 trial. Steady-state plasma exposure at doses by weight band are summarized in Table 8 [see Use in Specific Populations (8.4), Clinical Studies (14.2)].

Overall, exposures of abacavir, dolutegravir and lamivudine at the recommended doses for TRIUMEQ PD and TRIUMEQ are within the observed exposure ranges at the recommended doses of individual products in adults and pediatrics. Refer to the prescribing information for EPIVIR, TIVICAY, and ZIAGEN for pharmacokinetic information on lamivudine, dolutegravir, and abacavir, respectively, in pediatric patients.

Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. The pharmacokinetics of abacavir or lamivudine have not been studied in subjects older than 65 years.

Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.

Racial Groups: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.

Drug Interaction Studies

The drug interaction trials described were conducted with dolutegravir, abacavir, and/or lamivudine as single entities; no drug interaction trials have been conducted using the combination of abacavir, dolutegravir, and lamivudine. No clinically significant drug interactions are expected between dolutegravir, abacavir, and lamivudine.

Dosing recommendations as a result of established and other potentially significant drug-drug interactions with the individual components of TRIUMEQ and TRIUMEQ PD are provided in Section 7.3 [see Drug Interactions (7)].

Abacavir or Lamivudine: The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities.

Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents: In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: OATP1B1/3, BCRP or P-gp, OCT1, OCT2, OCT3 (lamivudine only), or MATE1 and MATE2‑K.

Abacavir, Dolutegravir, and Lamivudine: Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving TRIUMEQ is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see Drug Interactions (7.3)].

Effect of Other Agents on the Pharmacokinetics of Abacavir or Lamivudine: In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.

Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.

Lamivudine 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 lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.

Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.

Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.

Methadone: In a trial of 11 HIV‑1–infected subjects receiving methadone‑maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions (7.3)]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, 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 [hepatitis C virus] virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi‑drug regimen to HIV‑1/HCV co‑infected subjects.

Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 g, 10.2 g, or 13.4 g of sorbitol in solution. Coadministration of lamivudine 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 lamivudine, respectively.

Abacavir, Lamivudine, Zidovudine: Fifteen HIV‑1–infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.

Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV‑1–infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).

The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 11.