12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

TRIUMEQ and TRIUMEQ PD are a fixed-dose combination of the HIV‑1 antiretroviral agents abacavir, dolutegravir, and lamivudine [see Microbiology (12.4)].

12.2 Pharmacodynamics

Effects on Electrocardiogram

A thorough QT trial has been conducted for dolutegravir. Neither the effects of abacavir nor lamivudine as single entities or the combination of abacavir, dolutegravir, and lamivudine on the QT interval have been evaluated.

In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250‑mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.

Effects on Renal Function

The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

12.3 Pharmacokinetics

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.

Table 7. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1–Infected Adults
Parameter	50 mg Once Daily Geometric Mean (%CV)
AUC(0-24) (mcg•h/mL)	53.6 (27)
Cmax (mcg/mL)	3.67 (20)
Cmin (mcg/mL)	1.11 (46)

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.

Table 8. Summary of Pharmacokinetic Parameters in Pediatric HIV-1–Infected Subjects (IMPAACT 2019 Trial)
%CV, coefficient of variation expressed as a percentage.
a The relative dolutegravir bioavailability of TRIUMEQ PD tablets for oral suspension is ~1.7-fold that of TRIUMEQ tablets.
Drug	Weight Band	Dosea of single entities in TRIUMEQ or TRIUMEQ PD	n	Pharmacokinetic Parameter Geometric Mean (%CV)
Drug	Weight Band	Dosea of single entities in TRIUMEQ or TRIUMEQ PD	n	Cmax (mcg/mL)	AUC0-24h (mcg∙h/mL)	C24h (ng/mL)
Abacavir	6 to <10 kg	180 mg once daily TRIUMEQ PD	7	7.30 (20)	17.7 (34)	3 (128)
	10 to <14 kg	240 mg once daily TRIUMEQ PD	7	8.36 (44)	19.8 (51)	5 (127)
	14 to <20 kg	300 mg once daily TRIUMEQ PD	7	6.26 (31)	15.1 (40)	3 (108)
	20 to <25 kg	360 mg once daily TRIUMEQ PD	7	6.65 (28)	17.4 (19)	4 (85)
	25 to <40 kg	600 mg once daily TRIUMEQ	7	9.04 (22)	25.7 (15)	11 (229)
Dolutegravir	6 to <10 kg	15 mg once daily TRIUMEQ PD	7	7.40 (28)	75.9 (34)	910 (68)
	10 to <14 kg	20 mg once daily TRIUMEQ PD	7	8.85 (21)	91.0 (36)	1220 (77)
	14 to <20 kg	25 mg once daily TRIUMEQ PD	7	7.04 (17)	71.4 (23)	790 (44)
	20 to <25 kg	30 mg once daily TRIUMEQ PD	7	7.29 (17)	84.4 (26)	1350 (95)
	25 to <40 kg	50 mg once daily TRIUMEQ	7	6.25 (21)	71.8 (14)	980 (28)
Lamivudine	6 to <10 kg	90 mg once daily TRIUMEQ PD	7	2.29 (40)	10.7 (46)	55 (39)
	10 to <14 kg	120 mg once daily TRIUMEQ PD	7	3.55 (19)	14.2 (24)	46 (48)
	14 to <20 kg	150 mg once daily TRIUMEQ PD	7	2.92 (23)	13.0 (16)	58 (37)
	20 to <25 kg	180 mg once daily TRIUMEQ PD	7	2.99 (32)	14.5 (17)	60 (18)
	25 to <40 kg	300 mg once daily TRIUMEQ	7	4.15 (29)	21.7 (26)	84 (35)

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)].

Table 9. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs
a The number of subjects represents the maximum number of subjects that were evaluated.
Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Cmax	AUC	Cτ or C24
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)
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	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)

Table 10. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir
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.
Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00
Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	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 300/100 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 600/100 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 + 600/100 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 + 400/100 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 400/100 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 500/200 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 h	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 1,200 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 1,200 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 1,200 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)
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)

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.

Table 11. Effect of Coadministered Drugs on Abacavir or Lamivudine
↑ = Increase; ↔ = No significant change. a The drug-drug interaction was only evaluated in males.
Coadministered Drug and Dose	Drug and Dose	n	Concentrations of Abacavir or Lamivudine		Concentration of Coadministered Drug
Coadministered Drug and Dose	Drug and Dose	n	AUC	Variability	Concentration of Coadministered Drug
Ethanol 0.7 g/kg	Abacavir Single 600 mg	24	↑41%	90% CI: 35% to 48%	↔a
Nelfinavir 750 mg every 8 h x 7 to 10 days	Lamivudine Single 150 mg	11	↑10%	95% CI: 1% to 20%	↔
Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days	Lamivudine Single 300 mg	14	↑43%	90% CI: 32% to 55%	↔

12.4 Microbiology

Mechanism of Action

Dolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV‑1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV‑TP), an analogue of deoxyguanosine‑5′‑triphosphate (dGTP). CBV‑TP inhibits the activity of HIV‑1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.

Lamivudine: Lamivudine 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 RT via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity in Cell Culture

Dolutegravir: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV‑1 with mean concentration of drug necessary to affect viral replication by 50% (EC50) values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a median EC50 value of 0.54 nM (range: 0.41 to 0.60 nM) in a viral 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 with median EC50 values of 0.18 nM (n = 3, range: 0.09 to 0.5 nM), 0.08 nM (n = 5, range: 0.05 to 2.14 nM), 0.12 nM (n = 4, range: 0.05 to 0.51 nM), 0.17 nM (n = 3, range: 0.16 to 0.35 nM), 0.24 nM (n = 3, range: 0.09 to 0.32 nM), 0.17 nM (n = 4, range: 0.07 to 0.44 nM), 0.2 nM (n = 3, range: 0.02 to 0.87 nM), and 0.42 nM (n = 3, range: 0.41 to 1.79 nM) for clades A, B, C, D, E, F, and G, and group O viruses, respectively. Dolutegravir EC50 values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.

Abacavir: The antiviral activity of abacavir against HIV‑1 was assessed in a number of cell lines including in primary monocytes/macrophages and PBMCs. EC50 values ranged from 3,700 to 5,800 nM (1 nM = 0.28 ng/mL) and 70 to 1,000 nM against HIV‑1IIIB and HIV‑1BaL, respectively, and the mean EC50 value was 260 ± 180 nM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 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 24 to 490 nM.

Lamivudine: The antiviral activity of lamivudine 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 3 to 15,000 nM (1 nM = 0.23 ng/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) from 3 to 120 nM in PBMCs. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV‑1 activity of lamivudine by 3.5‑fold in MT‑4 cells.

Antiviral Activity in Combination with Other Antiviral Agents

Neither dolutegravir, abacavir, nor lamivudine were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir), TIVICAY (dolutegravir), and EPIVIR (lamivudine).

Resistance in Cell Culture

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.

Abacavir and Lamivudine: HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74V, or Y115F with M184V or I conferred a 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.

Resistance in Clinical Subjects

No subjects in the treatment arm receiving dolutegravir + EPZICOM in SINGLE (treatment- naive trial) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 11 with HIV-1 RNA >400 copies/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/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. No treatment-emergent genotypic resistance to abacavir and lamivudine, components of TRIUMEQ and TRIUMEQ PD, was observed in the arm receiving dolutegravir + EPZICOM in the SINGLE trial through Week 144. One ART-naïve subject receiving TRIUMEQ PD in the pediatric IMPAACT 2019 trial experienced confirmed virologic failure at Week 24 but subsequently suppressed to 76 copies/mL by Week 48 while on continued study treatment. The subject’s entry specimen (HIV-1 subtype AE) had the presence of baseline integrase substitution L74I polymorphism. Genotypic sequencing and phenotypic analyses failed at the confirmed virologic failure timepoint for this subject.

Cross-Resistance

Dolutegravir: Cross-resistance has been observed among INSTIs. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a >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 >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.

Abacavir and Lamivudine: Cross‑resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation (TAM) substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.