Lamivudine - How It Works

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 ].

12.2 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 , Warnings and Precautions ] .

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, C max 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 (t ½ ) was 1.54 ± 0.63 hours.

After intravenous administration, total clearance was 0.80 ± 0.24 L/h/kg (mean ± SD).