CLINICAL PHARMACOLOGY
Pharmacokinetics in Adults
EPZICOM
In a single-dose, 3-way crossover bioavailability study of 1 EPZICOM Tablet versus 2 ZIAGEN Tablets (2 x 300 mg) and 2 EPIVIR Tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component.
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 patients, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hr/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.
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 volunteers, 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•hr/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).
The steady-state pharmacokinetic properties of the EPIVIR 300-mg Tablet once daily for 7 days compared to the EPIVIR 150-mg Tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared to the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared to the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.
In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes.
The pharmacokinetic properties of abacavir and lamivudine in fasting patients are summarized in Table 1.
Table 1. Pharmacokinetic Parameters* for Abacavir and Lamivudine in Adults |
Parameter
|
Abacavir
|
Lamivudine
|
|
Oral bioavailability (%)
|
86 ± 25
|
n = 6
|
86 ± 16
|
n = 12
|
|
Apparent volume of distribution (L/kg)
|
0.86 ± 0.15
|
n = 6
|
1.3 ± 0.4
|
n = 20
|
|
Systemic clearance (L/hr/kg)
|
0.80 ± 0.24
|
n = 6
|
0.33 ± 0.06
|
n = 20
|
|
Renal clearance (L/hr/kg)
|
.007 ±.008
|
n = 6
|
0.22 ± 0.06
|
n = 20
|
|
Elimination half-life (hr)
|
1.45 ± 0.32
|
n = 20
|
5 to 7†
|
*Data presented as mean ± standard deviation except where noted.
†Approximate range.
Effect of Food on Absorption of EPZICOM
EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability study resulted in no change in AUClast, AUC∞, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC∞), but the rate of absorption (Cmax) was decreased approximately 24% compared to fasted conditions (n = 25). These results are similar to those from previous studies of the effect of food on abacavir and lamivudine tablets administered separately.
Special Populations
Impaired Renal Function
EPZICOM
Because lamivudine requires dose adjustment in the presence of renal insufficiency, EPZICOM is not recommended for use in patients with creatinine clearance <50 mL/min (see PRECAUTIONS).
Impaired Hepatic Function
EPZICOM
Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild hepatic impairment. Because EPZICOM is a fixed-dose combination and cannot be dose adjusted, EPZICOM is contraindicated for patients with hepatic impairment.
Pregnancy
See PRECAUTIONS: Pregnancy.
Abacavir and Lamivudine
No data are available on the pharmacokinetics of abacavir or lamivudine during pregnancy.
Nursing Mothers
See PRECAUTIONS: Nursing Mothers.
Abacavir
No data are available on the pharmacokinetics of abacavir in nursing mothers.
Lamivudine
Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.
Pediatric Patients
EPZICOM
The pharmacokinetics of EPZICOM in pediatric patients are under investigation. There are insufficient data at this time to recommend a dose (see PRECAUTIONS: Pediatric Use).
Geriatric Patients
The pharmacokinetics of abacavir and lamivudine have not been studied in patients over 65 years of age.
Gender
Abacavir
A population pharmacokinetic analysis in HIV-infected male (n = 304) and female (n = 67) patients showed no gender differences in abacavir AUC normalized for lean body weight.
Lamivudine
A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in lamivudine AUC∞ normalized for body weight.
Race
Abacavir
There are no significant differences between blacks and Caucasians in abacavir pharmacokinetics.
Lamivudine
There are no significant racial differences in lamivudine pharmacokinetics.
Drug Interactions
See PRECAUTIONS: Drug Interactions. The drug interactions described are based on studies conducted with the individual nucleoside analogues. In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.
Abacavir
Fifteen HIV-infected patients were enrolled in a crossover-designed drug interaction study 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.
In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.
Lamivudine
No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr). Lamivudine pharmacokinetics are not significantly affected by abacavir.
Table 2. Effect of Coadministered Drugs on Abacavir and Lamivudine AUC* Note: ROUTINE DOSE MODIFICATION OF ABACAVIR AND LAMIVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS. |
Drugs That May Alter Abacavir Blood Concentrations
|
|
Coadministered
|
Abacavir
| |
Abacavir
Concentrations
|
Concentration of Coadministered
|
|
Drug and Dose
|
Dose
|
n
|
AUC
|
Variability
|
Drug
|
|
Ethanol
0.7 g/kg
|
Single 600 mg
|
24
|
↑41%
|
90% CI:
35% to 48%
|
↔
|
|
Drugs That May Alter Lamivudine Blood Concentrations
|
|
Coadministered
|
Lamivudine
| |
Lamivudine
Concentrations
|
Concentration of Coadministered
|
|
Drug and Dose
|
Dose
|
n
|
AUC
|
Variability
|
Drug
|
|
Nelfinavir
750 mg q 8 hr x 7 to 10 days
|
Single 150 mg
|
11
|
↑10%
|
95% CI:
1% to 20%
|
↔
|
|
Trimethoprim 160 mg/
Sulfamethoxazole 800 mg daily x 5 days
|
Single 300 mg
|
14
|
↑43%
|
90% CI:
32% to 55%
|
↔
|
↑ = Increase; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.
*See PRECAUTIONS: Drug Interactions for additional information on drug interactions.
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/HCV 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/HCV co-infected patients (see WARNINGS).
ANIMAL TOXICOLOGY
Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.
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