Abacavir lamivudine zidovudine clinical pharmacology

# Clinical Pharmacology

## Pharmacokinetics
Pharmacokinetics in Adults:TRIZIVIR:  In a single-dose, 3-way crossover bioavailability trial of 1 TRIZIVIR Tablet versus 1 ZIAGEN Tablet (300 mg), 1 EPIVIR Tablet (150 mg), plus 1 RETROVIR Tablet (300 mg) administered simultaneously in healthy subjects (n = 24), 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 all 3 components. One TRIZIVIR Tablet was bioequivalent to 1 ZIAGEN Tablet (300 mg), 1 EPIVIR Tablet (150 mg), plus 1 RETROVIR Tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).
Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. Binding of abacavir to human plasma proteins is approximately 50%. Binding of abacavir to plasma proteins 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. 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).
Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3-amino-3-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.
In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes.
The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.
Effect of Food on Absorption of TRIZIVIR: Administration with food in a single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average  decrease in abacavir, lamivudine, and zidovudine Cmax was 32% , 18% , and 28% , respectively, when administered with a high-fat meal, compared with administration under fasted conditions. Administration of TRIZIVIR with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24) .

### Special Populations
Renal Impairment: TRIZIVIR: Because lamivudine and zidovudine require dose adjustment in the presence of renal insufficiency, TRIZIVIR is not recommended for use in patients with creatinine clearance <50 mL/min .
Hepatic Impairment: TRIZIVIR: TRIZIVIR is contraindicated for patients with impaired hepatic function because TRIZIVIR is a fixed-dose combination and the dosage of the individual components cannot be adjusted. Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild hepatic impairment.
Pregnancy: See Use in Specific Populations (8.1).
Abacavir and Lamivudine: No data are available on the pharmacokinetics of abacavir or lamivudine during pregnancy.
Zidovudine: Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. In a nonpregnant adult population, a potential for interaction has been identified .
Nursing Mothers: See Use in Specific Populations (8.3).
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.
Zidovudine: After administration of a single dose of 200 mg zidovudine to 13 HIV1-infected women, the mean concentration of zidovudine was similar in human milk and serum .
Pediatric Patients: TRIZIVIR is not intended for use in pediatric patients. TRIZIVIR is not recommended in adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose adjusted for this patient population.
Geriatric Patients: The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age.

### Gender
Abacavir: A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.
Lamivudine and Zidovudine: A pharmacokinetic trial in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in zidovudine exposure (AUC) or 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.
Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.