ABACAVIR, LAMIVUDINE AND ZIDOVUDINE (Page 5 of 7)

12.3 Pharmacokinetics

Pharmacokinetics in Adults

In a single-dose, 3-way crossover bioavailability trial of 1 abacavir, lamivudine and zidovudine 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 abacavir, lamivudine and zidovudine 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. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC(0 to 12 h) was 6.02 ± 1.73 mcg•hour per 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. 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.

Table 3. Pharmacokinetic Parameters * for Abacavir, Lamivudine, and Zidovudine in Adults
Parameter Abacavir Lamivudine Zidovudine
*
Data presented as mean ± standard deviation except where noted.
Approximate range.
Oral bioavailability (%) 86 ± 25 n = 6 86 ± 16 n = 12 64 ± 10 n = 5
Apparent volume of distribution (L/kg) 0.86 ± 0.15 n = 6 1.3 ± 0.4 n = 20 1.6 ± 0.6 n = 8
Systemic clearance (L/h/kg) 0.80 ± 0.24 n = 6 0.33 ± 0.06 n = 20 1.6 ± 0.6 n = 6
Renal clearance (L/h/kg) 0.007 ± 0.008 n = 6 0.22 ± 0.06 n = 20 0.34 ± 0.05 n = 9
Elimination half-life (h) 1.45 ± 0.32 n = 20 5 to 7 0.5 to 3

Effect of Food on Absorption of Abacavir, Lamivudine and Zidovudine Tablets

Administration with food in a single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with a high-fat meal, compared with administration under fasted conditions. Administration of abacavir, lamivudine and zidovudine tablets with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24) [see DOSAGE AND ADMINISTRATION (2.2)].

Specific Populations

Patients with Renal Impairment:

Abacavir, Lamivudine and Zidovudine Tablets

The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).

Patients with Hepatic Impairment:

Abacavir, Lamivudine and Zidovudine Tablets

The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine 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.

Zidovudine

Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those 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.

Geriatric Patients:

The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age.

Male and Female Patients :

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

Racial Groups:

Abacavir and Lamivudine

There are no significant or clinically relevant racial differences in pharmacokinetics of abacavir or lamivudine based on the available information that was analyzed for each of the individual components.

Zidovudine

The pharmacokinetics of zidovudine with respect to race have not been determined.

Drug Interaction Studies:

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

Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents :

Abacavir and lamivudine do not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9, or CYP2D6), therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. 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: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.

Effect of Other Agents on the Pharmacokinetics of Abacavir, Lamivudine, or Zidovudine:

Abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 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.

Glucuronyl Transferase :

Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in a crossover 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.

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 (7.1)]. 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 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 [see WARNINGS AND PRECAUTIONS (5.6)].

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 grams, 10.2 grams, or 13.4 grams 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.

The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.

Table 4. Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUC *

↑= Increase; ↓= Decrease; ↔= No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.

*
See DRUG INTERACTIONS (7) for additional information on drug interactions.
The drug-drug interaction was only evaluated in males.
Estimated range of percent difference.
Coadministered Drug and Dose Drug and Dose n Concentrations of Abacavir , Lamivudine , or Zidovudine Concentration of Coadministered Drug
AUC Variability
Ethanol0.7 g/kg Abacavir single600 mg 24 ↑41% 90% CI:35% to 48%
Nelfinavir750 mg every 8 h x 7 to 10 days Lamivudine single150 mg 11 ↑10% 95% CI:1% to 20%
Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine single300 mg 14 ↑43% 90% CI:32% to 55%
Atovaquone750 mg every 12 h with food Zidovudine200 mg every8 h 14 ↑31% Range: 23% to 78%
Clarithromycin 500 mg twice daily Zidovudine100 mg every4 h x 7 days 4 ↓12% Range:↓34% to ↑14% Not Reported
Fluconazole 400 mg daily Zidovudine200 mg every8 h 12 ↑74% 95% CI:54% to 98% Not Reported
Methadone 30 to 90 mg daily Zidovudine200 mg every4 h 9 ↑43% Range:16% to 64%
Nelfinavir 750 mg every 8 h x 7 to 10 days Zidovudinesingle200 mg 11 ↓35% Range:28% to 41%
Probenecid 500 mg every 6 h x2 days Zidovudine2 mg/kg every8 h x 3 days 3 ↑106% Range:100% to 170% c Not Assessed
Rifampin 600 mg daily x 14 days Zidovudine200 mg every8 h x 14 days 8 ↓47% 90% CI:41% to 53% Not Assessed
Ritonavir 300 mg every 6 h x 4 days Zidovudine200 mg every 8 h x 4 days 9 ↓25% 95% CI:15% to 34%
Valproic acid 250 mg or 500 mg every 8 h x 4 days Zidovudine100 mg every 8 h x4 days 6 ↑80% Range:64% to 130% Not Assesed

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