CLINICAL PHARMACOLOGY
Pharmacokinetics in Adults
COMBIVIR
One COMBIVIR Tablet was bioequivalent to 1 EPIVIR Tablet (150 mg) plus 1 RETROVIR Tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).
Lamivudine
The pharmacokinetic properties of lamivudine in fasting patients are summarized in Table 1. 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
The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 1. 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 3′-azido-3′-deoxy-5′- O -β- D -glucopyranuronosylthymidine (GZDV). GZDV area under the curve (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.
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Parameter
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Lamivudine
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Zidovudine
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Oral bioavailability (%)
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86 ± 16
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n = 12
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64 ± 10
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n = 5
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Apparent volume of distribution (L/kg)
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1.3 ± 0.4
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n = 20
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1.6 ± 0.6
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n = 8
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Plasma protein binding (%)
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<36
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<38
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CSF:plasma ratio†
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0.12 [0.04 to 0.47]
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n = 38‡
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0.60 [0.04 to 2.62]
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n = 39§
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Systemic clearance (L/hr/kg)
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0.33 ± 0.06
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n = 20
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1.6 ± 0.6
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n = 6
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Renal clearance (L/hr/kg)
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0.22 ± 0.06
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n = 20
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0.34 ± 0.05
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n = 9
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Elimination half-life (hr)║
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5 to 7
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0.5 to 3
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*Data presented as mean± standard deviation except where noted.
†Median [range].
‡Children.
§Adults.
║Approximate range.
Effect of Food on Absorption of COMBIVIR
COMBIVIR may be administered with or without food. The extent of lamivudine and zidovudine absorption (AUC) following administration of COMBIVIR with food was similar when compared to fasting healthy subjects (n = 24).
Special Populations
Impaired Renal Function
COMBIVIR
Because lamivudine and zidovudine require dose adjustment in the presence of renal insufficiency, COMBIVIR is not recommended for patients with impaired renal function (creatinine clearance <50 mL/min) (see PRECAUTIONS).
Impaired Hepatic Function
COMBIVIR
A reduction in the daily dose of zidovudine may be necessary in patients with mild to moderate impaired hepatic function or liver cirrhosis. Because COMBIVIR is a fixed-dose combination that cannot be adjusted for this patient population, COMBIVIR is not recommended for patients with impaired hepatic function.
Pregnancy
See PRECAUTIONS: Pregnancy.
COMBIVIR
No data are available.
Zidovudine
Zidovudine pharmacokinetics has been studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine was 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 (see CLINICAL PHARMACOLOGY: Drug Interactions).
Nursing Mothers
See PRECAUTIONS: Nursing Mothers.
COMBIVIR
No data are available.
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 HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum.
Pediatric Patients
COMBIVIR
COMBIVIR should not be administered to pediatric patients less than 12 years of age because it is a fixed-dose combination that cannot be adjusted for this patient population.
Geriatric Patients
The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.
Gender
COMBIVIR
A pharmacokinetic study 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
Lamivudine
There are no significant racial differences in lamivudine pharmacokinetics.
Zidovudine
The pharmacokinetics of zidovudine with respect to race have not been determined.
Drug Interactions
See PRECAUTIONS: Drug Interactions.
COMBIVIR
No drug interaction studies have been conducted using COMBIVIR Tablets.
Lamivudine Plus Zidovudine
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).
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Drugs That May Alter Lamivudine Blood Concentrations
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Coadministered Drug and Dose
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Lamivudine Dose
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n
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Lamivudine
Concentrations
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Concentration of Coadministered Drug
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AUC
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Variability
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Nelfinavir
750 mg q 8 hr x 7 to 10 days
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single 150 mg
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11
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↑AUC 10%
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95% CI:
1% to 20%
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↔
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Trimethoprim 160 mg/
Sulfamethoxazole 800 mg daily x 5 days
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single 300 mg
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14
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↑AUC 43%
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90% CI:
32% to 55%
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↔
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Drugs That May Alter Zidovudine Blood Concentrations
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Coadministered Drug and Dose
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Zidovudine Dose
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n
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Zidovudine
Concentrations
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Concentration of Coadministered Drug
|
|
AUC
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Variability
|
|
Atovaquone
750 mg q 12 hr
with food
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200 mg q 8 hr
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14
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↑AUC 31%
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Range
23% to 78%†
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↔
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Fluconazole
400 mg daily
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200 mg q 8 hr
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12
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↑AUC 74%
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95% CI:
54% to 98%
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Not Reported
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Methadone
30 to 90 mg daily
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200 mg q 4 hr
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9
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↑AUC 43%
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Range
16% to 64%†
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↔
|
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Nelfinavir
750 mg q 8 hr x 7 to 10 days
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single 200 mg
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11
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↓AUC 35%
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Range
28% to 41%
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↔
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Probenecid
500 mg q 6 hr x 2 days
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2 mg/kg q 8 hr x 3 days
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3
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↑AUC 106%
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Range
100% to 170%†
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Not Assessed
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Ritonavir
300 mg q 6 hr x 4 days
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200 mg q 8 hr x 4 days
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9
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↓AUC 25%
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95% CI:
15% to 34%
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↔
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Valproic acid
250 mg or 500 mg q 8 hr x 4 days
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100 mg q 8 hr x 4 days
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6
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↑AUC 80%
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Range
64% to 130%†
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Not Assessed
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[Symbol_Wingdings_225] = Increase; [Symbol_Wingdings_226]= Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.
*This table is not all inclusive.
†Estimated range of percent difference.
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).
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