RETROVIR (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Zidovudine is an antiviral agent [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

Absorption and Bioavailability: In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as RETROVIR Tablets or Syrup compared with RETROVIR Capsules. The pharmacokinetic properties of zidovudine in fasting adult patients are summarized in Table 6.

Table 6. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter

Mean ± SD

Oral bioavailability (%)

64 ± 10

Apparent volume of distribution (L/kg)

1.6 ± 0.6

Plasma protein binding (%)

<38

CSF:plasma ratioa

0.6 [0.04 to 2.62]

Systemic clearance (L/hr/kg)

1.6 ± 0.6

Renal clearance (L/hr/kg)

0.34 ± 0.05

Elimination half-life (hr)b

0.5 to 3

a Median [range].
b Approximate range.

Distribution: The apparent volume of distribution of zidovudine, following oral administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, <38% (Table 6).

Metabolism and Elimination: Zidovudine is primarily eliminated 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%, respectively, of the dose following oral administration. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.

Effect of Food on Absorption: RETROVIR may be administered with or without food. The zidovudine AUC was similar when a single dose of zidovudine was administered with food.

Special Populations: Renal Impairment: Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14) following a single 200-mg oral dose (Table 7). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.

Table 7. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal Impairmenta
a Data are expressed as mean ± standard deviation.
Parameter

Control Subjects

(Normal Renal Function)

Patients With Renal Impairment

CrCl (mL/min) 120 ± 8 18 ± 2
Zidovudine AUC (ng•hr/mL) 1,400 ± 200 3,100 ± 300
Zidovudine half-life (hr) 1.0 ± 0.2 1.4 ± 0.1

Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis [see Dosage and Administration (2.4)].

Hepatic Impairment: Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma concentrations would be increased following administration of the recommended adult doses to patients with hepatic impairment [see Dosage and Administration (2.5)].

Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric patients (Table 8).

Patients 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and Administration (2.1)].

Patients <3 Months of Age: Zidovudine pharmacokinetics have been evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for neonates [see Dosage and Administration (2.2)].

Table 8. Zidovudine Pharmacokinetic Parameters in Pediatric Patientsa
Parameter Birth to 14 Days of Age 14 Days to 3 Months of Age 3 Months to 12 Years of Age
Oral bioavailability (%)

89 ± 19

61 ± 19

65 ± 24

CSF:plasma ratio no data no data

0.68 [0.03 to 3.25]b

CL (L/hr/kg)

0.65 ± 0.29

1.14 ± 0.24

1.85 ± 0.47

Elimination half-life (hr)

3.1 ± 1.2

1.9 ± 0.7

1.5 ± 0.7

a Data presented as mean ± standard deviation except where noted.
b Median [range].

Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I study 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 [see Use in Specific Populations (8.1)].

Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum [see Use in Specific Populations (8.3)].

Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients over 65 years of age.

Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no differences in zidovudine AUC when a single dose of zidovudine was administered as the 300-mg RETROVIR Tablet.

Drug Interactions: [See Drug Interactions (7)].

Table 9. Effect of Coadministered Drugs on Zidovudine AUCa
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered Drug and Dose Zidovudine Dose n Zidovudine Concentrations Concentration of Coadministered Drug
AUC Variability

Atovaquone

200 mg q 8 hr 14

↑AUC

Range

b

Clarithromycin

100 mg q 4 hr x 7 days 4 ↓AUC 12%

Range

Not Reported

Fluconazole

200 mg q 8 hr 12

↑AUC

95% CI:

Not Reported

Lamivudine

single 200 mg 12

↑AUC

90% CI:

Methadone

200 mg q 4 hr 9

↑AUC

Range

b

Nelfinavir

single 200 mg 11

↓AUC

Range

Probenecid

2 mg/kg q 8 hr x 3 days 3

↑AUC

Range

b
Not Assessed

Rifampin

200 mg q 8 hr x 14 days 8

↓AUC

90% CI:

Not Assessed

Ritonavir

200 mg q 8 hr x 4 days 9

↓AUC

95% CI:

Valproic acid

100 mg q 8 hr x 4 days 6

↑AUC

Range

b
Not Assessed
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.
a This table is not all inclusive.
b Estimated range of percent difference.

Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic interaction study in which 12 HIV-1-positive volunteers received a single 300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.

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 patients [see Warnings and Precautions (5.4)].

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