Retrovir (Zidovudine) - Description and Clinical Pharmacology

DESCRIPTION

RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against HIV.

Tablets

RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.

Capsules

RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and titanium dioxide.

Syrup

RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to adjust pH.

The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural formula:

Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C₁₀H₁₃N₅O₄.

MICROBIOLOGY

Mechanism of Action

Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.

Antiviral Activity

The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC₅₀ and EC₉₀ values for zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to 9 μM, respectively. HIV from therapy-naive subjects with no mutations associated with resistance gave median EC₅₀ values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 93 baseline samples from COLA40263) and 0.02 µM (0.01 to 0.03 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC₅₀ values of zidovudine against different HIV-1 clades (A-G) rangedfrom 0.00018 to 0.02 μM, and against HIV-2 isolates from 0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Resistance

Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of mutations. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

Cross-Resistance

In a study of 167 HIV-infected patients, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated mutations with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M mutation being most commonly associated with multi-drug resistance. The mutation at codon 151 in combination with mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Adults

The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 1. Following oral administration, zidovudineis rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. Binding to plasma protein is low. Zidovudine is primarily eliminated 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%, 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.

The extent of absorption (AUC) was equivalent when zidovudine was administered as RETROVIR Tablets or Syrup compared to RETROVIR Capsules.

Table 1. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients

Parameter	Mean ± SD (except where noted)
Oral bioavailability (%)	64 ± 10 (n = 5)
Apparent volume of distribution (L/kg)	1.6 ± 0.6 (n = 8)
Plasma protein binding (%)	<38
CSF:plasma ratio*	0.6 [0.04 to 2.62] (n = 39)
Systemic clearance (L/hr/kg)	1.6 ± 0.6 (n = 6)
Renal clearance (L/hr/kg)	0.34 ± 0.05 (n = 9)
Elimination half-life (hr)†	0.5 to 3 (n = 19)

^*Median [range].

^†Approximate range.

Adults With Impaired Renal Function

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 2). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.

Table 2. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal Impairment*

Parameter	Control Subjects (Normal Renal Function) (n = 6)	Patients With Renal Impairment (n = 14)
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

^*Data are expressed as mean ± standard deviation.

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: Dose Adjustment).

Adults With Impaired Hepatic Function

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: Dose Adjustment).

Pediatrics

Zidovudine pharmacokinetics have been evaluated in HIV-infected pediatric patients (Table 3).

Patients From 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: Pediatrics).

Patients Younger Than 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: Neonatal Dosing.

Table 3. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*

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 (n = 15)	61 ± 19 (n = 17)	65 ± 24 (n = 18)
CSF:plasma ratio	no data	no data	0.68 [0.03 to 3.25]† (n = 38)
CL (L/hr/kg)	0.65 ± 0.29 (n = 18)	1.14 ± 0.24 (n = 16)	1.85 ± 0.47 (n = 20)
Elimination half-life (hr)	3.1 ± 1.2 (n = 21)	1.9 ± 0.7 (n = 18)	1.5 ± 0.7 (n = 21)

^*Data presented as mean ± standard deviation except where noted.

^†Median [range].

Pregnancy

Zidovudine pharmacokinetics have 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. 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. However, in another patient population, a potential for interaction has been identified (see PRECAUTIONS).

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. 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 (see PRECAUTIONS: Nursing Mothers).

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 exposure (AUC) when a single dose of zidovudine was administered as the 300-mg RETROVIR Tablet.

Effect of Food on Absorption

RETROVIR may be administered with or without food. The extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine was administered with food.

Drug Interactions

See Table 4 and PRECAUTIONS: Drug Interactions.

Zidovudine Plus 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 every 12 hours).

Table 4. Effect of Coadministered Drugs on Zidovudine AUC* Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.

Coadministered	Zidovudine		Zidovudine Concentrations		Concentration of Coadministered
Drug and Dose	Dose	n	AUC	Variability	Drug
Atovaquone 750 mg q 12 hr with food	200 mg q 8 hr	14	↑AUC 31%	Range 23% to 78%†	↔
Fluconazole 400 mg daily	200 mg q 8 hr	12	↑AUC 74%	95% CI: 54% to 98%	Not Reported
Methadone 30 to 90 mg daily	200 mg q 4 hr	9	↑AUC 43%	Range 16% to 64%†	↔
Nelfinavir 750 mg q 8 hr x 7 to 10 days	single 200 mg	11	↓AUC 35%	Range 28% to 41%	↔
Probenecid 500 mg q 6 hr x 2 days	2 mg/kg q 8 hr x 3 days	3	↑AUC 106%	Range 100% to 170%†	Not Assessed
Rifampin 600 mg daily x 14 days	200 mg q 8 hr x 14 days	8	↓AUC 47%	90% CI: 41% to 53%	Not Assessed
Ritonavir 300 mg q 6 hr x 4 days	200 mg q 8 hr x 4 days	9	↓AUC 25%	95% CI: 15% to 34%	↔
Valproic acid 250 mg or 500 mg q 8 hr x 4 days	100 mg q 8 hr x 4 days	6	↑AUC 80%	Range 64% to 130%†	Not Assessed

↑ = Increase; ↓ = 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 co-administered as part of a multi-drug regimen to HIV/HCV co-infected patients (see WARNINGS).