"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
Mechanism of Action
Zidovudine is an antiviral agent [see CLINICAL PHARMACOLOGY].
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 7.
Table 7: Zidovudine Pharmacokinetic Parameters in Fasting
|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 ratioa||0.6 [0.04 to 2.62]|
|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)b||0.5 to 3|
|(n = 19)|
|a Median [range].
b Approximate range.
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 7).
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.
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 8). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.
Table 8: Zidovudine Pharmacokinetic Parameters in Patients
With Severe Renal Impairmenta
|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|
|a Data are expressed as mean ± standard deviation.|
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].
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].
Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric patients (Table 9).
Patients Aged 3 Months to 12 Years: 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].
Patients Aged Less Than 3 Months: 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].
Table 9: Zidovudine Pharmacokinetic Parameters in Pediatric
|Parameter||Birth to 14 Days||Aged 14 Days to 3 Months||Aged 3 Months to 12 Years|
|Oral bioavailability (%)||89 ± 19||61 ± 19||65 ± 24|
|(n = 15)||(n = 17)||(n = 18)|
|CSF: plasma ratio||no data||no data||0.68 [0.03 to 3.25]b (n = 38)|
|CL (L/hr/kg)||0.65 ± 0.29||1.14 ± 0.24||1.85 ± 0.47|
|(n = 18)||(n = 16)||(n = 20)|
|Elimination half-life (hr)||3.1 ± 1.2||1.9 ± 0.7||1.5 ± 0.7|
|(n = 21)||(n = 18)||(n = 21)|
|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].
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].
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.
[See DRUG INTERACTIONS].
Table 10: 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|
|Atovaquone 750 mg q 12 hr with food||200 mg q 8 hr||14||↑AUC 31%||Range 23% to 78%b||↔|
|Clarithromycin 500 mg twice daily||100 mg q 4 hr x 7 days||4||↓AUC12%||Range X34% to T14%||Not Reported|
|Fluconazole 400 mg daily||200 mg q 8 hr||12||↑AUC 74%||95% CI: 54% to 98%||Not Reported|
|Lamivudine 300 mg q 12 hr||single 200 mg||12||↑AUC 13%||90% CI: 2% to 27%||↔|
|Methadone 30 to 90 mg daily||200 mg q 4 hr||9||↑AUC 43%||Range 16% to 64%b||↔|
|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%b||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||↑AUCC 80%||Range 64% to 130%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].
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 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases a and y and has been reported to be incorporated into the DNA of cells in culture.
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 然 (1然 = 0.27 mcg/mL) and 0.1 to 9 然, respectively. HIV-1 from therapy-naive subjects with no mutations associated with resistance gave median EC50 values of 0.011然 (range: 0.005 to 0.110然) from Virco (n = 92 baseline samples from COL40263) and 0.0017然 (0.006 to 0.0340然) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02然, and against HIV-2 isolates from 0.00049 to 0.004 然. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.
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 amino acid substitutions. 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 substitutions conferring resistance to zidovudine.
In a study of 167 HIV-1-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 amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M substitution being most commonly associated with multi-drug resistance. The substitution at codon 151 in combination with substitutions 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.
Reproductive and Developmental Toxicology Studies
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV-1 disease and to delay disease progression in asymptomatic HIV-1-infected patients.
RETROVIR in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.
The clinical efficacy of a combination regimen that includes RETROVIR was demonstrated in study ACTG 320. This study was a multi-center, randomized, double-blind, placebo-controlled trial that compared RETROVIR 600 mg/day plus EPIVIR 300 mg/day to RETROVIR plus EPIVIR plus indinavir 800 mg three times daily. The incidence of AIDS-defining events or death was lower in the triple-drug-containing arm compared with the 2-drug- containing arm (6.1% versus 10.9%, respectively).
In controlled studies of treatment-naive patients conducted between 1986 and 1989, monotherapy with RETROVIR, as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease (BW 002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts between 200 and 500 cells/mm³ (ACTG 016 and ACTG 019). A survival benefit for monotherapy with RETROVIR was not demonstrated in the latter 2 studies. Subsequent studies showed that the clinical benefit of monotherapy with RETROVIR was time limited.
ACTG 300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive pediatric patients were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells/mm³, and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration that patients remained on study was approximately 10 months. Results are summarized in Table 11.
Table 11: Number of Patients (%) Reaching a Primary
Clinical Endpoint (Disease Progression or Death)
|Endpoint||EPIVIR plus RETROVIR
(n = 236)
(n = 235)
|HIV disease progression or death (total)||15 (6.4%)||37 (15.7%)|
|Physical growth failure||7 (3.0%)||6 (2.6%)|
|Central nervous system deterioration||4 (1.7%)||12 (5.1%)|
|CDC Clinical Category C||2 (0.8%)||8 (3.4%)|
|Death||2 (0.8%)||11 (4.7%)|
Prevention of Maternal-Fetal HIV-1 Transmission
The utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm³ (median in the treated group: 560 cells/mm³) who had little or no previous exposure to RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of RETROVIR during labor and delivery. Following birth, neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving RETROVIR and the group receiving placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8% in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.
Last reviewed on RxList: 6/21/2012
This monograph has been modified to include the generic and brand name in many instances.
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