"Entry Inhibitors (including Fusion Inhibitors) and CCR5 Co-receptor Antagonist
Entry inhibitors block HIV entry into CD4+ cells.
The only drug in this class "...
Mechanism Of Action
Absorption and Bioavailability
Following IV dosing, dose-independent kinetics was observed over the range of 1 to 5 mg per kg. The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg per kg every 4 hours were 1.1 and 0.1 mcg per mL, respectively.
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 subjects are summarized in Table 7.
Table 7: Zidovudine Pharmacokinetic Parameters in
|Parameter||Mean ± SD (except where noted)|
|Oral bioavailability (%)||64 ± 10 (n = 5)|
|Apparent volume of distribution (L/kg)||1.6 ± 0.6 (n = 8)|
|Cerebrospinal fluid (CSF):plasma ratioa||0.6 [0.04 to 2.62] (n = 39)|
|Systemic clearance (L/h/kg)||1.6 ± 0.6 (n = 6)|
|Renal clearance (L/h/kg)||0.34 ± 0.05 (n = 9)|
|Elimination half-life (h)b||0.5 to 3 (n = 19)|
|aMedian [range] for 50 paired samples drawn 1 to 8 hours
after the last dose in subjects on chronic therapy with RETROVIR.
The apparent volume of distribution of zidovudine, is 1.6 ± 0.6 L per kg (Table 7); and binding to plasma protein is low (less than 38%).
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 and 18% and 60%, respectively, following IV dosing. A second metabolite, 3'-amino-3'-deoxythymidine (AMT), has been identified in the plasma following single-dose 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 per kg every 8 hours to 10 mg per 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 subjects with impaired renal function (n = 14) following a single 200-mg oral dose (Table 8). Plasma concentrations of AMT were not determined. No dose adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min.
Table 8. Zidovudine Pharmacokinetic Parameters in Subjects
with Severe Renal Impairmenta
|Parameter||Control Subjects (Normal Renal Function)
(n = 6)
|Subjects with Renal Impairment
(n = 14)
|CrCl (mL/min)||120 ± 8||18 ± 2|
|Zidovudine AUC (ng•h/mL)||1,400 ± 200||3,100 ± 300|
|Zidovudine half-life (h)||1.0 ± 0.2||1.4 ± 0.1|
|aData are expressed as mean ± standard deviation.|
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating oral 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 subjects 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, zidovudine is eliminated primarily by hepatic metabolism and it appears that zidovudine clearance is decreased and plasma concentrations are increased in subjects with hepatic impairment. There are insufficient data to recommend dose adjustment of RETROVIR in patients with impaired hepatic function or liver cirrhosis [see DOSAGE AND ADMINISTRATION].
Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric subjects (Table 9).
Patients Aged 3 Months to 12 Years: Overall, zidovudine pharmacokinetics in pediatric patients older than 3 months 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 per m² every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult subjects, the major route of elimination was by metabolism to GZDV. After IV 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 subjects 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 less than or equal to 14 days old, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric subjects older than 14 days. For dose recommendations for neonates [see DOSAGE AND ADMINISTRATION].
Table 9: Zidovudine Pharmacokinetic Parameters in
|Parameter||Birth to 14 Days||Aged 14 Days to 3 Months||Aged 3 Months to 12 Years|
|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]b
(n = 38)
|CL (L/h/kg)||0.65 ± 0.29
(n = 18)
|1.14 ± 0.24
(n = 16)
|1.85 ± 0.47
(n = 20)
|Elimination half-life (h)||3.1 ± 1.2
(n = 21)
|1.9 ± 0.7
(n = 18)
|1.5 ± 0.7
(n = 21)
|aData presented as mean ± standard deviation except where
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I 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 [see Use in Specific Populations].
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in subjects over 65 years of age.
Gender: A pharmacokinetic trial 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
|Coadministered Drug and Dose||Zidovudine Oral Dose||n||Zidovudine Concentrations||Concentration of Coadministered Drug|
|Atovaquone 750 mg every 12 h with food||200 mg every 8 h||14||↑AUC 31%||Range: 23% to 78%b||o|
|Clarithromycin 500 mg twice daily||100 mg every 4 h x 7 days||4||↓AUC12%||Range: ↓34% to ↑14%b||Not Reported|
|Fluconazole 400 mg daily||200 mg every 8 h||12||↑AUC74%||95% CI: 54% to 98%||Not Reported|
|Lamivudine 300 mg every 12 h||single 200 mg||12||↑AUC13%||90% CI: 2% to 27%||↔|
|Methadone 30 to 90 mg daily||200 mg every 4 h||9||↑AUC 43%||Range: 16% to 64%b||↔|
|Nelfinavir 750 mg every 8 h x 7 to 10 days||single 200 mg||11||↓AUC 35%||Range: 28% to 41%b||↔|
|Probenecid 500 mg every 6 h x 2 days||2 mg/kg every 8 h x 3 days||3||↑AUC106%||Range: 100% to 170%b||Not Assessed|
|Rifampin 600 mg daily x 14 days||200 mg q 8 h x 14 days||8||↓AUC47%||90% CI: 41% to 53%||Not Assessed|
|Ritonavir 300 mg every 6 h x 4 days||200 mg every 8 h x 4 days||9||↓AUC 25%||95% CI: 15% to 34%||↔|
|Valproic acid 250 mg or 500 mg every 8 h x 4 days||100 mg every 8 h x 4 days||6||↑AUC80%||Range: 64% to 130%b||Not Assessed|
|↑ = Increase; ↓ = Decrease; ↔ = no significant change;
AUC = area under the concentration versus time curve; CI = confidence interval.
aThis table is not all inclusive.
bEstimated 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 trial 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 subjects [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 α and γ 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 μM (1 μM = 0.27 mcg per mL) and 0.1 to 9 μM, respectively. HIV-1 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 = 92 baseline samples from COL40263) and 0.0017 μM (0.006 to 0.0340 μM) 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 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 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 subjects 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 subjects 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 trial of 167 HIV-1-infected subjects, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from subjects treated for at least 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.
Animal Toxicology And/Or Pharmacology
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg per kg per 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 per kg per day and rabbits given 500 mg per kg per 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 per kg per day (very near the oral median lethal dose in rats of 3,683 mg per 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 per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per 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 trial ACTG 320. This trial was a multi-center, randomized, double-blind, placebo-controlled trial that compared RETROVIR 600 mg per day plus EPIVIR 300 mg per day with 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 trials of treatment-naive subjects 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 trials enrolled subjects with advanced disease (BW 002), and asymptomatic or mildly symptomatic disease in subjects with CD4+ cell counts between 200 and 500 cells per mm³ (ACTG 016 and ACTG 019). A survival benefit for monotherapy with RETROVIR was not demonstrated in the latter 2 trials. Subsequent trials showed that the clinical benefit of monotherapy with RETROVIR was time limited.
ACTG 300 was a multi-center, randomized, double-blind trial that provided for comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive pediatric subjects 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 per mm³, and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies per mL. The median duration that subjects remained on trial was approximately 10 months. Results are summarized in Table 11.
Table 11: Number of Subjects (%) 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 per mm³ (median in the treated group: 560 cells per 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 trial 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 trial, 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: 1/20/2015
This monograph has been modified to include the generic and brand name in many instances.
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