"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
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.
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 uM = 0.27 mcg/mL) and 0.1 to 9 uM, respectively. HIV 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 = 93 baseline samples from COLA40263) and 0.02 然 (0.01 to 0.03 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 uM, and against HIV-2 isolates from 0.00049 to 0.004 uM. 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.
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.
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.
Adults: The pharmacokinetics of zidovudine have been evaluated in 22 adult HIV-infected patients in a Phase 1 dose-escalation study. Following intravenous (IV) dosing, dose-independent kinetics was observed over the range of 1 to 5 mg/kg. 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 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.
The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg/kg every 4 hours were 1.06 and 0.12 mcg/mL, respectively.
The zidovudine cerebrospinal fluid (CSF)/plasma concentration ratio was determined in 39 patients receiving chronic therapy with RETROVIR. The median ratio measured in 50 paired samples drawn 1 to 8 hours after the last dose of RETROVIR was 0.6.
Table 1. Zidovudine Pharmacokinetic Parameters Following
Intravenous Administration in HIV-Infected Patients
|Parameter|| Mean ± SD
(except where noted)
|Apparent volume of distribution (L/kg)|| 1.6 ± 0.6
(n = 11)
|Plasma protein binding (%)||< 38|
|CSF:plasma ratio*|| 0.6 [0.04 to 2.62]
(n = 39)
|Systemic clearance (L/hr/kg)|| 1.6 (0.8 to 2.7)
|Renal clearance (L/hr/kg)|| 0.34 ± 0.05
(n = 16)
|Elimination half-life (hr)†|| 1.1 (0.5 to 2.9)
(n = 19)
| *Median [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 oral 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 > 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
|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|| 0.26 ± 0.17†
(n = 28)
|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
†CSF ratio determined at steady-state on constant intravenous infusion.
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.
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 oral dose of zidovudine (200 mg) in combination with multiple oral 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 Drug and Dose||Zidovudine Oral Dose||n||Zidovudine Concentrations||Concentrationof Coadministered Drug|
750 mg q 12 hr with food
|200 mg q 8 hr||14||↑AUC 31%||Range 23% to 78%†||↔|
400 mg daily
|200 mg q 8 hr||12||↑AUC 74%||95% CI: 54% to 98%||Not Reported|
30 to 90 mg daily
|200 mg q 4 hr||9||↑AUC 43%||Range 16% to 64%†||↔|
750 mg q 8 hr x 7 to 10 days
|single 200 mg||11||↓AUC 35%||Range 28% to 41%||↔|
500 mg q 6 hr x 2 days
|2 mg/kg q 8 hr x 3 days||3||↑AUC 106%||Range100% to170%†||Not Assessed|
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%t||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 coadministered as part of a multi-drug regimen to HIV/HCV co-infected patients (see WARNINGS).
Description of Clinical Studies
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV disease at the initiation of therapy and to delay disease progression in asymptomatic HIV-infected patients.
RETROVIR in combination with other antiretroviral agents has been shown to be superior to monotherapy in one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA. The complete prescribing information for each drug should be consulted before combination therapy that includes RETROVIR is initiated.
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-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 intravenous 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 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 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: 4/29/2009
This monograph has been modified to include the generic and brand name in many instances.
Additional Retrovir IV Information
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