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Retrovir I.V. (Zidovudine Intravenous) - Description and Clinical Pharmacology



RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against human immunodeficiency virus (HIV). RETROVIR IV Infusion is a sterile solution for intravenous infusion only. Each mL contains 10 mg zidovudine in Water for Injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH to approximately 5.5. RETROVIR IV Infusion contains no preservatives.

The chemical name of zidovudine is 3'-azido-3'-deoxythymidine.

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.


Mechanism of Action: Zidovudine is a synthetic nucleoside analogue of the naturally occurring nucleoside, thymidine, in which the 3'-hydroxy (-OH) group is replaced by an azido (-N3) group.

Within cells, zidovudine is converted to the active metabolite, zidovudine 5'-triphosphate (AztTP), by the sequential action of the cellular enzymes. Zidovudine 5'-triphosphate inhibits the activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine 5'-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The active metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and mitochondrial polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture.

In Vitro HIV Susceptibility: The in vitro anti-HIV activity of zidovudine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and clinical isolates of HIV. The IC50 and IC90 values (50% and 90% inhibitory concentrations) were 0.003 to 0.013 and 0.03 to 0.13 mcg/mL, respectively (1 nM = 0.27 ng/mL). The IC50 and IC90 values of HIV isolates recovered from 18 untreated AIDS/ARC patients were in the range of 0.003 to 0.013 mcg/mL and 0.03 to 0.3 mcg/mL, respectively. Zidovudine showed antiviral activity in all acutely infected cell lines; however, activity was substantially less in chronically infected cell lines. In drug combination studies with zalcitabine, didanosine, lamivudine, saquinavir, indinavir, ritonavir, nevirapine, delavirdine, or interferon-alpha, zidovudine showed additive to synergistic activity in cell culture. The relationship between the in vitro susceptibility of HIV to reverse transcriptase inhibitors and the inhibition of HIV replication in humans has not been established.

Drug Resistance: HIV isolates with reduced sensitivity to zidovudine have been selected in vitro and were also recovered from patients treated with RETROVIR. Genetic analysis of the isolates showed mutations that result in 5 amino acid substitutions (Met41->Leu, A67->Asn, Lys70->Arg, Thr215->Tyr or Phe, and Lys219->Gln) in the viral reverse transcriptase. In general, higher levels of resistance were associated with greater number of mutations, with 215 mutation being the most significant.

Cross-Resistance: The potential for cross-resistance between HIV reverse transcriptase inhibitors and protease inhibitors is low because of the different enzyme targets involved. Combination therapy with zidovudine plus zalcitabine or didanosine does not appear to prevent the emergence of zidovudine-resistant isolates. Combination therapy with RETROVIR plus EPIVIR® delayed the emergence of mutations conferring resistance to zidovudine. In some patients harboring zidovudine-resistant virus, combination therapy with RETROVIR plus EPIVIR restored phenotypic sensitivity to zidovudine by 12 weeks of treatment. HIV isolates with multidrug resistance to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number of patients treated for >/=1 year with the combination of zidovudine and didanosine or zalcitabine. The pattern of resistant mutations in the combination therapy was different (Ala62->Val, Val75->Ile, Phe77->116Tyr, and Gln->151Met) from monotherapy, with mutation 151 being most significant for multidrug resistance. Site-directed mutagenesis studies showed that these mutations could also result in resistance to zalcitabine, lamivudine, and stavudine.


Pharmacokinetics: 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 -(beta)- 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)
(n = 18)
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].
***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
(n = 14)
CrCl (mL/min) 120 8 18 2
Zidovudine AUC (nghr/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. 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 0.26 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 where noted.
***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 that 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.

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 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 *
Drug and Dose
n Zidovudine
AUC Variability
750 mg q 12 hr with food
200 mg q 8 hr 14 up AUC
23% to 78%***
Fluconazole 400 mg daily 200 mg q 8 hr 12 up AUC
95% CI:
54% to 98%
Not Reported
Methadone 30 to 90 mg daily 200 mg q 4 hr 9 up AUC
16% to 64% ***
Nelfinavir 750 mg q 8 hr × 7 to 10 days single 200 mg 11 down AUC
28% to 41%
Probenecid 500 mg q 6 hr × 2 days 2 mg/kg q 8 hr
× 3 days
3 up AUC
100% to 170% ***
Not Assessed
Rifampin 600 mg daily × 14 days 200 mg q 8 hr
× 14 days
8 down AUC
90% CI:
41% to 53 ***
Not Assessed
Ritonavir 300 mg q 6 hr × 4 days 200 mg q 8 hr
× 4 days
9 down AUC
95% CI:
15% to 34%
Valproic acid 250 mg or 500 mg q 8 hr
× 4 days
100 mg q 8 hr
× 4 days
6 up AUC
64% to 130% ***
Not Assessed
up = Increase; down = 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.

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