Chemical formula: C₁₀H₁₃N₅O₄ Molecular mass: 267.241 g/mol PubChem compound: 35370
Zidovudine is an antiviral agent which is highly active in vitro against retroviruses including the Human Immunodeficiency Virus (HIV).
Zidovudine is phosphorylated in both infected and uninfected cells to the monophosphate (MP) derivative by cellular thymidine kinase. Subsequent phosphorylation of zidovudine-MP to the diphosphate (DP), and then the triphosphate (TP) derivative is catalysed by cellular thymidylate kinase and non-specific kinases respectively. Zidovudine-TP acts as an inhibitor of and substrate for the viral reverse transcriptase. The formation of further proviral DNA is blocked by incorporation of zidovudine-MP into the chain and subsequent chain termination. Competition by zidovudine-TP for HIV reverse transcriptase is approximately 100-fold greater than for cellular DNA polymerase alpha.
The relationships between in vitro susceptibility of HIV to zidovudine and clinical response to therapy remain under investigation. In vitro sensitivity testing has not been standardised and results may therefore vary according to methodological factors. Reduced in vitro sensitivity to zidovudine has been reported for HIV isolates from patients who have received prolonged courses of zidovudine therapy. The available information indicates that for early HIV disease, the frequency and degree of reduction of in vitro sensitivity is notably less than for advanced disease.
The reduction of sensitivity with the emergence of zidovudine resistant strains limits the usefulness of zidovudine monotherapy clinically. In clinical studies, clinical end-point data indicate that zidovudine, particularly in combination with lamivudine, and also with didanosine or zalcitabine results in a significant reduction in the risk of disease progression and mortality. The use of a protease inhibitor in a combination of zidovudine and lamivudine, has been shown to confer additional benefit in delaying disease progression, and improving survival compared to the double combination on its own.
The anti-viral effectiveness in vitro of combinations of anti-retroviral agents are being investigated. Clinical and in vitro studies of zidovudine in combination with lamivudine indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. Furthermore there is clinical evidence that zidovudine plus lamivudine delays the emergence of zidovudine resistance in anti-retroviral naive patients.
No antagonistic effects in vitro were seen with zidovudine and other anti-retrovirals (tested agents: abacavir, didanosine, lamivudine and interferon-alpha).
Zidovudine is well absorbed from the gut and, at all dose levels studied, the bioavailability was 60-70%. From a bioequivalence study, steady-state mean (CV%) Cssmax, Cssmin, and AUCss values in 16 patients receiving zidovudine 300 mg tablets twice daily were 8.57 (54%) microM (2.29 μg/ml), 0.08 (96%) microM (0.02 μg/ml), and 8.39 (40%) h*microM (2.24 h*μg/ml), respectively.
Dose-independent kinetics were observed in patients receiving one-hour infusions of 1 to 5 mg/kg 3 to 6 times daily. Mean steady state peak (Cssmax) and trough (Cssmin) plasma concentrations in adults following a one-hour infusion of 2.5 mg/kg every 4 hours were 4.0 and 0.4 µM, respectively (or 1.1 and 0.1 µg/ml).
From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours, the mean total body clearance was 27.1 ml/min/kg and the apparent volume of distribution was 1.6 Litres/kg.
In adults, the average cerebrospinal fluid/plasma zidovudine concentration ratio 2 to 4 hours after dosing was found to be approximately 0.5. Data indicate that zidovudine crosses the placenta and is found in amniotic fluid and foetal blood. Zidovudine has also been detected in semen and milk.
Plasma protein binding is relatively low (34 to 38%) and drug interactions involving binding site displacement are not anticipated.
Zidovudine is primarily eliminated by hepatic conjugation to an inactive glucoronidated metabolite. The 5'-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50-80% of the administered dose eliminated by renal excretion. 3'-amino-3'-deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenous dosing.
Renal clearance of zidovudine greatly exceeds creatinine clearance, indicating that significant tubular secretion takes place.
In children over the age of 5-6 months, the pharmacokinetic profile of zidovudine is similar to that in adults. Zidovudine is well absorbed from the gut and, at all dose levels studied, its bioavailability was 60-74% with a mean of 65%. Cssmax levels were 4.45µM (1.19 µg/ml) following a dose of 120 mg zidovudine (in solution)/m² body surface area and 7.7 µM (2.06 µg/ml) at 180 mg/m² body surface area. Dosages of 180 mg/m² four times daily in children produced similar systemic exposure (24 hour AUC 40.0 hr µM or 10.7 hr µg/ml) as doses of 200 mg six times daily in adults (40.7 hr µM or 10.9 hr µg/ml).
With intravenous dosing, the mean terminal plasma half-life and total body clearance were 1.5 hours and 30.9 ml/min/kg respectively.
In children the mean cerebrospinal fluid/plasma zidovudine concentration ratio ranged from 0.52-0.85, as determined during oral therapy 0.5 to 4 hours after dosing and was 0.87 as determined during intravenous therapy 1-5 hours after a 1 hour infusion. During continuous intravenous infusion, the mean steady-state cerebrospinal fluid/plasma concentration ratio was 0.24.
The major metabolite is 5'-glucuronide. After intravenous dosing, 29% of the dose was recovered unchanged in the urine and 45% excreted as the glucuronide.
Renal clearance of zidovudine greatly exceeds creatinine clearance indicating that significant tubular secretion takes place.
The data available on the pharmacokinetics in neonates and young infants indicate that glucuronidation of zidovudine is reduced with a consequent increase in bioavailability, reduction in clearance and longer half-life in infants less than 14 days old but thereafter the pharmacokinetics appear similar to those reported in adults.
The pharmacokinetics of zidovudine has been investigated in a study of eight women during the third trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine was similar to that of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in infant plasma at birth were essentially equal to those in maternal plasma at delivery.
No specific data are available on the pharmacokinetics of zidovudine in the elderly.
Compared to healthy subjects, patients with advanced renal failure have a 50% higher peak plasma concentration after oral administration. Systemic exposure (measured as area under the zidovudine concentration time curve) is increased 100%; the half-life is not significantly altered. In renal failure there is substantial accumulation of the major glucuronide metabolite but this does not appear to cause toxicity. Haemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination whereas elimination of the inactive glucuronide metabolite is increased.
There are limited data concerning the pharmacokinetics of zidovudine in patients with hepatic impairment. No specific data are available on the pharmacokinetics of zidovudine in the elderly.
No evidence of mutagenicity was observed in the Ames test. However, zidovudine was weakly mutagenic in a mouse lymphoma cell assay and was positive in an in vitro cell transformation assay. Clastogenic effects (chromosome damage) were observed in an in vitro study in human lymphocytes and in in vivo oral repeat dose micronucleus studies in rats and mice. An in vivo cytogenetic study in rats did not show chromosomal damage. A study of the peripheral blood lymphocytes of eleven AIDS patients showed a higher chromosome breakage frequency in those who had received zidovudine than in those who had not. A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults, including pregnant women, taking zidovudine as treatment for HIV-1 infection, or for the prevention of mother to child viral transmission. Zidovudine was also incorporated into DNA from cord blood leukocytes of infants from zidovudine-treated mothers. A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated that foetuses exposed in utero to the combination sustained a higher level of nucleoside analogue-DNA incorporation into multiple foetal organs, and showed evidence of more telomere shortening than in those exposed to zidovudine alone. The clinical significance of these findings is unknown.
In oral carcinogenicity studies with zidovudine in mice and rats, late appearing vaginal epithelial tumours were observed. A subsequent intravaginal carcinogenicity study confirmed the hypothesis that the vaginal tumours were the result of long term local exposure of the rodent vaginal epithelium to high concentrations of unmetabolised zidovudine in urine. There were no other drug-related tumours observed in either sex of either species.
In addition, two transplacental carcinogenicity studies have been conducted in mice. One study, by the US National Cancer Institute, administered zidovudine at maximum tolerated doses to pregnant mice from day 12 to 18 of gestation. One year post-natally, there was an increase in the incidence of tumours in the lung, liver and female reproductive tract of offspring exposed to the highest dose level (420 mg/kg term body weight).
In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24 months, with exposure beginning prenatally on gestation day 10. Treatment related findings were limited to late-occurring vaginal epithelial tumours, which were seen with a similar incidence and time of onset as in the standard oral carcinogenicity study. The second study thus provided no evidence that zidovudine acts as a transplacental carcinogen.
It is concluded that the transplacental carcinogenicity data from the first study represents a hypothetical risk, whereas the reduction in risk of maternal transfection of HIV to the uninfected child by the use of zidovudine in pregnancy has been well proven.
Studies in pregnant rats and rabbits given zidovudine orally at dosage levels up to 450 and 500 mg/kg/day respectively during the major period of organogenesis have revealed no evidence of teratogenicity. There was, however, a statistically significant increase in foetal resorptions in rats given 150 to 450 mg/kg/day and in rabbits given 500 mg/kg/day.
A separate study, reported subsequently, found that rats given a dosage of 3000 mg/kg/day, which is very near the oral median lethal dose (3683 mg/kg), caused marked maternal toxicity and an increase in the incidence of foetal malformations. No evidence of teratogenicity was observed in this study at the lower dosages tested (600 mg/kg/day or less).
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