Retrovir Mechanism of Action

Pharmacotherapeutic Group: nucleoside analogue. ATC Code: J05A F01.
Pharmacology: Pharmacodynamics: Mode of action: 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-TP 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.
Clinical virology: The relationships between in vitro susceptibility of HIV to zidovudine and clinical response to therapy remain under investigation. In vitro susceptibility 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 RETROVIR 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.
No antagonistic effects in vitro were seen with zidovudine and other antiretrovirals (tested agents: abacavir, didanosine, lamivudine and interferon-alpha).
Resistance to thymidine analogues (of which zidovudine is one) is well characterised and is conferred by the stepwise accumulation of up to six specific mutations in the HIV reverse transcriptase at codons 41, 67, 70, 210, 215 and 219. Viruses acquire phenotypic resistance to thymidine analogues through the combination of mutations at codons 41 and 215 or by the accumulation of at least four of the six mutations. These thymidine analogue mutations alone do not cause high-level cross-resistance to any of the other nucleosides, allowing for the subsequent use of any of the other approved reverse transcriptase inhibitors.
Two patterns of multi-drug resistance mutations, the first characterised by mutations in the HIV reverse transcriptase at codons 62, 75, 77, 116 and 151 and the second typically involving a T69S mutation plus a 6-base pair insert at the same position, result in phenotypic resistance to AZT as well as to the other approved nucleoside reverse transcriptase inhibitors. Either of these two patterns of multinucleoside resistance mutations severely limits future therapeutic options.
Syrup: 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.
In the US ACTGO76 trial, Retrovir was shown to be effective in reducing the rate of maternal-foetal transmission of HIV-1 (23% infection rate for placebo versus 8% for zidovudine) when administered (100 mg five times a day) to HIV-positive pregnant women (from week 14-34 of pregnancy) and their newborn infants (2 mg/kg every 6 hours) until 6 weeks of age. In the shorter duration 1998 Thailand CDC study, use of oral Retrovir therapy only (300 mg twice daily), from week 36 of pregnancy until delivery, also reduced the rate of maternal-foetal transmission of HIV (19% infection rate for placebo versus 9% for zidovudine). These data, and data from a published study comparing zidovudine regimens to prevent maternal-foetal HIV transmission have shown that short maternal treatments (from week 36 of pregnancy) are less efficacious than longer maternal treatments (from week 14-34 of pregnancy) in the reduction of perinatal HIV transmission.
IV infusion: Studies in vitro of zidovudine in combination with lamivudine indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. Evidence from clinical studies show that lamivudine plus zidovudine delays the emergence of zidovudine-resistant isolates in individuals with no prior anti- retroviral therapy.
Zidovudine has been widely used as a component of anti retroviral combination therapy with other anti retroviral agents of the same class (nucleoside reverse transcriptase inhibitors) or different classes (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).
Clinical Studies: The Antiretroviral Pregnancy Registry (APR) has received reports of over 13,000 exposures to zidovudine during pregnancy resulting in live birth. These consist of over 4,100 exposures during the first trimester, over 9,300 exposures during the second/third trimester and included 133 and 264 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.2% (2.7, 3.8%) and in the second/third trimester, 2.8% (2.5, 3.2%). This proportion is not significantly higher than those reported in the two population based surveillance systems (2.72 per 100 live births and 4.17 per 100 live births respectively). The APR does not show an increased risk of major birth defects zidovudine compared to the background rate.
Pharmacokinetics: Absorption: Syrup: Zidovudine is well absorbed from the gut and, at all dose levels studied, the bioavailability was 60 to 70%. From a Phase I study, mean steady state peak (C[ss]max) and trough (C[ss]min) plasma concentrations following oral administration of zidovudine (in solution) at doses of 5 mg/kg every 4 h were 7.1 and 0.4 micromol (or 1.9 and 0.1 micrograms/ml) respectively. From a bioequivalence study, mean C[ss]max and C[ss] min levels following oral administration of zidovudine capsules every 4 h and dose normalised to 200 mg were 4.5 micromol (or 1.2 micrograms/ml) and 0.4 micromol (or 0.1 micrograms/ml) respectively.
Bioequivalence: In HIV-infected patients on zidovudine therapy, the 300 mg zidovudine tablet at steady state was bioequivalent to the 250 mg capsule, when adjusted for dose. As the kinetics of zidovudine are dose-independent following multiple dose oral administration, the 200 mg RETROVIR tablets of identical formulation to the 300 mg tablet can also be considered bioequivalent to the 250 mg capsule after adjustment for dose.
RETROVIR oral solution was shown, in patients, to be bioequivalent to RETROVIR capsules in respect to the area under the zidovudine plasma concentration-time curve (AUC). The absorption of RETROVIR following the administration of the oral solution was marginally faster than that following the administration of capsules, with mean times to peak concentrations of 0.5 and 0.8 h respectively. Mean values for C[ss]max, dose- normalised to 200 mg were 5.8 micromol (or 1.55 micrograms/ml) and 4.5 micromol (1.2 micrograms/ml) for oral solution and capsules respectively. These data were generated using the US oral RETROVIR syrup but can be considered to apply equally to RETROVIR oral solution.
IV infusion: Dose-independent kinetics were observed in patients receiving 1 h infusions of 1 to 5 mg/kg three to six times daily. Mean steady state peak (C_ssmax) and trough (C_ssmin) plasma concentrations in adults following a 1 h infusion of 2.5 mg/kg every 4 h were 4.0 and 0.4 micromol respectively (or 1.1 and 0.1 micrograms/ml).
Distribution: From studies with i.v. zidovudine, the mean terminal plasma half- life was 1.1 h, the mean total body clearance was 27.1 ml/min/kg and the apparent volume of distribution was 1.6 l/kg.
In adults, the average cerebrospinal fluid/plasma zidovudine concentration ratio 2 to 4 h 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 interactions with other active substances involving binding site displacement are not anticipated.
Metabolism: The 5'-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50 to 80% of the administered dose eliminated by renal excretion. 3'amino- 3'- deoxythymidine (AMT) has been identified as a metabolite of zidovudine following i.v. dosing.
Elimination: Renal clearance of zidovudine greatly exceeds creatinine clearance, indicating that significant tubular secretion takes place.
Special Patient Populations: Children: In children over the age of 5 to 6 months, the pharmacokinetic profile of zidovudine is similar to that in adults.
In children, the mean cerebrospinal fluid/plasma zidovudine concentration ratio ranged from 0.52 to 0.85, as determined during oral therapy 0.5 to 4 h after dosing and was 0.87 as determined during i.v. therapy 1 to 5 h after a 1 h infusion. During continuous i.v. infusion, the mean steady-state cerebrospinal fluid/plasma concentration ratio was 0.24.
With i.v. dosing, the mean terminal plasma half-life and total body clearance were 1.5 h and 30.9 ml/min/kg respectively. The major metabolite is the 5'-glucuronide. After i.v. 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.
Syrup: Zidovudine is well absorbed from the gut and, at all dose levels studied, its bioavailability was 60 to 74% with a mean of 65%. C[ss]max levels were 4.45 micromol (1.19 micrograms/ml) following a dose of 120 mg zidovudine (in solution)/m² body surface area and 7.7 micromol (2.06 micrograms/ml) at 180 mg/m² body surface area.
IV infusion: C_ss max levels were 1.46 micrograms/ml following an i.v. dose of 80 mg zidovudine/m² body surface area, 2.26 micrograms/ml following 120 mg/m² and 2.96 micrograms/ml following 160 mg/m².
Elderly: The pharmacokinetics of zidovudine have not been studied in patients over 65 years of age.
Renal Impairment: Compared to healthy subjects, patients with advanced renal failure have a 50% higher peak plasma concentration of zidovudine. 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 glucuronide metabolite is increased (see Dosage & Administration).
Hepatic Impairment: Data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage adjustments may be necessary, but as there is only limited data available precise recommendations cannot be made (see Dosage & Administration).
Pregnancy: The pharmacokinetics of zidovudine has been investigated in a study of eight women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of accumulation of zidovudine. The pharmacokinetics of zidovudine was similar to that of non-pregnant adults. Consistent with passive transmission of zidovudine across the placenta, zidovudine concentrations in infant plasma at birth were essentially equal to those in maternal plasma at delivery.
Toxicology: Pre-clinical Safety Data: Carcinogenicity, Mutagenicity: 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 were observed in an in vitro study in human lymphocytes and 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 RETROVIR 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 RETROVIR 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. 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. There were no other zidovudine-related tumours observed in either sex of either species. 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. The predictive value of rodent carcinogenicity studies for humans is uncertain and thus the clinical significance of these findings is unclear.
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 (420mg/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.
Reproductive toxicology: Studies in pregnant rats and rabbits with zidovudine have shown increased incidences of early embryo deaths. A separate study in rats found that dosages very near the oral median lethal dose caused an increase in the incidence of foetal malformations. No evidence of teratogenicity has been observed at lower dosages tested.
Zidovudine did not impair male or female fertility in studies in rats.