Retrovir Online, Description, Chemistry, Ingredients - Zidovudine

Retrovir Online, Description, Chemistry, Ingredients - Zidovudine

RETROVIR^®

RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against human immunodeficiency virus (HIV).

Tablets : RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.

Capsules : RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and titanium dioxide. The blue band around the capsule consists of gelatin and FD&C Blue No. 2.

Syrup : RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to adjust pH.

The chemical name of zidovudine is 3¢-azido-3¢-deoxythymidine; it has the following structural formula:

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^Ò 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 ³1 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.