Chemical formula: C₁₀H₁₂N₂O₄ Molecular mass: 224.213 g/mol PubChem compound: 18283
Stavudine, a thymidine analogue, is phosphorylated by cellular kinases to stavudine triphosphate which inhibits HIV reverse transcriptase by competing with the natural substrate, thymidine triphosphate. It also inhibits viral DNA synthesis by causing DNA chain termination due to a lack of the 3'-hydroxyl group necessary for DNA elongation. Cellular DNA polymerase γ is also sensitive to inhibition by stavudine triphosphate, while cellular polymerases α and β are inhibited at concentrations 4,000-fold and 40-fold higher, respectively, than that needed to inhibit HIV reverse transcriptase.
Stavudine treatment can select for and/or maintain thymidine analogue mutations (TAMs) associated with zidovudine resistance. The decrease of susceptibility in vitro is subtle requiring two or more TAMs (generally M41L and T215Y) before stavudine susceptibility is decreased (>1.5 fold).
These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment.
The clinical relevance of these findings suggest that stavudine should be generally avoided in the presence of TAMs, especially M41L and T215Y.
The activity of stavudine is also affected by multi-drug resistance associated mutations such as Q151M. In addition, K65R has been reported in patients receiving stavudine/didanosine or stavudine/lamivudine, but not in patients receiving stavudine monotherapy. V75T is selected in vitro by stavudine and reduces susceptibility to stavudine by 2-fold. It occurs in ~1% of patients receiving stavudine.
The use of stavudine in adolescents, children and infants is supported by pharmacokinetic and safety data in paediatric patients.
The absolute bioavailability is 86±18%. After multiple oral administration of 0.5-0.67 mg/kg doses, a Cmax value of 810±175 ng/ml was obtained. Cmax and AUC increased proportionally with dose in the dose ranges, intravenous 0.0625-0.75 mg/kg, and oral 0.033-4.0 mg/kg. In eight patients receiving 40 mg twice daily in the fasted state, steady-state AUC0-12h was 1284±227 ng⋅h/ml (18%) (mean ± SD [% CV]), Cmax was 536±146 ng/ml (27%), and Cmin was 9±8 ng/ml (89%). A study in asymptomatic patients demonstrated that systemic exposure is similar while Cmax is lower and Tmax is prolonged when stavudine is administered with a standardised, high-fat meal compared with fasting conditions. The clinical significance of this is unknown.
The apparent volume of distribution at steady state is 46±21 l. It was not possible to detect stavudine in cerebrospinal fluid until at least 2 hours after oral administration. Four hours after administration, the CSF/plasma ratio was 0.39±0.06. No significant accumulation of stavudine is observed with repeated administration every 6, 8, or 12 hours. Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 μg/ml. Stavudine distributes equally between red blood cells and plasma.
Unchanged stavudine was the major drug-related component in total plasma radioactivity circulating after an oral 80 mg dose of 14C-stavudine in healthy subjects. The AUC(inf) for stavudine was 61% of the AUC(inf) of the total circulating radioactivity. Metabolites include oxidised stavudine, glucuronide conjugates of stavudine and its oxidised metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.
Following an oral 80-mg dose of 14C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and faeces, respectively. Approximately 70% of the orally administered stavudine dose was excreted as an unchanged drug in urine. Mean renal clearance of the parent compound is approximately 272 ml/min, accounting for approximately 67% of the apparent oral clearance, indicating active tubular secretion in addition to glomerular filtration.
In HIV-infected patients,total clearance of stavudine is 594±164 ml/min, and renal clearance is 237±98 ml/min. The total clearance of stavudine appears to be higher in HIV-infected patients, while the renal clearance is similar between healthy subjects and HIV-infected patients. The mechanism and clinical significance of this difference are unknown. After intravenous administration, 42% (range: 13% to 87%) of dose is excreted unchanged in the urine. The corresponding values after oral single and multiple dose administration are 35% (range: 8% to 72%) and 40% (range: 12% to 82%), respectively. The mean terminal elimination half-life of stavudine is 1.3 to 2.3 hours following single or multiple doses, and is independent of dose. In vitro, stavudine triphosphate has an intracellular half-life of 3.5 hours in CEM T-cells (a human T-lymphoblastoid cell line) and peripheral blood mononuclear cells, supporting twice daily dosing.
The pharmacokinetics of stavudine was independent of time, since the ratio between AUC(ss) at steady state and the AUC(0-t) after the first dose was approximately 1. Intra- and interindividual variation in pharmacokinetic characteristics of stavudine is low, approximately 15% and 25%, respectively, after oral administration.
The clearance of stavudine decreases as creatinine clearance decreases; therefore, it is recommended that the dosage of stavudine be adjusted in patients with reduced renal function.
Stavudine pharmacokinetics in patients with hepatic impairment were similar to those in patients with normal hepatic function.
Total exposure to stavudine was comparable between adolescents, children and infants ≥14 days receiving the 2 mg/kg/day dose and adults receiving 1 mg/kg/day. Apparent oral clearance was approximately 14 ml/min/kg for infants ages 5 weeks to 15 years, 12 ml/min/kg for infants ages 14 to 28 days, and 5 ml/min/kg for infants on the day of birth. Two to three hours post-dose, CSF/plasma ratios of stavudine ranged from 16% to 125% (mean of 59%±35%).
Animal data showed embryo-foetal toxicity at very high exposure levels. An ex vivo study using a term human placenta model demonstrated that stavudine reaches the foetal circulation by simple diffusion. A rat study also showed placental transfer of stavudine, with the foetal tissue concentration approximately 50% of the maternal plasma concentration.
Stavudine was genotoxic in in vitro tests in human lymphocytes possessing triphosphorylating activity (in which no no-effect level was established), in mouse fibroblasts, and in an in vivo test for chromosomal aberrations. Similar effects have been observed with other nucleoside analogues. Stavudine was carcinogenic in mice (liver tumours) and rats (liver tumours: cholangiocellular, hepatocellular, mixed hepatocholangiocellular, and/or vascular; and urinary bladder carcinomas) at very high exposure levels. No carcinogenicity was noted at doses of 400 mg/kg/day in mice and 600 mg/kg/day in rats, corresponding to exposures ~39 and 168 times the expected human exposure, respectively, suggesting an insignificant carcinogenic potential of stavudine in clinical therapy.
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