In silico study supports the efficacy of a reduced dose regimen for stavudine

Abstract

Stavudine (d4T) is used extensively as part of HAART in resource poor settings, despite its toxicities. The revised WHO guidelines specify replacement of d4T with less toxic but more expensive drugs when feasible, and that d4T doses be standardized to 30 mg twice daily (bid) (irrespective of body-weight), from the approved 40 mg bid in adults (body-weight ≥ 60 kg). Therefore, an in silico population pharmacokinetic and biochemical model was utilized to compare relative efficacies of the two doses in humans. Assessment of predicted quartile ranges of simulated concentrations of the triphosphate of d4T suggested sufficient trough concentrations to inhibit wild type HIV-1 reverse transcriptase at the reduced dose, lending support to the revised WHO recommendations.

Estimation of Intracellular Concentration of Stavudine Triphosphate in HIV-Infected Children Given a Reduced Dose of 0.5 Milligrams per Kilogram Twice Daily

“…The parameter estimates were 0.269 h Ϫ1 and 0.151 h Ϫ1 for k pp and k dp , respectively. The parameter estimates were markedly different from that reported by Hurwitz and Schinazi (24). The likely explanation for the discrepancy is that our pharmacokinetic model was a zero-order absorption model, which allowed for a rapid rise to peak concentration within approximately 0.3 h. In contrast, their model was originally from Panhard et al (30) and had a slow first-order absorption rate constant with an estimated time of peak concentration of approximately 1.5 to 2 h (30).…”

“…We assumed that stavudine rapidly reached equilibrium between extra-and intracellular concentrations, as it is known that transporters of nucleosides on the cell membranes of lymphocytes are efficient and that equilibrium is achieved within milliseconds (28,29). Hurwitz and Schinazi also had shown that the intracellular d4T-TP and extracellular stavudine concentrations were proportional, suggesting that phosphorylation was not saturable at the clinically relevant concentration (24). This supported the assumption that rapid equilibrium is achieved between extracellular and intracellular concentrations.…”

“…The intracellular concentrations of d4T-TP in adults weighing over 60 kg and those under 60 kg who were administered 40 mg or 30 mg stavudine BID, respectively, were obtained from the first figure from Becher et al (20). The same cellular parameters in the study by Hurwitz and Schinazi (24) were used to transform the intracellular concentrations from fmol/10 6 cells to M. The intracellular concentrations of d4T-TP were computed assuming a cell volume of 32 pl and 8% activated lymphocyte fraction (24)(25)(26)(27). We assumed that stavudine rapidly reached equilibrium between extra-and intracellular concentrations, as it is known that transporters of nucleosides on the cell membranes of lymphocytes are efficient and that equilibrium is achieved within milliseconds (28,29).…”

Effect of reducing the paediatric stavudine dose by half: A physiologically-based pharmacokinetic model

“…Formation of intracellular d4T-TP was previously described as a rapid event [12]. This phenomenon was assumed in the simulations.…”

“…achieves a median intracellular d4T-TP concentration in the mid range of the IC 50 values (ca. 2–3 μM) [12], yet produces an excellent virological response. As a result, several strategies of dose reduction have been hypothesised [12–14].…”