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

摘要: Owing to significant dose-related toxicity, the adult stavudine dose was reduced in 2007. The paediatric dose, however, has not been reduced. Although intended is 1 mg/kg twice daily (b.i.d.), current weight-band dosing approach results a mean actual of 1.23±0.47 mg/kg. Both efficacy and mitochondrial toxicity depend on concentration intracellular metabolite triphosphate (d4T-TP). We simulated effect reducing 0.5 A physiologically-based pharmacokinetic model consisting 13 tissue compartments plus full ADAM used describe elimination stavudine. volume distribution at steady-state apparent oral clearance were resulting AUC profile compared with literature data populations. biochemical reaction utilised simulate d4T-TP levels for both standard proposed doses. Simulated observed exposure after showed adequate agreement. Mean 1.23 b.i.d. 27.9 (90% CI 27.0-28.9) fmol/10(6) cells, 25% higher than that achieved by 40 mg dose. resulted 13.2 (12.7-13.7) slightly 20 [11.5 (11.2-11.9) cells], which excellent antiviral substantially less toxicity. Current may result even original Halving would significantly reduce risk without compromising efficacy.