Effect of reducing the paediatric stavudine dose by half: A physiologically-based pharmacokinetic model
2015
Sy, Sherwin K.B. | Malmberg, Ruben | Matsushima, Aoi | Asin-Prieto, Eduardo | Rosenkranz, Bernd | Cotton, Mark F. | Derendorf, Hartmut | Innes, Steve
Owing to significant dose-related toxicity, the adult stavudine dose was reduced in 2007. The paediatric dose, however, has not been reduced. Although the intended paediatric dose is 1mg/kg twice daily (b.i.d.), the current weight-band dosing approach results in a mean actual dose of 1.23±0.47mg/kg. Both efficacy and mitochondrial toxicity depend on the concentration of the intracellular metabolite stavudine triphosphate (d4T-TP). We simulated the effect of reducing the paediatric dose to 0.5mg/kg. A physiologically-based pharmacokinetic model consisting of 13 tissue compartments plus a full ADAM model was used to describe the elimination of stavudine. The volume of distribution at steady-state and apparent oral clearance were simulated and the resulting AUC profile was compared with literature data in adult and paediatric populations. A biochemical reaction model was utilised to simulate intracellular d4T-TP levels for both the standard and proposed reduced paediatric doses. Simulated and observed exposure after oral dosing showed adequate agreement. Mean steady-state d4T-TP for 1.23mg/kg b.i.d. was 27.9 (90% CI 27.0–28.9) fmol/10⁶ cells, 25% higher than that achieved by the 40mg adult dose. The 0.5mg/kg dose resulted in d4T-TP of 13.2 (12.7–13.7)fmol/10⁶ cells, slightly higher than the adult dose of 20mg b.i.d. [11.5 (11.2–11.9)fmol/10⁶ cells], which has excellent antiviral efficacy and substantially less toxicity. Current paediatric dosing may result in even higher d4T-TP than the original 40mg adult dose. Halving the paediatric dose would significantly reduce the risk of mitochondrial toxicity without compromising antiviral efficacy.
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