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

Abstract

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 1 mg/kg twice daily (b.i.d.), the current weight-band dosing approach results in a mean actual dose of 1.23 ± 0.47 mg/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 0.5 mg/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 1.23 mg/kg b.i.d. was 27.9 (90% CI 27.0–28.9) fmol/106 cells, 25% higher than that achieved by the 40 mg adult dose. The 0.5 mg/kg dose resulted in d4T-TP of 13.2 (12.7–13.7) fmol/106 cells, slightly higher than the adult dose of 20 mg 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 40 mg adult dose. Halving the paediatric dose would significantly reduce the risk of mitochondrial toxicity without compromising antiviral efficacy.

Pharmacokinetics, Pharmacodynamics and Dermal Distribution of 5-Methoxypsoralen Based on a Physiologically Based Pharmacokinetic Model to Support Phytotherapy Using Brosimum gaudichaudii

“…PK parameter observed mean PK parameter predicted mean (4) The model was considered acceptable if all predicted PK parameters were within twofold of the corresponding observed value (MFE 0.5 to 2.0), as is commonly applied in assessing PBPK model performance [29,30].…”

Physiologically based pharmacokinetic‐pharmacodynamic evaluation of meropenem plus fosfomycin in paediatrics

“…Given that the exposure parameters predicted by the full PBPK model were based on the physicochemical properties and demographical properties of the population, none of the exposure parameters from the literature were used in the model development, except for the comparison of summary statistics. The overall accuracy of the predicted pharmacokinetic parameters was assessed using the mean fold‐error (difference between predicted and observed in vivo values) 38,39 : The model was accepted when all predicted pharmacokinetic (PK) parameters were within two‐fold of the corresponding observed values (eg, MFE 0.5‐2.0) 38–41 …”

Application of antimicrobial drugs in perioperative surgical incision

“…However, the side effects of antimicrobial agents limit their application in acute surgical incision treatment. Many antimicrobial agents have concentration-dependent tissue toxicity, and some of their components enhance local toxicity [ 32 , 33 ]. Moreover, antimicrobial agents may also interfere with wound healing [ 34 – 36 ].…”