title: 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/10(6) 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/10(6) cells, slightly higher than the adult dose of 20 mg b.i.d. [11.5 (11.2-11.9) fmol/10(6) 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.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Malmberg
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Aoi
authors.initials: A
authors.lastname: Matsushima
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Asin-Prieto
authors.affiliation: Division of Clinical Pharmacology, Stellenbosch University, Cape Town, South Africa.
authors.forename: Bernd
authors.initials: B
authors.lastname: Rosenkranz
authors.affiliation: Children's Infectious Diseases Clinical Research Unit, Tygerberg Children's Hospital and Stellenbosch University, Cape Town, South Africa.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Cotton
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA. Electronic address: hartmut@cop.ufl.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
authors.affiliation: Children's Infectious Diseases Clinical Research Unit, Tygerberg Children's Hospital and Stellenbosch University, Cape Town, South Africa.
authors.forename: Steve
authors.initials: S
authors.lastname: Innes
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D018119:Stavudine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D018119:Stavudine
keywords: Advanced dissolution, absorption and metabolism (ADAM) model; Optimization of antiretroviral doses in children; Paediatric reduced dose; Physiologically-based pharmacokinetics; Stavudine