title: Estimation of intracellular concentration of stavudine triphosphate in HIV-infected children given a reduced dose of 0.5 milligrams per kilogram twice daily.
abstract: The antiviral efficacy of stavudine depends on the trough concentration of its intracellular metabolite, stavudine-triphosphate (d4T-TP), while the degree of stavudine's mitochondrial toxicity depends on its peak concentration. Rates of mitochondrial toxicity are high when stavudine is used at the current standard pediatric dose (1 mg/kg twice daily [BID]). Evidence from adult work suggests that half of the original standard adult dose (i.e., 20 mg BID) may be equally effective, with markedly less mitochondrial toxicity. We present a population pharmacokinetic model to predict intracellular d4T-TP concentrations in pediatric HIV-infected patients administered a dose of 0.5 mg/kg BID. Our model predicted that the reduced pediatric dose would result in a trough intracellular d4T-TP concentration above that of the reduced 20-mg adult dose and a peak concentration below that of the 20-mg adult dose. The simulated pediatric intracellular d4T-TP at 0.5 mg/kg BID resulted in median peak and trough values of approximately 23.9 fmol/10(6) cells (95% prediction interval [PI], 14.2 to 41 fmol/10(6) cells) and 14.8 fmol/10(6) cells (95% PI, 7.2 to 31 fmol/10(6) cells), respectively. The peak and trough concentrations resulting from a 20-mg BID adult dose were 28.4 fmol/10(6) cells (95% PI, 17.3 to 45.5 fmol/10(6) cells) and 13 fmol/10(6) cells (95% PI, 6.8 to 28.6 fmol/10(6) cells), respectively. Halving the current standard pediatric dose should therefore not compromise antiviral efficacy, while markedly reducing mitochondrial toxicity.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
authors.forename: Steve
authors.initials: S
authors.lastname: Innes
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
authors.forename: Mark F
authors.initials: MF
authors.lastname: Cotton
authors.forename: Bernd
authors.initials: B
authors.lastname: Rosenkranz
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D002648:Child; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D006678:HIV / Q000187:drug effects / Q000502:physiology; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D015233:Models, Statistical; D018119:Stavudine / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D018119:Stavudine