3 years ago

CAN WE IMPROVE STAVUDINE'S SAFETY PROFILE IN CHILDREN? PHARMACOKINETICS OF INTRACELLULAR STAVUDINE-TRIPHOSPHATE WITH REDUCED-DOSING.

Paolo Denti, Peter L Anderson, Louvina van der Laan, Mark Cotton, Steve Innes
Introduction Stavudine remains a useful replacement option for HIV+ children. WHO reduced the adult dose to 30mg twice-daily, which maintains efficacy and lowers mitochondrial toxicity. We explored intracellular stavudine-triphosphate levels in children receiving a reduced dose of 0.5-0.75mg/kg twice-daily to investigate whether a similar dose optimization can safely be made.Methods A population pharmacokinetic model was developed to describe the pharmacokinetics of intracellular stavudine-triphosphate in 23 HIV+ children and 24 HIV+ adults who received stavudine at 0.5mg/kg and 20mg twice-daily for 7 days, respectively. Simulations were employed to optimise the paediatric dosing regimen to match exposures in adults receiving the current WHO-recommended dose of 30mg twice-daily.Results A bi-phasic disposition model with first-order appearance and disappearance described the pharmacokinetics of stavudine-triphosphate. The use of allometric scaling with fat-free mass characterised well the pharmacokinetics in both adults and children, and no other significant effect could be detected. Simulations of 30mg twice-daily in adults predicted median (interquartile range) stavudine-triphosphate Cmin and Cmax values of 13 (10-19) and 45 (38-53)fmol/106 cells, respectively. Targeting this exposure, simulations in HIV+ children were used to identify a suitable weight-band dosing approach (0.5-0.75mg/kg), which was predicted to achieve Cmin and Cmax of 13 (9-18) and 49 (40-58)fmol/106 cells, respectively.Conclusion Weight-band dosing using a stavudine dose of 0.5-0.75mg/kg is proposed and it shows comparable exposures to adults receiving the current WHO recommended dose of 30mg twice-daily. Our pharmacokinetic results suggest that the decreased stavudine dose in children >2years would have a reduced toxic effect while retaining antiretroviral efficacy.

Publisher URL: http://doi.org/10.1128/AAC.00761-18

DOI: 10.1128/AAC.00761-18

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