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Antiviral Agents

Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing

Steve Innes, Louvina van der Laan, Peter L. Anderson, Mark Cotton, Paolo Denti
Steve Innes
Family Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Louvina van der Laan
Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South AfricaDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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Peter L. Anderson
Department of Pharmaceutical Sciences, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA
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Mark Cotton
Family Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Paolo Denti
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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DOI: 10.1128/AAC.00761-18
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ABSTRACT

Stavudine remains a useful replacement option for treatment for HIV+ children. WHO reduced the adult dose to 30 mg twice daily, which maintains efficacy and lowers mitochondrial toxicity. We explored intracellular stavudine triphosphate levels in children receiving a reduced dose of 0.5 to 0.75 mg/kg of body weight twice daily to investigate whether a similar dose optimization can safely be made. 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 0.5 mg/kg and 20 mg twice daily for 7 days, respectively. Simulations were employed to optimize the pediatric dosing regimen to match exposures in adults receiving the current WHO-recommended dose of 30 mg twice daily. A biphasic disposition model with first-order appearance and disappearance described the pharmacokinetics of stavudine triphosphate. The use of allometric scaling with fat-free mass characterized well the pharmacokinetics in both adults and children, and no other significant effect could be detected. Simulations of 30 mg twice daily in adults predicted median (interquartile range [IQR]) stavudine triphosphate minimum drug concentration (Cmin) and maximum drug concentration (Cmax) values of 13 (10 to 19) and 45 (38 to 53) fmol/106 cells, respectively. Targeting this exposure, simulations in HIV+ children were used to identify a suitable weight-band dosing approach (0.5 to 0.75 mg/kg), which was predicted to achieve median (IQR) Cmin and Cmax values of 13 (9 to 18) and 49 (40 to 58) fmol/106 cells, respectively. Weight-band dosing using a stavudine dose of 0.5 to 0.75 mg/kg is proposed, and it shows comparable exposures to adults receiving the current WHO-recommended dose of 30 mg twice daily. Our pharmacokinetic results suggest that the decreased stavudine dose in children >2 years would have a reduced toxic effect while retaining antiretroviral efficacy.

FOOTNOTES

    • Received 16 April 2018.
    • Returned for modification 22 May 2018.
    • Accepted 6 August 2018.
    • Accepted manuscript posted online 13 August 2018.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00761-18.

  • Copyright © 2018 Innes et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing
Steve Innes, Louvina van der Laan, Peter L. Anderson, Mark Cotton, Paolo Denti
Antimicrobial Agents and Chemotherapy Oct 2018, 62 (11) e00761-18; DOI: 10.1128/AAC.00761-18

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Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing
Steve Innes, Louvina van der Laan, Peter L. Anderson, Mark Cotton, Paolo Denti
Antimicrobial Agents and Chemotherapy Oct 2018, 62 (11) e00761-18; DOI: 10.1128/AAC.00761-18
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KEYWORDS

antiretroviral agents
children
intracellular drug concentration
population pharmacokinetics
stavudine

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