Cargando…
Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing
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...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201115/ https://www.ncbi.nlm.nih.gov/pubmed/30104267 http://dx.doi.org/10.1128/AAC.00761-18 |
_version_ | 1783365448356593664 |
---|---|
author | Innes, Steve van der Laan, Louvina Anderson, Peter L. Cotton, Mark Denti, Paolo |
author_facet | Innes, Steve van der Laan, Louvina Anderson, Peter L. Cotton, Mark Denti, Paolo |
author_sort | Innes, Steve |
collection | PubMed |
description | 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 (C(min)) and maximum drug concentration (C(max)) values of 13 (10 to 19) and 45 (38 to 53) fmol/10(6) 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) C(min) and C(max) values of 13 (9 to 18) and 49 (40 to 58) fmol/10(6) 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. |
format | Online Article Text |
id | pubmed-6201115 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-62011152018-11-15 Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing Innes, Steve van der Laan, Louvina Anderson, Peter L. Cotton, Mark Denti, Paolo Antimicrob Agents Chemother Antiviral Agents 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 (C(min)) and maximum drug concentration (C(max)) values of 13 (10 to 19) and 45 (38 to 53) fmol/10(6) 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) C(min) and C(max) values of 13 (9 to 18) and 49 (40 to 58) fmol/10(6) 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. American Society for Microbiology 2018-10-24 /pmc/articles/PMC6201115/ /pubmed/30104267 http://dx.doi.org/10.1128/AAC.00761-18 Text en Copyright © 2018 Innes et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Antiviral Agents Innes, Steve van der Laan, Louvina Anderson, Peter L. Cotton, Mark Denti, Paolo Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing |
title | Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing |
title_full | Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing |
title_fullStr | Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing |
title_full_unstemmed | Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing |
title_short | Can We Improve Stavudine's Safety Profile in Children? Pharmacokinetics of Intracellular Stavudine Triphosphate with Reduced Dosing |
title_sort | can we improve stavudine's safety profile in children? pharmacokinetics of intracellular stavudine triphosphate with reduced dosing |
topic | Antiviral Agents |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201115/ https://www.ncbi.nlm.nih.gov/pubmed/30104267 http://dx.doi.org/10.1128/AAC.00761-18 |
work_keys_str_mv | AT innessteve canweimprovestavudinessafetyprofileinchildrenpharmacokineticsofintracellularstavudinetriphosphatewithreduceddosing AT vanderlaanlouvina canweimprovestavudinessafetyprofileinchildrenpharmacokineticsofintracellularstavudinetriphosphatewithreduceddosing AT andersonpeterl canweimprovestavudinessafetyprofileinchildrenpharmacokineticsofintracellularstavudinetriphosphatewithreduceddosing AT cottonmark canweimprovestavudinessafetyprofileinchildrenpharmacokineticsofintracellularstavudinetriphosphatewithreduceddosing AT dentipaolo canweimprovestavudinessafetyprofileinchildrenpharmacokineticsofintracellularstavudinetriphosphatewithreduceddosing |