Louvina van der Laan(1), Steve Innes(2), Peter L. Anderson(3), Mark Cotton(2), Paolo Denti(1)
(1) Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; (2) Family Clinical Research Unit, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town; (3) Department of Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.
Objectives:
Stavudine is being phased out as a first-line ART option due to cumulative mitochondrial toxicity, but it remains an important replacement option for HIV+ children in sub-Saharan Africa. At the recommended dose, it causes stigmatizing lipoatrophy(1–4). A lower adult dose of 30 mg twice daily maintains efficacy, but with less mitochondrial toxicity(5). Although the adult dose was formally reduced in 2007 from 40 to 30 mg twice daily(6), the children’s dose (1 mg/kg twice daily) was not correspondingly lowered, due to concerns about efficacy. We therefore compared intracellular stavudine-triphosphate levels in children receiving 0.5-0.75 mg/kg twice daily to adults receiving 30 mg twice daily.
Methods:
23 HIV+ children and 24 HIV+ adults from South-Africa received stavudine at 0.5 mg/kg and 20 mg twice daily for 7 days, respectively. As the study linked with a concurrent adult randomized clinical trial of stavudine 20mg twice daily (NCT02670772), our initial model design was based on adults receiving a stavudine dose of 20mg twice daily. Since no evidence exists to suggest non-linearity, simulations were carried out for adults receiving the current WHO recommended dose of 30mg twice daily. Stavudine suspension was used for children and capsules for adults. Blood samples were taken pre-dose and either at 1, 2, and 6, or 3, 4, and 8 hours post dose. Intracellular stavudine-triphosphate in peripheral blood mononuclear cells was assayed using Liquid Chromatography Tandem Mass Spectrometry. A population pharmacokinetic model was developed to describe the data using Monolix software version 2016R1 and SAEM, together with simulations using the Simulx package in R to explore the effect of dose reduction in HIV+ children.
Results:
Median (interquartile range) age and weight were 8 (7, 9) years and 23 (20, 26) kg in children and 36 (30, 40) years and 83 (70, 98) kg for adults. A bi-phasic disposition model with first-order appearance and disappearance described the pharmacokinetics of stavudine-triphosphate. Accounting for the effect of body size using allometric scaling based on fat-free body mass improved the model fit. No significant differences other than those accounted for with allometric scaling were detected in any pharmacokinetic parameter between adults and children, although a non-significant trend towards children having lower bioavailability was observed. Using a large unrelated adult dataset, simulations of 30 mg twice daily predicted median (IQR) stavudine-triphosphate Cmin and Cmax values of 14 (9, 19) and 45 (38, 53) fmol/10^6 cells. Similarly, simulations in an unrelated dataset of HIV+ children receiving newly proposed weight-band dosing (0.5-0.75 mg/kg) predicted a Cmin and Cmax of 14 (10, 21) and 58 (50, 68) fmol/10^6 cells.
Conclusions:
Pharmacokinetic parameters of stavudine-triphosphate in children receiving the reduced stavudine dose of 0.5 mg/kg twice daily were similar to adults receiving 20 mg twice daily. The trend observed for a lower bioavailability in children may be due to difficulty in drug administration or the different formulations used. Weight band dosing using a stavudine dose of 0.5-0.75mg/kg is proposed as 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 >7kg would have a reduced toxic effect while maintaining viral suppression.
References:
[1]. Amaya RA, Kozinetz CA, Mcmeans ANN, Schwarzwald H, Kline MW. 2002. Lipodystrophy syndrome in human immunodeficiency virus-infected children. Pediatr Infect Dis J 21:405–410.
[2]. Ene L, Goetghebuer T, Hainaut M, Peltier A, Toppet V, Levy J. 2007. Prevalence of lipodystrophy in HIV-infected children: A cross-sectional study. Eur J Pediatr 166:13–21.
[3]. European Paediatric Lipodystrophy Group. 2004. Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS 18:1443–1451.
[4]. Innes S, Levin L, Cotton M. 2009. Lipodystrophy Syndrome in Hiv-Infected Children on Haart. South Afr J HIV Med 10:76–80.
[5]. Hill A, Ruxrungtham K, Hanvanich M, Katlama C, Wolf E, Soriano V, Milinkovic A, Gatell J, Ribera E. 2007. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Expert Opin Pharmacother 8:679–688.
[6]. World Health Organization. 2006. ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN ADULTS AND ADOLESCENTS: Recommendations for a public health approach. World Heal Organ 1–134.
Reference: PAGE 27 (2018) Abstr 8459 [www.page-meeting.org/?abstract=8459]
Poster: Drug/Disease Modelling - Paediatrics