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Pediatric Underdosing of Efavirenz: A Pharmacokinetic Study in Uganda

Fillekes, Quirine MSc*; Natukunda, Eva MBChB; Balungi, Jackie MBChB; Kendall, Lindsay MSc§; Bwakura-Dangarembizi, Mutsa MBChB; Keishanyu, Rosette MBChB; Ferrier, Alex MSc§; Lutakome, Joseph MBChB; Gibb, Diana M. MD, PhD§; Burger, David M. PharmD, PhD*; Walker, A. Sarah PhD§; On Behalf of the ARROW Trial Team

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 December 2011 - Volume 58 - Issue 4 - p 392–398
doi: 10.1097/QAI.0b013e318235e560
Clinical Science

Objectives: To evaluate international pediatric efavirenz dosing recommendations using full pharmacokinetic (PK) information.

Design: Open-label, multicenter, PK study.

Methods: Forty-one HIV-infected Ugandan children (3–12 years) on efavirenz + lamivudine + abacavir were enrolled in a study of twice-daily to once-daily lamivudine + abacavir 36 weeks after antiretroviral therapy initiation in the ARROW trial. Once-daily efavirenz doses were 200, 250, 300, 350 mg for children weighing 10 to <15, 15 to <20, 20 to <25, 25 to <30 kg, respectively, using 200/50 mg capsules or halved 600 mg tablets in case of 300 and 350 mg doses. Intensive plasma PK sampling (t = 0, 1, 2, 4, 6, 8, 12 hours postobserved ingestion) was performed at steady state (PK1) and repeated 4 weeks later (PK2, including a further 24-hour sample).

Results: Forty-one and 39 children had evaluable efavirenz profiles at PK1 and PK2, respectively. Seventeen (41%) were boys. Five, 16, 17, 3 were in the 10 to <15, 15 to <20, 20 to <25, 25 to <30 kg weight bands. The geometric mean (%CV) the area under the concentration–time curve 0–24 hours postdose was 50.8 (90.8%) and 55.5 (82.7%) h·mg·L-1 at PK1 and PK2, respectively. Six children at PK1 and 7 at PK2 had subtherapeutic C8h and/or C12h (<1.0 mg/L), 7 of 41 (17%) at either visit. At PK2, 15 of 39 (38%) children had C24h <1.0 mg/L (median (interquartile range) [range] 1.1 (0.7–2.9) [0.3–18.4]). Ten children at PK1 and 11 at PK2 had C8h and/or C12h >4.0 mg/L; 12 of 41 (29%) at either visit.

Conclusions: African children aged 3–12 years, on efavirenz dosed according to 2006 WHO/manufacturer's recommendations, had lower and highly variable efavirenz PK parameters compared with adult data from manufacturer's leaflet. There were no differences across weight bands, suggesting no major effect of using half tablets. Higher pediatric efavirenz doses, as per WHO 2010 recommendations, should be used and investigated further but may risk increasing the proportion of children with potentially toxic levels.

*Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Joint Clinical Research Centre, Kampala, Uganda

Pediatric Infectious Diseases Centre, Mulago, Uganda

§MRC Clinical Trials Unit, London, United Kingdom

University of Zimbabwe Medical School, Department of Paediatrics and Child Health, Harare, Zimbabwe

MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.

Correspondence to: Quirine Fillekes, Msc, Radboud University Nijmegen Medical Centre, 864 Department of Pharmacy, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands (e-mail Q.Fillekes@akf.umcn.nl).

Nucleoside reverse transcriptase inhibitors used in ARROW were supplied by GlaxoSmithKline, Triangle Park, USA, who also provided funding for this pharmacokinetic substudy. The ARROW trial was funded by the UK Medical Research Council and the UK Department for International Development.

Meetings at which parts of the data were presented at Conference on Retroviruses and Opportunistic Infections (CROI), February 16–19, 2010, San Francisco, CA; The Netherlands Congress for HIV (NCHIV), November 23, 2010, Amsterdam, The Netherlands.

The authors have no conflicts of interest to disclose.

The members of the ARROW Trial team are listed in Appendix I.

Received May 2, 2011

Accepted September 2, 2011

© 2011 Lippincott Williams & Wilkins, Inc.