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Pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda
Quirine Fillekes1, Eva Natukunda, Jackie Balungi
1Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Q.Fillekes@akf.umcn.nl
Insights
Pediatric efavirenz dosing based on 2006 WHO guidelines resulted in lower and highly variable pharmacokinetic parameters in African children. Higher doses may be needed, but further investigation is required to assess potential toxicity risks.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Pediatric Infectious Diseases
- Global Health
Background:
- Current international pediatric efavirenz dosing recommendations may not ensure optimal drug exposure in children.
- Understanding efavirenz pharmacokinetics (PK) is crucial for effective HIV treatment in pediatric populations.
Purpose of the Study:
- To evaluate the adequacy of international pediatric efavirenz dosing recommendations using comprehensive pharmacokinetic data.
- To assess efavirenz exposure in HIV-infected Ugandan children aged 3-12 years.
Main Methods:
- An open-label, multicenter pharmacokinetic study involving 41 HIV-infected Ugandan children (3-12 years).
- Children received efavirenz, lamivudine, and abacavir, with efavirenz dosed according to 2006 WHO/manufacturer guidelines.
- Intensive plasma sampling was conducted at steady state (PK1 and PK2) to determine efavirenz concentration-time profiles.
Main Results:
- Efavirenz pharmacokinetic parameters, including area under the concentration-time curve (AUC), were lower and highly variable compared to adult data.
- A significant proportion of children (17% at PK1, 38% at PK2) had subtherapeutic efavirenz levels (C24h <1.0 mg/L).
- Approximately 29% of children exhibited potentially toxic efavirenz levels (C8h and/or C12h >4.0 mg/L).
Conclusions:
- The 2006 WHO/manufacturer efavirenz dosing recommendations lead to suboptimal and highly variable drug exposure in African children.
- Current dosing strategies may not be effective, and higher doses, as suggested by 2010 WHO guidelines, warrant further investigation.
- Increased efavirenz doses may improve efficacy but carry a risk of elevated concentrations and potential toxicity, necessitating careful monitoring and further research.
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 C(8h) and/or C(12h) (<1.0 mg/L), 7 of 41 (17%) at either visit. At PK2, 15 of 39 (38%) children had C(24h) <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 C(8h) and/or C(12h) >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.
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