A pharmacokinetic and pharmacogenetic study of efavirenz in children: Dosing guidelines can result in subtherapeutic concentrations

Rob ter Heine, Henriette J. Scherpbier, Kristel M.L. Crommentuyn, Vincent Bekker, Jos H. Beijnen, Taco W. Kuijpers, Alwin D.R. Huitema

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

52 Citaten (Scopus)

Samenvatting

Background: Our main objectives were to study the population pharmacokinetics of efavirenz and to explore the adequacy of dosing guidelines. Methods: A total of 33 HIV-1-infected patients were recruited from the Emma Children's Hospital (Amsterdam, the Netherlands). Gender, age, drug formulation, the presence of the c.516G>T polymorphism in the CYP2B6 gene and the quantitation of liver enzymes alanine aminotransferase and aspartate aminotransferase at baseline were collected. A non-linear mixed effect pharmacokinetic model was developed. Results: CYP2B6 genotype and drug formulation significantly influenced efavirenz pharmacokinetics. Clearance was 29.7% lower in children carrying the CYP2B6-516-G/T genotype compared with children carrying the G/G genotype. Relative bioavailiability of the oral liquid compared with tablets or capsules was 46.6%. Children carrying the CYP2B6-516-G/G genotype had a 50-70% probability of developing a subtherapeutic trough level of efavirenz and only 1-3% probability of developing a trough level >4 mg/l. To reduce the probability of developing a subtherapeutic trough concentration, we propose to give an adult efavirenz dose to children weighing ≥25 kg and to allometrically scale doses for other weight levels a priori. The dose of the oral solution should be twice the dose of capsules. Conclusions: Population pharmacokinetics of efavirenz in children were adequately described. Current dosing guidelines can result in subtherapeutic concentrations in children carrying the CYP2B6-516-G/G genotype and with the liquid formulation. A priori dose adaptations in the paediatric population seem feasible and need prospective validation.

Originele taal-2Engels
Pagina's (van-tot)779-787
Aantal pagina's9
TijdschriftAntiviral Therapy
Volume13
Nummer van het tijdschrift6
StatusGepubliceerd - 2008
Extern gepubliceerdJa

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