A pharmacokinetic and pharmacogenetic study of efavirenz in children: dosing guidelines can result in subtherapeutic concentrations.
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 > or =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.
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands. rob.terheine@slz.nl
Rob
R
ter Heine
Henriette J
HJ
Scherpbier
Kristel M L
KM
Crommentuyn
Vincent
V
Bekker
Jos H
JH
Beijnen
Taco W
TW
Kuijpers
Alwin D R
AD
Huitema
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D048588:Benzoxazines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D017410:Practice Guidelines as Topic
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz