Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism.
BACKGROUND
The CYP2B6-G516T polymorphism has been shown to alter plasma efavirenz (EFV) concentrations in adults. The impact of CYP2B6-G516T polymorphisms on EFV concentrations may be different in children because of differences in liver maturation and drug dosage.


METHODS
The CYP2B6-G516T polymorphisms were analyzed in 71 HIV-1-infected children receiving highly active antiretroviral therapy (HAART) containing EFV for >or=6 months. EFV pharmacokinetics, toxicity profiles, and viral resistance data were also evaluated.


RESULTS
The median oral clearance (CL/F) rate was significantly lower in children with the CYP2B6-516-T/T genotype (3.0 L/h/m2, n=13) than in children with the G/T genotype (5.7 L/h/m2, n=30; P=0.02) or the G/G genotype (7.0 L/h/m2, n=31; P=0.003). In children with the CYP2B6-516-G/G genotype, which is associated with higher expression of hepatic CYP2B6, the clearance rate was significantly higher in younger children (<5 years of age) than in older children (>or=5 years of age) (9.7 L/h/m2 vs. 6.6 L/h/m2; P=0.03). No association was found between CYP2B6-G516T polymorphisms and virologic or immunologic responses, toxicity, or the development of viral resistance against EFV.


CONCLUSIONS
CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.
Saitoh
Akihiko
A
Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0672, USA. asaitoh@ucsd.edu
Fletcher
Courtney V
CV
Brundage
Richard
R
Alvero
Carmelita
C
Fenton
Terrence
T
Hsia
Karen
K
Spector
Stephen A
SA
D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics
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