title: Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism.
abstract: 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.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0672, USA. asaitoh@ucsd.edu
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saitoh
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
authors.forename: Richard
authors.initials: R
authors.lastname: Brundage
authors.forename: Carmelita
authors.initials: C
authors.lastname: Alvero
authors.forename: Terrence
authors.initials: T
authors.lastname: Fenton
authors.forename: Karen
authors.initials: K
authors.lastname: Hsia
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Spector
mesh_terms: 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
chemical_list: 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