title: CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children.
abstract: OBJECTIVE
  CYP3A5, MDR1 (ABCB1), and OATP1 (SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5 A6986G, ABCB1 (C3435T and G2677T), and SLCO1B1 (T521C and A388AG) polymorphisms on the PK and virologic outcome of lopinavir/ritonavir (LPV/RTV) in HIV-infected children.
  
  
  METHODS
  We conducted a prospective cohort study in children (4-18 years old) on stable antiretroviral therapy with LPV/RTV. CYP3A5, ABCB1, and SLCO1B1 genotypes were determined using polymerase chain reaction amplification with allelic discrimination assays. The 12-hour plasma area under the concentration-time curves (AUC) and clearances (CL) of LPV and RTV were estimated using noncompartmental models. HIV RNA viral load was evaluated every 12 weeks for a total study period of 52 weeks. Analysis of covariance models with adjustment for age and adherence and allometric adjustment of CL were used to assess associations between studied polymorphisms and AUC, CL, and HIV RNA.
  
  
  RESULTS
  Fifty children (median age 11.2 years) were enrolled. Allele frequencies of the genotypes studied were in Hardy-Weinberg equilibrium. There was no statistically significant association between LPV or RTV AUC or CL, and CYP3A5, ABCB1, or SLCO1B1 A388G polymorphisms. There was a significant association between SLCO1B1 T521C genotype and increased LPV AUC (P = 0.042) and a nearly significant association with decreased LPV CL (P = 0.063). None of the studied polymorphisms, including SLCO1B1 T521C, were associated with virologic outcome during 52 weeks of study follow-up.
  
  
  CONCLUSIONS
  There was no statistically significant influence of the CYP3A5, ABCB1, or SLCO1B1 A388AG polymorphisms on the PK and virologic outcome of LPV/RTV in HIV-infected children. SLCO1B1 T521C polymorphism was significantly associated with an increase in LPV AUC but was not associated with undetectable HIV RNA during the study period.
authors: Division of Infectious Diseases, Children's National Medical Center, Washington, DC, USA. nrakhman@cnmc.org
authors: Natella Y
authors: NY
authors: Rakhmanina
authors: Michael N
authors: MN
authors: Neely
authors: Ron H N
authors: RH
authors: Van Schaik
authors: Heather A
authors: HA
authors: Gordish-Dressman
authors: Keetra D
authors: KD
authors: Williams
authors: Steven J
authors: SJ
authors: Soldin
authors: John N
authors: JN
authors: van den Anker
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D061466:Lopinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D061466:Lopinavir; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir