title: CYP3A4*22 (c.522-191 C>T; rs35599367) is associated with lopinavir pharmacokinetics in HIV-positive adults.
abstract: The CYP3A4*22 (c.522-191 C>T; rs35599367) single nucleotide polymorphism has been associated with lower CYP3A4 mRNA expression and activity. We investigated the association of CYP3A4*22 with the pharmacokinetics of lopinavir through a population pharmacokinetic approach. The minor allele frequency for CYP3A4*22 was 0.035, and seven of 375 patients had a combination of CYP3A4*22 and SLCO1B1 521T>C alleles. Lack of information on the ethnicity in this cohort should be considered as a limitation. However, in the final model, the population clearance was 5.9 l/h and patients with CYP3A4*22/*22 had 53% (P=0.023) lower clearance compared with noncarriers. In addition, the combined effect of CYP3A4*22 with SLCO1B1 521T>C (previously shown to be associated with lopinavir plasma concentration) was analysed. We observed a 2.3-fold higher lopinavir trough concentration (Ctrough) in individuals with CYP3A4*22/*22, a 1.8-fold higher Ctrough with SLCO1B1 521CC and a 9.7-fold higher Ctrough in individuals homozygous for both single nucleotide polymorphisms, compared with noncarriers. A simulated dose-reduction scenario showed that 200/100 mg lopinavir/ritonavir was adequate to achieve therapeutic concentration in individuals with CYP3A4*22/*22 alone or in combination with SLCO1B1 521CC. These data further our understanding of the genetic basis for variability in the pharmacokinetics of lopinavir.
authors.affiliation: aDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK bFaculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Adeniyi
authors.initials: A
authors.lastname: Olagunju
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Deirdre
authors.initials: D
authors.lastname: Egan
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; 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; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D017320:HIV Protease Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D061466:Lopinavir; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human