CYP3A4*22 (c.522-191 C>T; rs35599367) is associated with lopinavir pharmacokinetics in HIV-positive adults : Pharmacogenetics and Genomics

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CYP3A4*22 (c.522-191 C>T; rs35599367) is associated with lopinavir pharmacokinetics in HIV-positive adults

Olagunju, Adeniyi*,a,b; Schipani, Alessandro*,a; Siccardi, Marcoa; Egan, Deirdrea; Khoo, Sayea; Back, Davida; Owen, Andrewa

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Pharmacogenetics and Genomics 24(9):p 459-463, September 2014. | DOI: 10.1097/FPC.0000000000000073


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.

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

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