Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics

Journal of Clinical Pharmacology
Jonathan B WagnerJ Steven Leeder

Abstract

This study investigated the impact of allelic variation in SLCO1B1, a gene encoding for the liver-specific solute carrier organic anion transporter family member 1B1 protein (SLCO1B1), on simvastatin and simvastatin acid (SVA) systemic exposure in children and adolescents. Participants (8-20 years old) with at least 1 variant SLCO1B1 c.521T>C allele (521TC, n = 15; 521CC, n = 2) and 2 wild-type alleles (521TT, n = 15) completed a single oral dose pharmacokinetic study. At equivalent doses, SVA exposure was 6.3- and 2.5-fold greater in 521CC and TC genotypes relative to 521TT (Cmax, 2.1 ± 0.2 vs 1.0 ± 0.5 vs 0.4 ± 0.3 ng/mL; P < .0001; and AUC, 12.1 ± 0.3 vs 4.5 ± 2.5 vs 1.9 ± 1.8 ng·h/mL; P < .0001). The impact of the SLCO1B1 c.521 genotype was more pronounced in children, although considerable interindividual variability in SVA exposure was observed within genotype groups. In addition, SVA systemic exposure was negligible in 25% of pediatric participants. Further investigation of the ontogeny and genetic variation of SVA formation and SLCO1B1-mediated hepatic uptake is necessary to better understand the variability in SVA exposure in children and its clinical consequences.

Associated Clinical Trials

Feb 11, 2015·Jon Wagner

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Citations

Apr 11, 2019·Clinical Pharmacology and Therapeutics·Jonathan B Wagner
Dec 15, 2018·Clinical Pharmacology and Therapeutics·Jonathan B WagnerJ Steven Leeder
Aug 23, 2019·Journal of Clinical Pharmacy and Therapeutics·Zi-Wan GuanYan Li
Jun 7, 2019·European Journal of Clinical Pharmacology·Kayode OgungbenroAleksandra Galetin
Jan 26, 2020·Clinical and Translational Science·Jonathan B WagnerJ Steven Leeder
Aug 25, 2020·Current Opinion in Pediatrics·Uma Ramaswami, Steve E Humphries
Jul 10, 2019·Annual Review of Pharmacology and Toxicology·Laura B RamseySara L Van Driest
Jul 31, 2020·Expert Opinion on Drug Metabolism & Toxicology·Takeshi HirotaIchiro Ieiri
Oct 8, 2020·Scandinavian Journal of Rheumatology·J RoszkiewiczE Smolewska
Oct 14, 2020·Clinical and Translational Science·Timothy A RobertsStephani L Stancil
Sep 7, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jonathan B WagnerBruno Hagenbuch
Dec 15, 2020·JAMA Network Open·Laura B RamseyUNKNOWN IGNITE Pharmacogenetics Working Group
Apr 7, 2021·Drug Metabolism Reviews·Laura E RussellVolker M Lauschke
Apr 8, 2021·Pediatric Research·Sonya C Tang GirdwoodLaura B Ramsey
Mar 19, 2021·British Journal of Clinical Pharmacology·Brian D ChapronJ Steven Leeder
Jun 15, 2021·Clinical and Translational Science·Zachary L TaylorLaura B Ramsey

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