Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics

Research output: Contribution to journalArticle

Authors

  • Jonathan B Wagner
  • Susan Abdel-Rahman
  • Leon Van Haandel
  • Andrea Gaedigk
  • Roger Gaedigk
  • Geetha Raghuveer
  • Ralph Kauffman
  • J. Steven Leeder

External Institution(s)

  • Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation
  • University of Missouri at Kansas City
  • Ward Family Heart Center

Details

Original languageEnglish (US)
Pages (from-to)823-833
Number of pages11
JournalJournal of Clinical Pharmacology
Volume58
Issue number6
StatusPublished - Jun 1 2018
Peer-reviewedYes

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.

    Research areas

  • cholesterol, lipids, pediatrics, pharmacogenomics, pharmacokinetics, statin

Citation formats

APA

Wagner, J. B., Abdel-Rahman, S., Van Haandel, L., Gaedigk, A., Gaedigk, R., Raghuveer, G., ... Leeder, J. S. (2018). Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics. Journal of Clinical Pharmacology, 58(6), 823-833. https://doi.org/10.1002/jcph.1080

Harvard

Wagner, JB, Abdel-Rahman, S, Van Haandel, L, Gaedigk, A, Gaedigk, R, Raghuveer, G, Kauffman, R & Leeder, JS 2018, 'Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics', Journal of Clinical Pharmacology, vol. 58, no. 6, pp. 823-833. https://doi.org/10.1002/jcph.1080