SLCO1B1 Genetic Variation Influence on Atorvastatin Systemic Exposure in Pediatric Hypercholesterolemia

Creator(s)

Jonathan B. Wagner, Children's Mercy HospitalFollow
Susan Abdel-Rahman
Geetha Raghuveer, Children's Mercy HospitalFollow
Andrea Gaedigk, Children's Mercy Kansas CityFollow
Erin C. Boone, Children's Mercy HospitalFollow
Roger Gaedigk
Vincent S. Staggs
Gregory A. Reed
Na Zhang
J Steven Leeder, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

1-15-2024

Identifier

DOI: 10.3390/genes15010099

Abstract

This clinical study examined the influence of SLCO1B1 c.521T >C (rs4149056) on plasma atorvastatin concentrations in pediatric hypercholesterolemia. The participants (8-21 years), including heterozygous (c.521T/C, n = 13), homozygous (c.521C/C, n = 2) and controls (c.521T/T, n = 13), completed a single-oral-dose pharmacokinetic study. Similar to in adults, the atorvastatin (AVA) area-under-concentration-time curve from 0 to 24 h (AUC_0-24) was 1.7-fold and 2.8-fold higher in participants with c.521T/C and c.521C/C compared to the c.521T/T participants, respectively. The inter-individual variability in AVA exposure within these genotype groups ranged from 2.3 to 4.8-fold, indicating that additional factors contribute to the inter-individual variability in the AVA dose-exposure relationship. A multivariate model reinforced the SLCO1B1 c.521T >C variant as the central factor contributing to AVA systemic exposure in this pediatric cohort, accounting for ~65% of the variability in AVA AUC_0-24. Furthermore, lower AVA lactone concentrations in participants with increased body mass index contributed to higher exposure within the c.521T/T and c.521T/C genotype groups. Collectively, these factors contributing to higher systemic exposure could increase the risk of toxicity and should be accounted for when individualizing the dosing of atorvastatin in eligible pediatric patients.

Journal Title

Genes (Basel)

Volume

15

Issue

1

First Page

99

MeSH Keywords

Adult; Humans; Child; Hypercholesterolemia; Atorvastatin; Genotype; Heterozygote; Genetic Variation; Liver-Specific Organic Anion Transporter 1

Keywords

cholesterol; lipids; pediatrics; pharmacogenomics; pharmacokinetics; statins

Comments

Grants and funding

• KL2TR002367/TR/NCATS NIH HHS/United States

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Publisher's Link: https://www.mdpi.com/2073-4425/15/1/99

Recommended Citation

Wagner JB, Abdel-Rahman S, Raghuveer G, et al. SLCO1B1 Genetic Variation Influence on Atorvastatin Systemic Exposure in Pediatric Hypercholesterolemia. Genes (Basel). 2024;15(1):99. Published 2024 Jan 15. doi:10.3390/genes15010099