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Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics

Jonathan B Wagner1,2,3, Susan Abdel-Rahman2,3, Leon Van Haandel2,3

  • 1Ward Family Heart Center, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, MO, USA.

Journal of Clinical Pharmacology
|February 23, 2018
PubMed

Insights

Genetic variations in SLCO1B1 significantly affect simvastatin acid exposure in children and adolescents. Higher variant allele copies led to substantially increased simvastatin acid levels, highlighting genetic influences on drug metabolism.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Pediatric Pharmacology

Background:

  • The SLCO1B1 gene encodes the liver-specific solute carrier organic anion transporter family member 1B1 protein.
  • SLCO1B1 plays a crucial role in the hepatic uptake of various drugs, including statins.
  • Genetic variations in SLCO1B1 can influence drug exposure and efficacy.

Purpose of the Study:

  • To investigate the impact of SLCO1B1 allelic variation on simvastatin and simvastatin acid (SVA) systemic exposure in pediatric and adolescent populations.
  • To determine the relationship between SLCO1B1 c.521T>C genotype and SVA pharmacokinetics.

Main Methods:

  • A pharmacokinetic study involving oral administration of simvastatin to children and adolescents (8-20 years old).
  • Participants were genotyped for the SLCO1B1 c.521T>C polymorphism (521TT, 521TC, 521CC).
  • Systemic exposure of simvastatin acid (SVA) was measured using Cmax and AUC.

Main Results:

  • SVA exposure was significantly higher in individuals with variant SLCO1B1 genotypes (521CC and 521TC) compared to wild-type (521TT).
  • Specifically, SVA Cmax and AUC were 6.3-fold and 2.5-fold greater in 521CC and 521TC genotypes, respectively.
  • The effect of SLCO1B1 genotype was more pronounced in younger children, with considerable interindividual variability observed.

Conclusions:

  • SLCO1B1 c.521T>C genotype is a significant determinant of SVA systemic exposure in pediatric and adolescent populations.
  • The findings underscore the importance of pharmacogenomic considerations in simvastatin therapy for younger individuals.
  • Further research is needed to elucidate the ontogeny of SVA formation and SLCO1B1-mediated uptake to explain variability in SVA exposure.

Keywords:
cholesterollipidspediatricspharmacogenomicspharmacokineticsstatin

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