Abstract 15784: Impact of SLCO1B1 Genotype on Pediatric Simvastatin Pharmacokinetics
Background: Simvastatin (SV) is administered as a lactone prodrug requiring hydrolysis to its active moiety, simvastatin acid (SA), to disrupt hepatic cholesterol biosynthesis. In adults, allelic variation of SLCO1B1 encoding the liver-specific organic anion transporting polypeptide (OATP1B1) drug uptake transporter reduces statin cellular uptake. As a consequence, concentrations at the site of action are lower compromising efficacy and circulating plasma concentrations are increased, placing patients at higher risk for adverse events. Expression of OATPs in mice changes during development, raising the question of whether in humans the genotype-phenotype relationship observed in adults is relevant in the developing child.
Methods: Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521 T>C (521TC; n=12, 521CC; n=2) and wild type controls (521TT; n=12) completed a single oral dose pharmacokinetics (PK) study. SV, SA, and metabolites were quantified by liquid chromatography tandem mass spectrometry. A model-independent PK approach was used to define the peak plasma concentration (Cmax) and area under the curve (AUC) over the sampling period.
Results: At equivalent doses, SA exposure was 6- and 3-fold greater in 521CC and 521TC subjects relative to 521TT (Cmax 2.14 vs. 1.09 vs. 0.39 ng/ml; p=<0.0001 and AUC 12.09 vs. 5.15 vs. 1.86 ng/ml*h; p=<0.0001; Fig. 1). SA formation was decreased and delayed among children compared to existing adult data. Of concern, although SV and metabolites were present, SA concentrations was negligible during the sampling period in 25% of c.521TT participants.
Conclusion: The impact of the SLCO1B1 c.521 gene variants on SA PK was marked in our cohort with a decrease in the rate and extent of SA formation when compared to adults. Further investigation of the ontogeny and genetic variation of SA formation is necessary to better understand the dose-exposure relationship for SA in children beyond SLCO1B1 genotype.
Author Disclosures: J. Wagner: None. S. Abdel-Rahman: None. L. van Haandel: None. A. Gaedigk: None. R. Gaedigk: None. G. Raghuveer: None. R. Kauffman: None. J.S. Leeder: None.
- © 2016 by American Heart Association, Inc.