PII-115 - PHARMACOMETABOLOMICS OF STATIN DISPOSITION AND RESPONSE IN CHILDREN.

J. Wagner¹, G. Raghuveer¹, V. Shakhnovich^1,2,3; ¹Children's Mercy Kansas City, Kansas City, MO, USA, ²University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA, ³Center for Children's Healthy Lifestyles and Nutrition, Kansas City, MO, USA.

Background: Our recent pediatric pharmacokinetic (PK) study reported variable systemic drug exposures for atorvastatin (AVA) and rosuvastatin (RVA) based on SLCO1B1 genotype. The objective herein was to evaluate what effect genotype may have on metabolomic pharmacodynamic (PD) markers for statins.

Methods: Pre- and post-dose plasma samples from our AVA and RVA (n=28, age 9.8-21.3yr) SLCO1B1 c.521 T>C genotype-stratified single dose PK studies were analyzed on a Waters ACQUITY triple quadrupole tandem mass spectrometer (MS) with a novel ultra-high pressure liquid chromatography-tandem MS method validated at Metabolon©. Matched Pairs and Welch’s two-sample t-test were used to identify biochemicals that differed significantly between experimental groups. Statistical significance was set at (p≤0.05) and a false discovery rate at q < 0.10.

Results: A total of 1071 compounds of known identity were quantitated. Compared to pre-dose samples, cholesterol was not reduced after AVA or RVA dosing, nor was there an SLCO1B1 genotype effect. Post-drug administration, there was a significant 1.5 to 2-fold decrease in many fatty acids, with a significantly greater reduction of some in the reference TT genotype group compared to TC/CC (p < 0.05). 3 to 5-fold higher primary bile acid concentration (glycochenodeoxycholate and glycocholate glucuronides) was observed in the SLCO1B1 TC/CC group both pre and post-dose (p < 0.05).

Conclusion: Consistent with studies in adults, cholesterol was not significantly altered in children based on SLCO1B1 genotype. However, attenuated reduction in fatty acids was observed in SLCO1B1 TC/CC individuals and warrants further investigation. Higher concentrations of primary bile acids, especially in pre-dose samples, suggests their candidacy as a phenotypic OATP1B1 biomarker.

Wagner JB, Rahman S, Gaedigk A, Gaedigk R, Raghuveer G, Staggs VS, Van Haandel L, Leeder JS. “Impact of SLCO1B1 genetic variation on rosuvastatin systemic exposure in pediatric hypercholesterolemia.” Clin Transl Sci. 2020 May;13(3):628-637. doi:10.111/cts.12749 [Epub ahead of print]. PMID 31981411.