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Impact of Genetic Variation on Pravastatin Systemic Exposure in Pediatric Hypercholesterolemia
Author(s) -
Wagner Jonathan B.,
AbdelRahman Susan,
Gaedigk Roger,
Gaedigk Andrea,
Raghuveer Geetha,
Staggs Vincent S.,
Kauffman Ralph,
Van Haandel Leon,
Leeder J. Steven
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1330
Subject(s) - pravastatin , genotype , medicine , pharmacokinetics , cohort , pharmacology , gastroenterology , gene , biology , genetics , cholesterol
This study investigated the impact of SLCO 1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8–20 years) with at least one allelic variant of SLCO 1B1 c.521T>C (521 TC , n = 15; 521 CC , n = 2) and wild‐type controls (521 TT , n = 15) completed a single oral dose pharmacokinetic study. Interindividual variability of pravastatin acid ( PVA ) exposure within SLCO 1B1 genotype groups exceeded the approximately twofold difference in mean PVA exposure observed between SLCO 1B1 genotype groups ( P > 0.05, q > 0.10). The 3′α‐iso‐pravastatin acid and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO 1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable to previous studies in adults. However, other demographic and physicochemical factors seem to also contribute to interindividual variability in the dose–exposure relationship.