Abstract
PurposePoor adherence to dietary/behaviour modifications as interventions for hypercholesterolemia in paediatric patients often necessitates the initiation of statin therapy. The aim of this study was to develop a joint population pharmacokinetic model for simvastatin and four metabolites in children and adolescents to investigate sources of variability in simvastatin acid exposure in this patient population, in addition to SLCO1B1 genotype status.MethodsPlasma concentrations of simvastatin and its four metabolites, demographic and polymorphism data for OATP1B1 and CYP3A5 were analysed utilising a population pharmacokinetic modelling approach from an existing single oral dose (10 mg < 17 years and 20 mg ≥ 18 years) pharmacokinetic dataset of 32 children and adolescents.ResultsThe population PK model included a one compartment disposition model for simvastatin with irregular oral absorption described by two parallel absorption processes each consisting of sequential zero and first-order processes. The data for each metabolite were described by a one-compartment disposition model with the formation and elimination apparent parameters estimated. The model confirmed the statistically significant effect of c.521T>C (rs4149056) on the pharmacokinetics of the active metabolite simvastatin acid in children/adolescents, consistent with adult data. In addition, age was identified as a covariate affecting elimination clearances of 6-hydroxymethyl simvastatin acid and 3, 5 dihydrodiol simvastatin metabolites.ConclusionThe model developed describes the pharmacokinetics of simvastatin and its metabolites in children/adolescents capturing the effects of both c.521T>C and age on variability in exposure in this patient population. This joint simvastatin metabolite model is envisaged to facilitate optimisation of simvastatin dosing in children/adolescents.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Simvastatin (SV) is a 3-hydroxy-3methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor licensed for the treatment of lipid disorders including hypercholesterolemia [1]
SV pharmacokinetics (PK) is complex; it is administered as an inactive lactone prodrug that is converted to the active form simvastatin acid (SVA) by hydrolysis or enzymatically by carboxylesterases and by paraoxonases in plasma [5, 6]
Apparent parameters for the formation and elimination of SV and the metabolites were described by first-order processes using a onecompartment model
Summary
Simvastatin (SV) is a 3-hydroxy-3methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor licensed for the treatment of lipid disorders including hypercholesterolemia [1]. Simvastatin is considered to be safe and well tolerated; skeletal muscle toxicity, ranging from myalgia to rhabdomyolysis, can lead to significant morbidity and mortality [4]. SV pharmacokinetics (PK) is complex; it is administered as an inactive lactone prodrug that is converted to the active form simvastatin acid (SVA) by hydrolysis or enzymatically by carboxylesterases (in the liver and small intestine) and by paraoxonases in plasma [5, 6]. SVA can be converted back to SV via an acyl-glucuronide intermediate. In adults, both SV and SVA are extensively metabolised by CYP3A4/5
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