title: Population pharmacokinetics of atorvastatin and its active metabolites in children and adolescents with heterozygous familial hypercholesterolemia: selective use of informative prior distributions from adults.
abstract: The population pharmacokinetics (PPK) of atorvastatin and its principal active metabolite, o-hydroxyatorvastatin, were described in 6-17 years old pediatric hypercholesterolemia patients with a 2-compartment model for both parent and metabolite. Informative prior distributions on selected parameters, based on adult data, were required to stabilize the model and were implemented using a Bayesian penalty term on the likelihood function in the nonlinear mixed effects model (NONMEM VI with PRIOR). Concentrations below the limit of quantitation were treated as censored data using a conditional likelihood function. Atorvastatin apparent oral clearance (CL/F) was described as a function of body weight using an allometric equation. Based on the final model, the typical CL/F estimates for a Tanner Stage 1 patient (35 kg weight) and Tanner Stage ≥2 (50 kg weight), would be 553 and 543 L/hour, respectively. When scaled allometrically, CL/F was similar to values reported for adults. Variability in atorvastatin PK was primarily affected by weight.
authors: Metrum Research Group LLC, Tariffville, CT 06081, USA.
authors: William
authors: W
authors: Knebel
authors: Marc R
authors: MR
authors: Gastonguay
authors: Bimal
authors: B
authors: Malhotra
authors: Ahmed
authors: A
authors: El-Tahtawy
authors: Frank
authors: F
authors: Jen
authors: Kuan
authors: K
authors: Gandelman
mesh_terms: D000293:Adolescent; D000328:Adult; D000069059:Atorvastatin / Q000031:analogs & derivatives; D002648:Child; D006538:Heptanoic Acids / Q000378:metabolism / Q000493:pharmacokinetics*; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism*; D008954:Models, Biological; D011758:Pyrroles / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; C518964:4-hydroxyatorvastatin; D000069059:Atorvastatin