title: Prediction of clinical irrelevance of PK differences in atorvastatin using PK/PD models derived from literature-based meta-analyses.
abstract: To support the development of a fixed-dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met traditional BE bounds except for atorvastatin peak plasma concentration (Cmax) at two intermediate doses. Literature-based metadata analysis predicted that the observed difference in Cmax between an ezetimibe+atorvastatin FDC and coadministration of these agents translates directly into a non-clinically significant change of <1.2% absolute difference in the percentage lowering of low-density-lipoprotein cholesterol . Both FDC doses were confirmed to be clinically equivalent to coadministration in the subsequent clinical equivalence trials. These data suggest that modeling of dose-response relationships may be useful in predicting clinical equivalence, lowering cost/timelines through effective powering of studies, and predicting the effectiveness of new dosage formulations without the need for additional clinical efficacy trials in regulatory settings.
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, Merck & Co., Whitehouse Station, New Jersey, USA.
authors.forename: R
authors.initials: R
authors.lastname: Vargo
authors.affiliation: Alcon, Fort Worth, Texas, USA.
authors.forename: A
authors.initials: A
authors.lastname: Adewale
authors.affiliation: Clinical Biophamaceutics, Merck & Co., Whitehouse Station, New Jersey, USA.
authors.forename: M O
authors.initials: MO
authors.lastname: Behm
authors.affiliation: Quantitative Solutions, Menlo Park, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mandema
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, Merck & Co., Whitehouse Station, New Jersey, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kerbusch
mesh_terms: D000069059:Atorvastatin; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000097:blood; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D006538:Heptanoic Acids / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D015201:Meta-Analysis as Topic; D008954:Models, Biological; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology; D013810:Therapeutic Equivalency
chemical_list: D001384:Azetidines; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D000069438:Ezetimibe