Prediction of clinical irrelevance of PK differences in atorvastatin using PK/PD models derived from literature-based meta-analyses

Clin Pharmacol Ther. 2014 Jul;96(1):101-9. doi: 10.1038/clpt.2014.66. Epub 2014 Mar 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atorvastatin
  • Azetidines / pharmacokinetics
  • Azetidines / pharmacology
  • Cholesterol, LDL / blood
  • Drug Therapy, Combination
  • Ezetimibe
  • Heptanoic Acids / pharmacokinetics*
  • Heptanoic Acids / pharmacology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Meta-Analysis as Topic
  • Models, Biological*
  • Pyrroles / pharmacokinetics*
  • Pyrroles / pharmacology
  • Therapeutic Equivalency

Substances

  • Azetidines
  • Cholesterol, LDL
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrroles
  • Atorvastatin
  • Ezetimibe