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.
Subject(s)
Heptanoic Acids/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Models, Biological , Pyrroles/pharmacokinetics , Atorvastatin , Azetidines/pharmacokinetics , Azetidines/pharmacology , Cholesterol, LDL/blood , Drug Therapy, Combination , Ezetimibe , Heptanoic Acids/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Meta-Analysis as Topic , Pyrroles/pharmacology , Therapeutic EquivalencyABSTRACT
Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.