Clinical Pharmacokinetics and Pharmacodynamics of Dalcetrapib

Abstract

The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.

Fig. 1

Primary metabolic route of dalcetrapib. DTT dithiothreitol, NEM N-ethylmaleimide

Fig. 2

Model-predicted dalcetrapib clearance for individual subjects by genotype. The horizontal line represents the overall median of 606 subjects from the dal-OUTCOMES study (AA = 99 subjects, AG = 283 subjects, GG = 224 subjects) [data derived from dal-Outcomes [11, 12] but were not part of the published analysis]. CL clearance