Preliminary Population PK-PD of Dalcetrapib: an Agent Targeting CETP to Raise HDL-C and Prevent Cardiovascular Morbidity and Mortality
F. Hoffmann-La Roche Ltd, Basel, Switzerland
Background: In a meta-analysis, after 1 year of statin treatment, a 23% reduction in the incidence of 1st major coronary events was observed per mmol/L reduction in LDL-C. However, despite standard of care, substantial residual cardiovascular (CV) risk remains. A strategy to further decrease CV risk is to increase HDL-C levels, by reducing activity of cholesteryl ester transfer protein (CETP). Dalcetrapib effectively decreased CETP activity, increased HDL-C, and was generally well tolerated in Phase II studies; the dal-OUTCOMES study to assess the effect of dalcetrapib on CV outcomes is ongoing.
Objectives: A PK-PD analysis to characterize the effect of exposure to dalcetrapib on levels of HDL-C as a function of CETP activity.
Methods: Data were obtained from a phase II randomized study in which patients received dalcetrapib 300, 600 or 900 mg/day or placebo, in combination with pravastatin 40 mg for 12 weeks (84 days). PK evaluations were performed on trough samples (before dosing) on days 14, 28, 56, 81 and between 1.5-5 hours post-dose on day 84. HDL-C levels and CETP activity were measured in trough samples during pre-randomization, on days 0 (baseline), 14, 28, 56 and 84, and at follow-up on day 112. A population PK-PD analysis was performed using NONMEM VI and a sequential PK-PD approach. First, a model describing the cascade of events i.e. dose-exposure-CETP activity-HDL-C was developed. Thereafter, a simplified model of dose-exposure-HDL-C was developed to investigate if change in HDL-C level could be predicted directly from drug exposure data.
Results: An effect compartment model was used to describe the drug exposure-CETP activity relationship. The relationship between CETP activity and HDL-C level was described using an indirect type II ‘turnover' model incorporating an inhibition Emax model with a baseline. The relationship between drug exposure and HDL-C (omitting CETP) was also described using an indirect type II ‘turnover' model incorporating an inhibition Emax model with a baseline. Full covariate analysis was not performed. The diagnostic plots and posterior predictive check showed that both models described the data adequately.
Conclusions: Using the empirical models described here, exposure data can be used to predict CETP activity decreases and HDL-C increases caused by dalcetrapib treatment. The model describing HDL-C as a function of exposure could be used to describe dalcetrapib-induced HDL-C changes where CETP activity is not measured.
 Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-1278