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De la dose à l'effet clinique : utilisation de la modélisation dans les différentes étapes du processus de prédiction du critère clinique : Exemple avec un nouveau médicament en prévention secondaire de la morbidité-mortalité cardiovasculaire

Abstract : Epidemiological data demonstrate an inverse correlation between HDL-cholesterol (HDL-C) levels and cardiovascular risk. Therefore, drugs as cholesteryl ester transfer protein (CETP) inhibitors that lead to a significant HDL-C increase are believed to reduce the occurrence of coronary events. We aimed to evaluate the clinical efficacy of one CETP inhibitor, dalcetrapib, by using various modeling techniques while only pharmacokinetic (PK) and pharmacodynamlc (PD) data were available. First, we analyzed individual data from dyslipidemic patients using a population approach in order to establish the PK/PD relationship between dalcetrapib concentrations and HDL-C change. The results show that an average raise of 26.4 % is expected in comparison to placebo with the 5th (P5) and 95th (P95) percentile of the mean average at 20.7 % and 31.9 % respectively. The increase in HDL-C is explained by a delayed catabolism following the transfer inhibition of cholesterol ester from HDL to Apo-B rich lipoproteins. We endeavored then to correlate HDL-C increase to coronary events by using a meta-regression analysis on randomized trials that evaluated the clinical efficacy of main dyslipidemic drugs on coronary events in secondary prevention. The modeling did not show a statistical association between HDL-C change (P5-P95:-3.0 and 36 %) and coronary risk reduction. A sensitivity analysis by drug class suggests that the same HDL-C increase resulting from different mechanisms of action may not impact the cardiovascular risk in the same way. This would indicate that HDL-C could not be used as a risk marker since it might not be an independent predictor of cardiovascular risk
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Submitted on : Wednesday, April 16, 2014 - 3:19:25 PM
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Florence Hourcade-Potelleret. De la dose à l'effet clinique : utilisation de la modélisation dans les différentes étapes du processus de prédiction du critère clinique : Exemple avec un nouveau médicament en prévention secondaire de la morbidité-mortalité cardiovasculaire. Médecine humaine et pathologie. Université Jean Monnet - Saint-Etienne, 2012. Français. ⟨NNT : 2012STET003T⟩. ⟨tel-00979667⟩

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