Michael Block (1), Thomas Mrziglod (1), Soundos Saleh (2), Corina Becker, Erich Brendel (2), Rolf Burghaus (2), Jörg Lippert (2).
(1) Bayer Technology Services GmbH, Technology Development, Enabling Technologies, Computational Systems Biology, Leverkusen, Germany; (2) Bayer Pharma AG, Clinical Pharmacometrics, Wuppertal, Germany.
Objectives: Calcium channel blocker (CCB) and Angiotensin II receptor blocker (ARB) have demonstrated their efficacy in reducing blood pressure in patients with mild to moderate essential hypertension [1-7]. The aim of this study was to analyze the pharmacological potency of combinations of Nifedipine and Candesartan by integrating all available relevant study information into a unified and consistent model and to predict the expected clinical endpoint variables for combinations of these drugs. The results of the afterwards performed clinical trial were compared to the prediction of the model and discussed in detail.
Methods: Based on data from literature an analysis of monotherapies of dihydropyridines and ARBs was performed by a “maximum effect approach”. Outcome of this first modeling step was a model-based representation of the pharmacological efficacy following a monotherapeutic treatment of selected CCBs and ARBs separately. In the second step a model was trained to best reflecting the study data including both, monotherapies and combination therapies. This model then was the base for a systematic prediction of the blood pressure reductions and the defined specific clinical endpoints for 20 combinations of Nifedipine and Candesartan (reduction in comparison to Nifedipine monotherapy). The resulting effect matrix for the diastolic and systolic blood pressure reduction was then recalculated to give access to the clinical endpoints.
Results: The model approach resulted in a consistent very accurate representation of both monotherapies and combination therapies for all included CCBs and ARBs. The prediction of combinations for Candesartan and Nifedipine could be performed based on this model and were used for the decision on doses in the clinical trial. As an outcome of the clinical trial the predicted ranges for the clinical endpoints showed a very good agreement with the clinical study, so that the prediction of the endpoints was overall very successful.
Conclusions: A data-based model was developed to predict the blood pressure reduction for Nifedipine and Candesartan combinations. Predictions of blood pressure reductions and clinical endpoints could successfully be made for the different possible combinations of standard doses of Candesartan and Nifedipine. The comparison to the outcome of the later performed clinical trial showed that such model predictions can support the decision making and planning of clinical trials.
References:
[1] Saito I. Saruta T. Hypertens Res. 2006 Oct;29(10):789-96.
[2] Kuschnir E, Bendersky M, Resk J, Pañart MS, Guzman L, Plotquin Y, Grassi G, Mancia G, Wagener G. J Cardiovasc Pharmacol. 2004 Feb;43(2):300-5.
[3] Kloner RA, Weinberger M, Pool JL, Chrysant SG, Prasad R, Harris SM, Zyczynski TM, Leidy NK, Michelson EL. Am J Cardiol. 2001 Mar 15;87(6):727-31.
[4] Littlejohn TW 3rd. Majul CR. Olvera R. Seeber M. Kobe M. Guthrie R. Oigman W. J Clin Hypertens (Greenwich). 2009 Apr;11(4):207-13.
[5] Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. Clin Ther. 2008 Apr;30(4):587-604.
[6] Littlejohn TW 3rd, Majul CR, Olvera R, Seeber M, Kobe M, Guthrie R, Oigman W. Postgrad Med. 2009 Mar;121(2):5-14.
Reference: PAGE 22 () Abstr 2786 [www.page-meeting.org/?abstract=2786]
Poster: Other Drug/Disease Modelling