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Clinical Trial Simulation Using Therapeutic Effect Modeling: Application to Ivabradine Efficacy in Patients with Angina Pectoris

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Abstract

Ivabradine is a new bradycardic agent with a potential indication for stable angina pectoris. To investigate the best compromise between efficacy, safety, drug regimen, and number of patients to include in a phase III study, we conducted Monte Carlo simulations using a full therapeutic model. The binary clinical outcome, chest pain, was simulated using a physiologic model in which the coronary reserve was derived from the heart rate. Safety was defined as being heart rate dependent. Using real data to build a pharmacokinetic–pharmacodynamic model controlling drug effect (i.e., heart rate decrease), and resampling heart rate profiles from the database, 100 clinical trials (N=200) were simulated for five oral doses (2.5, 5, 10, 20, and 40 mg QD or BID) of ivabradine. Only 25% of the simulated trials showed a significant effect of ivabradine with doses up to 10 mg QD, and 48 and 55% of the trials with doses of 10 mg BID and 20 mg QD, respectively, and more than 80% of the trials with a 40 mg daily dose. For safety, 4% of patients had at least one adverse event in the untreated group, and from 5 to 13% in the treated groups for the lowest to the highest dose, respectively. The number of subjects to include in a future trial to obtain a 15% decrease in chest pain under the assumption of a 68% base risk, is 239 subjects per group with 10 mg BID or 196 with 20 mg QD. These results illustrate how clinical trial simulations including a PK/PD model as well as a physiopathologic mechanistic model, describing the relationship between the intermediate and clinical endpoint, and the resampling of real patients from a large database can help in designing future phase III trials.

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Authors and Affiliations

  1. Service de Pharmacologie Clinique, EA643, Lyon, France

    Sylvie Chabaud, Pascal Girard, Patrice Nony & Jean-Pierre Boissel

  2. THERapeutic MOdeling and Simulation group, France

    Sylvie Chabaud, Pascal Girard, Patrice Nony & Jean-Pierre Boissel

Authors
  1. Sylvie Chabaud
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  2. Pascal Girard
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  3. Patrice Nony
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  4. Jean-Pierre Boissel
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Correspondence to Sylvie Chabaud.

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Chabaud, S., Girard, P., Nony, P. et al. Clinical Trial Simulation Using Therapeutic Effect Modeling: Application to Ivabradine Efficacy in Patients with Angina Pectoris. J Pharmacokinet Pharmacodyn 29, 339–363 (2002). https://doi.org/10.1023/A:1020953107162

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