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   Paris, France

Simulations using a mechanistic DDI model: individual risk assessment.

Christian Laveille, PharmD (1), Lewis Sheiner, MD (2), Vincent Duval, PharmD (1), Guillemette Resplandy, PhD (1), and Roeline Jochemsen, PhD (1)

(1)Institut de Recherches Internationales Servier, Courbevoie, France; (2)University of California San Francisco, USA

S 16257 is a selective heart rate reducing agent which is developed for the treatment of stable angina pectoris. It is extensively metabolized by a single enzyme, cytochrome P450 3A4 (CYP 3A4), resulting in the formation of an active metabolite, S 18982, also metabolized by the CYP 3A4. Using pharmacokinetic studies in healthy volunteers, a population mechanistic drug-drug interaction (DDI) model was built, derived from Piotrovskij and Van Peer (Pharm Res, 1997). During these phase I studies the parent drug (S 16257) or the active metabolite (S 18982) were administrated by intravenous or oral route, without and with co-administration of substrates and/or inhibitors of the CYP 3A4 (grapefruit juice, verapamil, ketoconazole and josamycin) and all available concentrations (plasma and urine) were used to characterize this population DDI model.

Concurrently, heart rate was measured at rest and during bicycle exercise tolerance tests (ETT). The starting workload was usually 50 Watts and then it was increased by 25/50 Watts every 3 minutes for a total duration of 9/12 minutes. A population PK/PD model was defined taking into account both the concentrations of S 16257 and S 18982 as well as all measured heart rates independently of the workload (from 0 (at rest) to 200 Watts).

After qualification of the different models, it is quite straightforward to predict the population response after administration of substrates and/or inhibitors of the CYP 3A4 in combination with S 16257 or S 18982. However in the case of DDI, the risk of reaching higher exposure is possible in some patients. The evaluation of such patients is important since strong CYP 3A4 inhibitors would be considered for co-administration with S 16257.

After definition of a cardiac safety criterion (for example heart rate at rest below 45 bpm) and software implementation, simulations were performed in order to assess the individual risk which could involve a dose adjustment.