Nathalie Perdaems
Technologie Servier
Objectives: To apply a translational modeling approach to help the first in man. A reflex tachycardia was observed in rats due to the decrease of the blood pressure, so the administration of a modified release formulation in human is discussed in order to limit this increase of heart rate.
Methods: Interrelationship between blood pressure, cardiac output and total peripheral resistance have already been described in the literature using mechanism-based models [1, 2, 3]. A simple mechanism-based model was developped in pigs to describe the relationship between blood pressure and heart rate in order to describe the reflex tachycardia due to the decrease of blood pressure. The mechanism-based model approach will then be applied to other species (at least human). A population PK model was developped in pigs after IV administration. Two baseline models were developped for the blood pressure and the heart rate in pigs. A PKPD model taking into account the baseline of blood pressure and the effect of the S compound on the blood pressure was developped. The PKPDPD (PKPD model and interrelationship between blood pressure and heart rate) model is still under development. This PKPD model was first developped in pigs and will then be transposed into other species and human. Then, the effect of the absorption rate of the drug will be tested in order to limit the reflex tachycardia in human.
Results: The population PK model, the baseline models (for blood pressure and heart rate) and the PKPD model were developed in pigs.
Conclusions: One model to group together all the models is still in development in pigs. Then this PKPD model will be transposed into other species and human in order to help the development of a modified release formulation.
References:
[1] Snelder N. and al. PKPD modeling of the interrelationship between mean arterial blood pressure, cardiac output and total peripheral resistance in conscious rats. British Journal of Pharmacology. 2013, 169: 1510-24.
[2] Francheteau P. and al. A mathematical model for dynamics of cardiovascular drug action: application to intravenous dihydropyridines in healthy volunteers. Journal of Pharmacokinetics and biopharmaceutics. 1993, 21; 5: 489-514.
[3] Albaghdadi M. Baroreflex control of long-term arterial pressure. Rev Bras Hipertens. 2007, 14; 4: 212-25.
Reference: PAGE 23 (2014) Abstr 3079 [www.page-meeting.org/?abstract=3079]
Poster: Drug/Disease modeling - Other topics