2010 - Berlin - Germany

PAGE 2010: Applications- CVS
Sergej Ramusovic

An integrated whole-body physiology based pharmacokinetic/pharmacodynamic model of enalapril and the RAA-system

Ramusovic, S.(1), Willmann, S.(2), Frobel, A.-K.(1), Laeer, S.(1)

(1) Department of Clinical Pharmacy and Pharmacotherapy, University of Duesseldorf, Germany, (2) 2Competence Center Systems Biology, Bayer Technology Services GmbH (BTS), 51368 Leverkusen, Germany 2Competence Center Systems Biology, Bayer Technology Services GmbH (BTS), 51368 Leverkusen, Germany

Objectives: Integrated physiology based (PB) modelling could provide comprehensive platforms to simulate the mechanistic interactions between the pharmakokinetic and pharmacodynamic behavior of a drug. Here, we built a physiology based model of intravenous enalaprilate (Enaat) and oral enalapril (Ena) application to study their effect the RAA-system.

Methods: First, a PBPK model of Ena and its conversion metabolite enalaprilate (Enaat) was developed in PK-SIM (v. 4.1, BTS) and the software MoBi (v. 2.2, BTS). Then, using MoBi, the pharmacodynamic RAA-system model (PD) was built. In both models literature data on biomarker concentrations, enzymatic and drug specific parameters were used. Missing parameters were obtained by fitting procedures using MATLAB (v. R2008b). Resulting PK and PD models were merged in MoBi. The final model then served as the basis for simulations and comparison to literature data.

Results: The final model encompasses hepatic/intrarenal conversion of Ena to Enaat, Enaat binding to ACE, urinary excretion of Ena and Enaat, generation and degradation of RAA components including angiotensin (Ang)1, Ang2, renin and the negative feedback of Ang2 on renin production. The simulations (Sim) provide a description of the literature data on plasma concentration time profiles of Ena and Enaat [1,2], their fractional urinary excretion after intravenous (Enaat: after 1440 min 86.65% Sim, 85.5 ±13.5% data [3]) and oral application (Ena: 24.29% after 4320 min Sim, 19.87% data; Enaat: 34.37% after 4320 min Sim, 30.41% data [4]) as well as Ang1 and Ang2 concentrations [5] after oral Ena application.

Conclusions: Coupling a PB model of Ena pharmacokinetics and a PB pharmacodynamic model of the RAA-system, we were able to develop an integrated whole body PBPKPD model of intravenous Ennat and oral Ena application that describes plasma concentrations of Ena, Enaat, Ang1 and Ang2 as well as urinary excretion data of Ena and Enaat. The modular nature of this model allows for expansion to other drugs and further investigation of PBPK and PBPD relationships.

[1] Naji NM. Biopharmaceutics & drug disposition 2003;24(7):315–20 [2] Hockings N. BJCP 1986;21(4):341–8 [3] Vlasses PH. Clinical pharmacy;4(1):27–40 [4] Rippley RK. Biopharmaceutics & drug disposition 2000;21(9):339–44 [5] Juillerat L. Hypertension 1990;16(5):564–72

Reference: PAGE 19 (2010) Abstr 1865 [www.page-meeting.org/?abstract=1865]
Poster: Applications- CVS