J.G.C. van Hasselt (1), M.L. Rizk (2), S.A.G. Visser (2), T. Kerbusch (2), M. Danhof (1), P.H. van der Graaf (1)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands. (2) Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, New Jersey, USA
Objectives: In this project, we aim to develop a model-based framework that combines PBPK models for the prediction of target-site concentration with PK-PD models that describe the bacterial exposure-response relationships in order to predict clinical response. We will use carbapenem antibiotics (imipenem and ertapenem) as proof-of-concept compounds.
This poster describes the conceptual approach of the project and discusses potential challenges and opportunities of an integrated model-based framework that will take into account key physiological and pharmacological factors that are closely related to treatment efficacy, and which may be potentially of relevance to support the clinical development of antibiotic agents.
Methods: As first step, we aim to develop a physiologically-based pharmacokinetic (PBPK) model for ertapenem and imipenem in humans that can be applied to predict tissue-site concentrations [1] at potential infection sites. Previously reported tissue concentration-time curves for ertapenem and imipenem will be used to evaluate predictions of the developed PBPK models. Subsequently, we will develop a series of pharmacokinetic-pharmacodynamic (PK-PD) models [2] based on in vitro time kill experiments that describe the dynamics of antibiotic exposure-response relationships of ertapenem and imipenem for a number of clinically relevant bacterial strains.
Application: The integrated PBPK-PD framework will be used to address two key challenges in antibiotic drug development. First, we aim to evaluate the relevance of using a PBPK-PD modeling approach that takes into account local tissue concentrations and the full dynamics of antibiotic drug action, in comparison to conventional plasma-concentration based PK-PD indices. Subsequently the PBPK-PD models will be embedded in a clinical trial simulation (CTS) framework. This framework will first be applied to evaluate the predictions of clinical response according to the characteristics (trial design, patient population) of pivotal trials for ertapenem and imipenem. Thereafter, we will evaluate the CTS framework for its value to support informative clinical trial design.
References
[1] Liu P, Derendorf H. Antimicrobial tissue concentrations. Infect. Dis. Clin. North Am. 2003 Sep;17(3):599–613.
[2] Nielsen EI, Friberg LE. Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs. Pharmacol. Rev. 2013;65:1053–90.
Reference: PAGE 23 (2014) Abstr 3013 [www.page-meeting.org/?abstract=3013]
Poster: Drug/Disease modeling - Infection