Sulav Duwal (1), Kaveh Pouran Yousef (1), Roland Marquet (2), Max von Kleist (1)
(1) Dep. of Mathematics and Computer Science, Freie Universität Berlin, Germany, (2) Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg, France
Objectives: Nucleoside analogs (NAs) are an important drug class for the treatment of viral infections (HBV, HCV, HSV and HIV) and cancer. They are administered as pro-drugs, which, after intracellular phosphorylation, compete with endogenous nucleotides (dNTP/NTP) for incorporation into nascent DNA/RNA. Incorporated NAs prevent subsequent primer extension by chain termination, which ultimately inhibits replication/proliferation. Plasma- and effect-site pharmacokinetics are usually asynchronous and cell-specific for this inhibitor class, which is also true for the pharmaco-/toxicodynamics, due to their mechanism of action [1,2]. Within this project, we elucidated pharmacokinetic- as well as pharmacodynamic limitations through an integrative systems’ pharmacology modelling approach, which we validated by HIV-1 enzyme kinetics, drug resistance mechanisms and in vivo dynamics following drug application.
Methods: We formulated the underlying dose-response relation of NAs in terms of a mean first-hitting-time model, which could be solved analytically to derive a mechanistic expression for the IC50 value, revealing kinetic, as well as cell-specific parameters of drug efficacy [3]. We used reverse transcriptase kinetic data from known drug resistance patterns in HIV-1 to elucidate the validity of the model. Pharmacokinetic models for prototypic HIV-1 NA inhibitors (NRTIs) were derived to predict clinical effects for this inhibitor class [4].
Results: Our derived model of NA inhibition revealed kinetic, as well as cell-specific parameters of drug efficacy [3]. Kinetic changes induced by drug resistance mutations in HIV-1 made perfect sense in the light of the developed model, which considered their interaction in distinct cellular environments. The pharmacodynamic model revealed that drug inhibition by NAs depended on endogeneous substrate concentrations, as well as concentrations of co-substrates, leading to heterogeneous inhibition and toxicodynamics in distinct target cells/cellular activation states. Plasma- and cellular pharmacokinetics of prototypic HIV-1 inhibitors were then used to predict viral dynamics following drug application in agreement with clinical [4] and ex vivo data [5].
Conclusions: The presented approach allows combining bottom-up and top-down approaches to quantify and elucidate mechanisms of NA drug efficacy. This allows for a more complete picture of drug-interference on the molecular, cellular and whole body level that can be highly useful for drug design.
References:
[1] Cheng YC and Prusoff WH (1973) Biochem Pharm 22: 3099-3103
[2] Swinney DC (2004) Nat Rev Drug Discov 3: 801-808
[3] von Kleist M, Metzner P, Marquet R and Schütte C (2012) PLoS Comp. Biol. 8: e1002359
[4] Duwal S, Schütte C and von Kleist M (2012) PLoS One 7:e40382
[5] Rath B, Yousef KP, Katzenstein DK, Shafer RW, Schütte C, von Kleist M, Merigan TC (2013), submitted
Reference: PAGE 22 () Abstr 2722 [www.page-meeting.org/?abstract=2722]
Poster: New Modelling Approaches