W.E.A. de Witte, M. Danhof, P.H. van der Graaf, E.C.M. de Lange
Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
Objectives: Drug-target binding kinetics is an important determinant of the time course of target occupancy and low drug-target dissociation rates (koff) are increasingly used as a selection criterion in drug discovery to obtain a prolonged duration of drug action[1–3]. However, drug-target binding can also influence the pharmacokinetics of a drug in blood and at the tissue and cellular level. This interaction is commonly referred to as “Target-Mediated Drug Disposition” (TMDD)[4, 5], “rebinding”[6] or “diffusion-limited binding”. Our objective is to generate a comprehensive understanding into the influence of drug-target binding kinetics on the time course of target occupancy in vivo.
Methods: Available mathematical models provide a basis to predict the change in target occupancy over time, but do not provide a direct insight into the relative contributions of the pharmacokinetic and drug-target binding parameters. Mathematical analysis and simulations on the basis of these models were used to gain insight into the role of drug-target binding kinetics as a determinant of the target occupancy profile. Model simplification was achieved by assuming that the decrease in target occupancy is influenced mostly by the slowest step, which can be dissociation, distribution or elimination.
Results: Our analysis of a one-compartment model with target binding and a two compartment model with target binding in the peripheral compartment demonstrates that the duration of target occupancy can be prolonged by high drug-target association (kon) and low drug distribution rate constants. Moreover, this analysis identifies a number of algebraic expressions that describe the negative log-linear slope of the target occupancy versus time curve and that constitute a basis to identify the rate-limiting step in the decrease of target occupancy.
Conclusions: In contrast to the current focus on koff, optimising the duration of target occupancy should be based on the values of both koff and kon, according to a set of algebraic equations that integrate pharmacokinetics and drug-target binding. We propose the use of the derived negative slope of target occupancy versus time curve for prediction of the duration of target occupancy together with the identification of the rate-limiting step, to inform on the most relevant parameters for drug discovery.
References:
[1] F. Schiele, P. Ayaz, A. Fernández-Montalván, A universal, homogenous assay for high throughput determination of binding kinetics. Anal. Biochem. 468, 42–49 (2014).
[2] S. J. Ramsey, N. J. Attkins, R. Fish, P. H. van der Graaf, Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo. Br. J. Pharmacol. 164, 992–1007 (2011).
[3] G. Dahl, T. Akerud, Pharmacokinetics and the drug-target residence time concept. Drug Discov. Today. 18, 697–707 (2013).
[4] P. Dua, E. Hawkins, P. van der Graaf, A Tutorial on Target-Mediated Drug Disposition (TMDD) Models. CPT Pharmacometrics Syst. Pharmacol. 4, 324–337 (2015).
[5] G. Levy, Pharmacologic target-mediated drug disposition. Clin. Pharmacol. Ther. 56, 248–252 (1994).
[6] G. Vauquelin, S. Bostoen, P. Vanderheyden, P. Seeman, Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism. Naunyn. Schmiedebergs. Arch. Pharmacol. 385, 337–72 (2012).
Reference: PAGE 25 () Abstr 5959 [www.page-meeting.org/?abstract=5959]
Poster: Drug/Disease modeling - Other topics