Research project

Drug-target binding kinetics in vivo

A next, general pharmacological problem to be tackled is how drug-target binding kinetics in vivo, affects target occupancy as an important indicator of the time-course of drug effects.

Contact: Elizabeth (Liesbeth) de Lange

Drug target binding kinetics (BK) typically has been determined in isolation, while in the living body all PK processes in the body occur in parallel. Therefore, there is a need for integration of these processes. This was part of the IMI K4DD project. Several generic mathematical models have been developed that provide substantial insights in the condition-dependent contribution of these different processes.

_{De Witte WE, Wong YC, Nederpelt I, Heitman LH, Danhof M, van der Graaf PH, Gilissen RA, de Lange EC. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients. Expert Opin Drug Discov. 2015 Oct 20:1-19. [Epub ahead of print]}
_{De Witte WEA, Danhof M, van der Graaf PH, de Lange EC. The implications of target saturation for the use of drug-target residence time. Nat Rev Drug Discov. 2018 Dec 28;18(1):82-84.}
_{De Witte WEA, Rottschäfer V, Danhof M, van der Graaf PH, Peletier LA, de Lange ECM. Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models. J Pharmacokinet Pharmacodyn. 2018 Aug;45(4):621-635. doi: 10.1007/s10928-018-9593-x. Epub 2018 May 18.}
_{De Witte WEA, Rottschäfer V, Danhof M, van der Graaf PH, Peletier LA, de Lange ECM. Correction to: Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models. J Pharmacokinet Pharmacodyn. 2018 Oct;45(5):763. doi: 10.1007/s10928-018-9604-y.}
_{De Witte WEA, Vauquelin G, van der Graaf PH, de Lange EC. The influence of drug distribution and drug-target binding on target occupancy: The rate-limiting step approximation. Eur J Pharm Sci. 2017 May 12. pii: S0928-0987(17)30252-X. doi: 10.1016/j.ejps.2017.05.024}
_{de Witte WEA, Versfelt JW, Kuzikov M, Rolland S, Georgi V, Gribbon P, Gul S, Huntjens D, van der Graaf PH, Danhof M, Fernández-Montalván A, Witt G, de Lange ECM. In vitro and in silico analysis of the effects of D2 receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations. Br J Pharmacol. 2018 Nov;175(21):4121-4136. doi: 10.1111/bph.14456. Epub 2018 Sep 21}
_{De Witte W, Danhof M, Van der Graaf PH, de Lange EC. In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant. Trends Pharmacol Sci. 2016 Oct;37(10):831-42}
_{Nederpelt I, Kuzikov M, de Witte WEA, Schnider P, Tuijt B, Gul S, IJzerman AP, de Lange ECM, Heitman LH. From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action. Sci Rep. 2017 Oct 26;7(1):14169. doi: 10.1038/s41598-017-14257-4.}
_{Vlot AHC, Witte WEA, Danhof M, van der Graaf PH, van Westen GJP, de Lange ECM*. Target and tissue selectivity prediction by integrated mechanistic pharmacokinetic-target binding and quantitative structure activity modelling AAPSJ. 2017 Dec 4;20(1):11. doi: 10.1208/s12248-017-0172-7.}

This work is now proceeded by PhD student Divakar Budda in QSPainRelief (see above).

Drug-target binding kinetics in vivo

De Witte WE, Wong YC, Nederpelt I, Heitman LH, Danhof M, van der Graaf PH, Gilissen RA, de Lange EC. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients. Expert Opin Drug Discov. 2015 Oct 20:1-19. [Epub ahead of print]

De Witte WEA, Danhof M, van der Graaf PH, de Lange EC. The implications of target saturation for the use of drug-target residence time. Nat Rev Drug Discov. 2018 Dec 28;18(1):82-84.

De Witte WEA, Vauquelin G, van der Graaf PH, de Lange EC. The influence of drug distribution and drug-target binding on target occupancy: The rate-limiting step approximation. Eur J Pharm Sci. 2017 May 12. pii: S0928-0987(17)30252-X. doi: 10.1016/j.ejps.2017.05.024

De Witte W, Danhof M, Van der Graaf PH, de Lange EC. In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant. Trends Pharmacol Sci. 2016 Oct;37(10):831-42

Nederpelt I, Kuzikov M, de Witte WEA, Schnider P, Tuijt B, Gul S, IJzerman AP, de Lange ECM, Heitman LH. From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action. Sci Rep. 2017 Oct 26;7(1):14169. doi: 10.1038/s41598-017-14257-4.

Vlot AHC, Witte WEA, Danhof M, van der Graaf PH, van Westen GJP, de Lange ECM*. Target and tissue selectivity prediction by integrated mechanistic pharmacokinetic-target binding and quantitative structure activity modelling AAPSJ. 2017 Dec 4;20(1):11. doi: 10.1208/s12248-017-0172-7.

_{De Witte WE, Wong YC, Nederpelt I, Heitman LH, Danhof M, van der Graaf PH, Gilissen RA, de Lange EC. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients. Expert Opin Drug Discov. 2015 Oct 20:1-19. [Epub ahead of print]}

_{De Witte WEA, Danhof M, van der Graaf PH, de Lange EC. The implications of target saturation for the use of drug-target residence time. Nat Rev Drug Discov. 2018 Dec 28;18(1):82-84.}

_{De Witte WEA, Vauquelin G, van der Graaf PH, de Lange EC. The influence of drug distribution and drug-target binding on target occupancy: The rate-limiting step approximation. Eur J Pharm Sci. 2017 May 12. pii: S0928-0987(17)30252-X. doi: 10.1016/j.ejps.2017.05.024}

_{De Witte W, Danhof M, Van der Graaf PH, de Lange EC. In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant. Trends Pharmacol Sci. 2016 Oct;37(10):831-42}

_{Nederpelt I, Kuzikov M, de Witte WEA, Schnider P, Tuijt B, Gul S, IJzerman AP, de Lange ECM, Heitman LH. From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action. Sci Rep. 2017 Oct 26;7(1):14169. doi: 10.1038/s41598-017-14257-4.}

_{Vlot AHC, Witte WEA, Danhof M, van der Graaf PH, van Westen GJP, de Lange ECM*. Target and tissue selectivity prediction by integrated mechanistic pharmacokinetic-target binding and quantitative structure activity modelling AAPSJ. 2017 Dec 4;20(1):11. doi: 10.1208/s12248-017-0172-7.}