Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.
BACKGROUND
Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics.


METHODS
In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles.


CONCLUSIONS
More scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.
a Division of Pharmacology, Leiden Academic Centre for Drug Research , Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands.
Wilhelmus E A
WE
de Witte
a Division of Pharmacology, Leiden Academic Centre for Drug Research , Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands.
Yin Cheong
YC
Wong
b Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research , Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands.
Indira
I
Nederpelt
b Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research , Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands.
Laura H
LH
Heitman
a Division of Pharmacology, Leiden Academic Centre for Drug Research , Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands.
Meindert
M
Danhof
a Division of Pharmacology, Leiden Academic Centre for Drug Research , Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands.
Piet H
PH
van der Graaf
c A Division of Janssen Pharmaceutica N.V., Janssen Research and Development , Turnhoutseweg 30, Beerse 2340 , Belgium.
Ron A H J
RA
Gilissen
a Division of Pharmacology, Leiden Academic Centre for Drug Research , Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands.
Elizabeth C M
EC
de Lange
D000818:Animals; D016503:Drug Delivery Systems; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011485:Protein Binding
D004364:Pharmaceutical Preparations
PKPD modeling; drug-target binding kinetics; endogenous competition; in vitro; in vivo; mechanistic; nonspecific binding; patients; rebinding; target turnover