Modelling the genesis and treatment of cancer: the potential role of physiologically based pharmacodynamics.
Physiologically based modelling of pharmacodynamics/toxicodynamics requires an a priori knowledge on the underlying mechanisms causing toxicity or causing the disease. In the context of cancer, the objective of the expert meeting was to discuss the molecular understanding of the disease, modelling approaches used so far to describe the process, preclinical models of cancer treatment and to evaluate modelling approaches developed based on improved knowledge. Molecular events in cancerogenesis can be detected using 'omics' technology, a tool applied in experimental carcinogenesis, but also for diagnostics and prognosis. The molecular understanding forms the basis for new drugs, for example targeting protein kinases specifically expressed in cancer. At present, empirical preclinical models of tumour growth are in great use as the development of physiological models is cost and resource intensive. Although a major challenge in PKPD modelling in oncology patients is the complexity of the system, based in part on preclinical models, successful models have been constructed describing the mechanism of action and providing a tool to establish levels of biomarker associated with efficacy and assisting in defining biologically effective dose range selection for first dose in man. To follow the concentration in the tumour compartment enables to link kinetics and dynamics. In order to obtain a reliable model of tumour growth dynamics and drug effects, specific aspects of the modelling of the concentration-effect relationship in cancer treatment that need to be accounted for include: the physiological/circadian rhythms of the cell cycle; the treatment with combinations and the need to optimally choose appropriate combinations of the multiple agents to study; and the schedule dependence of the response in the clinical situation.
Steimer
Jean-Louis
JL
Novartis Pharma AG, Basel, Switzerland.
Dahl
Svein G
SG
De Alwis
Dinesh P
DP
Gundert-Remy
Ursula
U
Karlsson
Mats O
MO
Martinkova
Jirina
J
Aarons
Leon
L
Ahr
Hans-Jürgen
HJ
Clairambault
Jean
J
Freyer
Gilles
G
Friberg
Lena E
LE
Kern
Steven E
SE
Kopp-Schneider
Annette
A
Ludwig
Wolf-Dieter
WD
De Nicolao
Giuseppe
G
Rocchetti
Maurizio
M
Troconiz
Iñaki F
IF
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002940:Circadian Rhythm / Q000502:physiology; D055870:Drug Chronotherapy; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics
D000970:Antineoplastic Agents