Testing additivity of anticancer agents in pre-clinical studies: a PK/PD modelling approach.
In clinical oncology, combination regimens may result in a synergistic, additive or antagonistic interaction (i.e. the effect of the combination is greater, similar or smaller than the sum of the effects of the individual compounds). For this reason, during the drug development process, in vivo pre-clinical studies are performed to assess the interaction of anticancer agents given in combination. Starting from a widely used single compound PK/PD model, a new additivity model able to predict the tumour growth inhibition in xenografted mice after the administration of compounds in combination was developed, under the assumption of a pharmacodynamic null interaction. By comparing the predicted curves with actual tumour weight data, possible departures from additivity can be immediately ascertained by visual inspection; a statistical procedure based on a chi(2) test has also been developed for this aim. The advantages of the proposed approach in comparison to other modelling methodologies are discussed and its application to four combination studies is presented.
Rocchetti
M
M
Pharmacokinetics and Modeling, Accelera S.r.l., Viale Pasteur 10, 20014 Nerviano (MI), Italy. maurizio.rocchetti@accelera.org
Del Bene
F
F
Germani
M
M
Fiorentini
F
F
Poggesi
I
I
Pesenti
E
E
Magni
P
P
De Nicolao
G
G
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D051379:Mice; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays