Preclinical pharmacokinetic/pharmacodynamic models to predict synergistic effects of co-administered anti-cancer agents.
OBJECTIVE
Pharmacokinetic/pharmacodynamic (PK/PD) models have been shown to be useful in predicting tumor growth rates in mouse xenografts. We applied novel PK/PD models to the published anticancer combination therapies of tumor growth inhibition to simulate synergistic changes in tumor growth rates. The parameters from the PK/PD model were further used to estimate clinical doses of the combination.


METHODS
A PK/PD model was built that linked the dosing regimen of a compound to the inhibition of tumor growth in mouse xenograft models. Two subsequent PK/PD models were developed to simulate the published tumor growth profiles of combination treatments. Model I predicts the tumor growth curve assuming that the effect of two anticancer drugs, AZD7762 and irinotecan, is synergistic when given in combination. Model II predicts the tumor growth curve assuming that the effect of co-administering flavopiridol and irinotecan is maximally synergistic when dosed at an optimal interval.


RESULTS
Model I was able to account for the synergistic effects of AZD7762 following the administration of irinotecan. When Model II was applied to the antitumor activity of irinotecan and flavopiridol combination therapy, the modeling was able to reproduce the optimal dosing interval between administrations of the compounds. Furthermore, Model II was able to estimate the biologically active dose of flavopiridol recommended for phase II studies.


CONCLUSIONS
The timing of clinical combination therapy doses is often selected empirically. PK/PD models provide a theoretical structure useful in the design of the optimal clinical dose, frequency of administration and the optimal timing of administration between anticancer agents to maximize tumor suppression.
Goteti
Kosalaram
K
Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Kosalaram.Goteti@astrazeneca.com
Garner
C Edwin
CE
Utley
Lucas
L
Dai
Jing
J
Ashwell
Susan
S
Moustakas
Demetri T
DT
Gönen
Mithat
M
Schwartz
Gary K
GK
Kern
Steven E
SE
Zabludoff
Sonya
S
Brassil
Patrick J
PJ
D000465:Algorithms; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D049109:Cell Proliferation; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data*; D004357:Drug Synergism; D005419:Flavonoids / Q000008:administration & dosage; D018816:Genes, cdc / Q000187:drug effects; D006131:Growth Inhibitors / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D015233:Models, Statistical; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000008:administration & dosage; D011237:Predictive Value of Tests; D013876:Thiophenes / Q000008:administration & dosage; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D006131:Growth Inhibitors; D010880:Piperidines; D013876:Thiophenes; C077990:alvocidib; D000077146:Irinotecan; D014508:Urea; D002166:Camptothecin