Preclinical pharmacokinetic/pharmacodynamic models to predict synergistic effects of co-administered anti-cancer agents Journal Article


Authors: Goteti, K.; Garner, C. E.; Utley, L.; Dai, J.; Ashwell, S.; Moustakas, D. T.; Gonen, M.; Schwartz, G. K.; Kern, S. E.; Zabludoff, S.; Brassil, P. J.
Article Title: Preclinical pharmacokinetic/pharmacodynamic models to predict synergistic effects of co-administered anti-cancer agents
Abstract: Purpose: 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 coadministering 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.
Keywords: controlled study; unclassified drug; cancer combination chemotherapy; drug potentiation; nonhuman; methodology; antineoplastic agent; cell proliferation; mass spectrometry; animal cell; mouse; animal; animals; mice; gene; statistics; steady state; tumor volume; antineoplastic combined chemotherapy protocols; animal experiment; animal model; antineoplastic agents, phytogenic; camptothecin; in vivo study; antineoplastic activity; drug potency; drug effect; drug screening; xenograft model antitumor assays; drug evaluation, preclinical; algorithms; prediction; irinotecan; drug synergism; cancer inhibition; drug antagonism; nude mouse; mice, nude; algorithm; models, statistical; prediction and forecasting; predictive value of tests; drug derivative; malignant neoplastic disease; flavonoid; flavonoids; flavopiridol; piperidines; drug blood level; maximum tolerated dose; neoplasm transplantation; drug half life; tumor growth; combination therapy; drug dose regimen; liquid chromatography; statistical model; distribution volume; genes, cdc; cancer transplantation; compartment model; urea; pk-pd; xenograft mice; azd 7762; 3 (carbamoylamino) 5 (3 fluorophenyl) n (3 piperidyl)thiophene 2 carboxamide; 3-(carbamoylamino)-5-(3-fluorophenyl)-n-(3-piperidyl)thiophene-2-carboxamide; growth inhibitor; piperidine derivative; thiophene derivative; growth inhibitors; thiophenes
Journal Title: Cancer Chemotherapy and Pharmacology
Volume: 66
Issue: 2
ISSN: 0344-5704
Publisher: Springer  
Date Published: 2010-07-01
Start Page: 245
End Page: 254
Language: English
DOI: 10.1007/s00280-009-1153-z
PUBMED: 19841922
PROVIDER: scopus
DOI/URL:
Notes: --- - "Export Date: 20 April 2011" - "CODEN: CCPHD" - "Source: Scopus"
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MSK Authors
  1. Gary Schwartz
    383 Schwartz
  2. Mithat Gonen
    782 Gonen