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Pharmacodynamic modeling of sequence-dependent antitumor activity of insulin-like growth factor blockade and

Amit Khatri1, Richard C Brundage, Jessica M Hull

  • 1Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, 55455, USA.

The AAPS Journal
|November 22, 2011
PubMed

Insights

Administering Gemcitabine before the small molecule receptor tyrosine kinase inhibitor PQIP demonstrated superior in vitro antitumor effects compared to the reverse sequence. This finding is crucial for optimizing combination cancer therapy strategies.

Area of Science:

  • Pharmacology and Oncology
  • Drug Combinations and Sequencing

Background:

  • Insulin-like growth factor (IGF) signaling inhibitors are in clinical trials for cancer treatment.
  • Combination therapy may enhance antitumor effects, but optimal administration sequences are not well-defined.

Purpose of the Study:

  • To investigate the impact of administration sequence on the in vitro antitumor activity of Gemcitabine and a novel small molecule receptor tyrosine kinase inhibitor (PQIP).
  • To compare the efficacy of a forward (Gemcitabine then PQIP) versus a reverse (PQIP then Gemcitabine) treatment sequence.

Main Methods:

  • Three human breast cancer cell lines (MCF-7, MDA-MB-231, Hs-578T) were treated with Gemcitabine and PQIP as single agents and in combination.
  • Combination treatments were administered in both forward and reverse sequences.
  • Antitumor effects were assessed longitudinally using Bayesian analysis with WinBUGS for pharmacodynamic modeling.

Main Results:

  • The pharmacodynamic model accurately predicted observed cell-kill data.
  • Significant differences in cell-kill rate constants were observed between the forward and reverse sequences, ranging from 0.11 to 0.64 day(-1).
  • The superiority of one sequence over the other was generally dependent on the specific cell line and PQIP concentration used.

Conclusions:

  • The in vitro data strongly suggest that initiating treatment with Gemcitabine followed by PQIP is a more effective sequence than the reverse order.
  • These findings provide critical insights for optimizing the clinical application of this combination therapy in breast cancer.

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