Drug efficacy: pharmacology vs transport

9 April 2010

Rami Tzafriri
Concord Biomedical Sciences and Emerging Technologies
Lexington, MA

Abstract

Drug discovery programs typically focus on optimizing pharmacological potency. Yet, there is an increasing appreciation that receptor binding and pharmacological potencies are poor predictors of in-vivo drug effects in solid tissue [1,2]. Thus, drug delivery to tumors, muscle tissue and the walls of arteries all emphasize the fundamental need for a deep understanding of extracellular transport, cell pharmacokinetics, not only pharmacology. Mathematical modeling offers a convenient framework for elucidating and integrating all these processes. In this talk, I will review how mathematical modeling is helping us elucidate the physiological barriers shaping the efficacy of local therapies aimed at inducing angiogenesis [3] or at inhibiting tissue hyperplasia [4].

References

1. R K Jain, "The next frontier of molecular medicine: delivery of therapeutics", Nat Med 4:655-657 1998. PubMed
2. M A Lovich E R Edelman, "Tissue concentration of heparin, not administered dose, correlates with the biological response of injured arteries in vivo", PNAS 96:11111-6 1999. PubMed
3. K N Le, C W Hwang, A R Tzafriri, M A Lovich, A Hayward, E R Edelman, "Vascular regeneration by local growth factor release is self-limited by microvascular clearance", Circulation 119:2928-35 2009. PubMed
4. A R Tzafriri, A D Levin, E R Edelman, "Diffusion-limited binding explains binary dose response for local arterial and tumor drug delivery", Cell Prolif 42:348-363 2009. PubMed