title: Array of translational systems pharmacodynamic models of anti-cancer drugs.
abstract: Cancer is a complex disease that is characterized by an uncontrolled growth and spread of abnormal cells. Drug development in oncology is particularly challenging and is associated with one of the highest attrition rates of compounds despite substantial investments in resources. Pharmacokinetic and pharmacodynamic (PK/PD) modeling seeks to couple experimental data with mathematical models to provide key insights into factors controlling cytotoxic effects of chemotherapeutics and cancer progression. PK/PD modeling of anti-cancer compounds is equally challenging, partly based on the complexity of biological and pharmacological systems. However, reliable mechanistic and systems PK/PD models for anti-cancer agents have been developed and successfully applied to: (1) provide insights into fundamental mechanisms implicated in tumor growth, (2) assist in dose selection for first-in-human phase I studies (e.g., effective dose, escalating doses, and maximal tolerated doses), (3) design and optimize combination drug regimens, (4) design clinical trials, and (5) establish links between drug efficacy and safety and the concentrations of measured biomarkers. In this commentary, classes of relevant mechanism-based and systems PK/PD models of anti-cancer agents that have shown promise in translating preclinical data and enhancing stages of the drug development process are reviewed. Specific features of such models are discussed including their strengths and limitations along with a prospectus of using these models alone or in combination for cancer therapy.
authors: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, 6550 Sanger Road, Room 469, Orlando, FL, 32827, USA. sihem.bihorel@cop.ufl.edu.
authors: Sihem
authors: 0000-0001-8152-3150
authors: S
authors: Ait-Oudhia
authors: Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
authors: Donald E
authors: DE
authors: Mager
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents
keywords: Disease progression; Enhanced pharmacodynamics; Quantitative systems pharmacology, combination therapy