Positron emission tomography (PET): expanding the horizons of oncology drug development.
Positron emission tomography (PET) allows three-dimensional quantitative determination of the distribution of radioactivity permitting measurement of physiological, biochemical, and pharmacological functions at the molecular level. Until recently, no method existed to directly and noninvasively assess transport and metabolism of neoplastic agents as a function of time in various organs as well as in the tumor. Standard preclinical evaluation of potential anticancer agents entails radiolabeling the agent, usually with tritium or 14C, sacrifice experiments, and high-performance liquid chromatography (HPLC) analysis to determine the biodistribution and metabolism in animals. Radiolabeling agents with positron-emitting radionuclides allows the same information to be obtained as well as in vivo pharmacokinetic (PK) data by animal tissue and plasma sampling in combination with PET scanning. In phase I/II human studies, classic PK measurements can be coupled with imaging measurements to define an optimal dosing schedule and help formulate the design of phase III studies that are essential for drug licensure [1]. Many of the novel agents currently in development are cytostatic rather than cytotoxic and therefore, the traditional standard endpoints in phase I and II studies may no longer be relevant. The use of a specialized imaging modality that allows PK and pharmacodynamic (PD) evaluation of a drug of interest has been proposed to permit rapid and sensitive assessment of the biological effects of novel anticancer agents. The progress to date and the challenges of incorporating PET technology into oncology drug development from the preclinical to clinical setting are reviewed in this article.
Hammond
Lisa A
LA
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229, USA. Lhammond@idd.org
Denis
Louis
L
Salman
Umber
U
Jerabek
Paul
P
Thomas
Charles R
CR
Kuhn
John G
JG
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D007553:Isotope Labeling; D009369:Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed / Q000379:methods* / Q000639:trends
D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals