Clinical Pharmacology Analytical Core

The Clinical Pharmacology Analytical Core (CPAC) is available to assist Indiana University Melvin and Bren Simon Cancer Center (IUSCC) investigators as well as external partners with pre-clinical and clinical pharmacokinetics in support of their research projects and scientific goals.

CPAC has been in existence since September 2004, primarily working with clinical investigators to provide detailed information on drug interactions and pharmacokinetics.

As a result of the identified need for pre-clinical pharmacokinetic and drug metabolism measurements earlier in the drug discovery process (via ITRAC experimental design mapping), CPAC began to expand its capabilities to include discovery pharmacokinetics and preliminary determination of drug metabolism.

The process of rational drug design should be based upon a strong foundation of biology, chemistry, in vivo pharmacology, and pharmacokinetics.  Relevant pharmacokinetic and metabolism studies should be conducted in small animal models or in vitro systems before first drug administration in humans.  This allows for the iterative process of implementing structural changes in the drug molecule to optimize the activity of the drug and its pharmacological and pharmacokinetic properties prior to moving to the more regulated and expensive clinical phase of drug development. For these reasons, CPAC is now interacting closely with another IUSCC-shared resource, the In Vivo Therapeutics (IVT) Core, to coordinate these efforts.

Over the past year, the CPAC and IVT Core have worked together to generate data allowing principal investigators to better evaluate molecules being developed within the IUSCC that show promise as novel cancer drugs.

Pharmacokinetic and metabolism data provide important information to guide drug design and treatment  in pre-clinical drug discovery (bench) as well as in clinical drug development and treatment (bedside). Using state-of-the art technology, CPAC supports the development of safe and more efficacious drug treatment for IUSCC investigators.

The following are some examples of how CPAC has contributed to the development of IUSCC-investigator initiated research - these vignettes are illustrative of how CPAC has helped the IUSCC advance and take the lead in precision prescribing, which refers to the process of matching patients to drugs that will trigger the best response based on an individual’s genetic makeup. CPAC has been of critical importance in some noteworthy findings that are described below.

    Dr. Jamie Renbarger, a clinical pharmacologist and pediatric oncologist,  focuses on the pharmacogenetics of vincristine, the most commonly used anticancer agent in children. Her laboratory work resulted in defining the metabolism of vincristine, identification of the structures of its metabolites, and development, in conjunction with the CPAC, of an extremely sensitive assay for measurement of vincristine and its primary metabolite  This work may explain the observed racial disparities in the outcome of childhood cancer treatment and lead to more effective vincristine dosing schemes. An NIH K23 award supports the work of this young investigator.
    Dr. Christopher J. Sweeney, while working in the Phase I clinic at IUSCC, designed a study to look at the possibility of drug-drug interactions of paclitaxel with PTK 787. Both of these drugs are metabolized by enzymes which have pharmacogenetic polymorphisms. The CPAC developed an assay to quantify paclitaxel and both metabolites in plasma to assist Dr. Sweeney in the identification of the cause of the observed drug-drug interaction which has resulted in PTK787 increasing the clearance of paclitaxel. The results in 18/20 subjects showed a decreased area under the plasma concentration time curve for each compound (on Day 15), illustrating a significant and previously un-indentified drug-drug interaction. This has led to planned studies with the developmental therapeutics/phase 1 group and CPAC to define the mechanisms of this interaction.
    CPAC has also provided preclinical analytical support to several projects identified and supported through the ITRAC mapping process. Karen Pollok and Lindsey Mayo’s projects focused on utilizing the HDM2 inhibitor, nutlin-3, in treatment strategies for chemotherapy-resistant cancers such as melanoma and glioblastoma. CPAC has developed an assay to effectively measure nutlin -3 in vitro and in vivo – generating strong preliminary data in support of the investigator’s hypothesis in their recently submitted R01 application.