In a collaborative effort, Absorption Systems is working with Drs Ken Korzekwa and Swati Nagar of Temple University and Dr Jeff Jones of Washington State University to develop technologies to improve the predictive power of certain in vitro-in vivo correlations (IVIVCs). Preclinical studies, including in vitro studies, always precede clinical trials of new drugs in humans. To the extent that cheaper, faster in vitro studies can predict what will happen in humans, the development of life-saving drugs can proceed faster, more safely, and at a lower cost. This collaboration will focus specifically on the prediction of pharmacokinetics (PK), an area in which Absorption Systems, a global contract research organization, has considerable expertise. The academic partners in this collaboration will develop mathematical models based on in vitro data generated by Absorption Systems.
The goal of most in vitro drug metabolism and PK studies is ultimately to predict or explain the clinical PK of drugs in humans. A number of in vitro test systems are available, and in many cases they successfully predict the PK of drug candidates. However, the behaviour of many other drugs continues to defy prediction, for reasons that we are only beginning to understand.
All IVIVCs make certain assumptions; in this case, one of them is the concentration of a drug at the active site of a target enzyme, which is often inside a cell. This turns out to be an exceedingly difficult parameter to estimate, as it is greatly affected by the extent of protein binding, the passive permeability of the drug, the activities of various uptake and efflux transporters, etc. Thus, the drug concentration that is convenient to measure (the unbound concentration in the plasma) can be much higher or much lower than the concentration inside a cell.
For this collaborative research project, in vitro data on drug-metabolizing enzymes, membrane partitioning, cellular permeability, and drug transporters will be used to develop improved mathematical models for human PK prediction. Absorption Systems is providing experimental test systems, data, and expertise in permeability and transporters. Using computer simulations, Drs Korzekwa, Nagar, and Jones are developing models to predict the extent of involvement of various clearance processes for a structurally diverse set of drugs. In preliminary experiments, permeability and transport have been simulated for a number of compounds.
Said Dr Ken Korzekwa, associate professor, School of Pharmacy, Temple University, “We anticipate that this research will result in improved methods that can be used broadly within the industry to predict a number of PK parameters and potential drug-drug interactions.”
Dr Ismael Hidalgo, chief scientist of Absorption Systems, added “We look forward to collaborating with our academic research colleagues in this important project, which we expect will lead to the creation of tools of great practical value.”