Applied Clinical Trials
A purely empirical approach to drug development may allow for evaluation of the overt factors that impact the balance of benefit and risk, but it will never uncover all potential scenarios for which companies are now being held accountable.
A purely empirical approach to drug development may allow for evaluation of the overt factors that impact the balance of benefit and risk, but it will never uncover all potential scenarios for which companies are now being held accountable. Blind empiricism, in response to demands for evidence in support of potential worst-case scenarios, is commercially unsustainable. Aeronautical engineers have long explored extreme what-if scenarios through mathematical models and computer simulations. The time has come for our scientists to follow suit.
Steve Toon, PhD
The pharmacokinetic characteristics of a drug fundamentally impact its commercial viability. Pharmacokinetic evaluation is a significant part of the drug development process, allowing for quantification of the relationship between the administered dose and the subsequent concentrations of the drug within the body—a determinant of both beneficial and adverse biological effects.
Most of the biological processes that drive and impact pharmacokinetics are well understood and documented. By random statistical sampling of values for each of these physiological variables/processes one can build physiologically based pharmacokinetic (PBPK) models, or more simply put: virtual patients. Relating drug dose to systemic drug concentration through a mechanistic mathematical description of intervening biological processes in this way is rapidly becoming a fundamental component of drug development.
Historically, simulations derived from pharmacokinetic models have incorporated population averaged values for physiological parameters. Consequently, the results only hold true for Mr. Average Patient. However, rarely is it the clinical findings for Mr. Average that lead to the demise of a new medicine. In reality, it is often patients at the extremes of the normal range who are most at risk for unanticipated drug effects. Although the commercial fate of a drug may be determined by these individuals, they are often excluded from purely empirical clinical development programs.
Incorporating PBPK modeling and simulation into virtual patient populations using a platform such as the Simcyp Population-based ADME Simulator allows clinically extreme what-if scenarios to be explored in the safety of a computer. Those what-if scenarios include questions such as what if my highly metabolized drug were coadministered with a number of other drugs that, individually, are weak enzyme inhibitors? What if the patient, who is a poor metabolizer of my drug, goes into renal failure? Such questions are very difficult to answer safely by empiricism.
In addition, clinical trials in the young have always proved problematic. Often regarded as small adults when selecting dosing regimens, the assumption has been that human physiological development is linear and in proportion to age. For many processes it is not. So such developmental changes have also been incorporated into virtual population PBPK models, offering the opportunity for a more scientific approach to pediatric drug development.
Examining potential pharmacokinetic issues in a virtual in-silico world to prioritize experimental resources for further investigations has been adopted by researchers within leading pharma and biotech companies. Using the technology to full advantage to meet the demands of modern drug development may prove to be the next major advancement for the pharmaceutical industry as a whole.