How to Optimize Your Drug Label Using Modeling and Simulation Technology

How to Optimize Your Drug Label Using Modeling and Simulation Technology

As a trained pharmacist and scientist, I think a lot about patient care and how the drug development process impacts drug labels and the clinical use of medicines. Modeling and simulation technology encompasses methods such as physiologically based pharmacokinetic (PBPK) models. PBPK provides insight into drug mechanisms. It also helps clinicians provide the safest and most effective treatment to patients.

How can PBPK inform drug labels?

Dedicated clinical pharmacology studies can quantify the impact of certain intrinsic and extrinsic factors on drug exposure. But, investigating every possible scenario is often cost-prohibitive or unethical. This is especially true when there is complex interplay between factors.

PBPK considers both intrinsic and extrinsic factors. These factors include genotype, disease state, renal/hepatic impairment, ethnicity and age. PBPK models incorporate information about how drug exposure changes with drug-induced enzymatic inhibition. Thus, the models can predict and quantify the magnitude of potential drug-drug interactions (DDIs). Sometimes, they can even eliminate the need for additional clinical studies.

The Simcyp Simulator is Certara’s PBPK platform. It streamlines drug development through modeling drug effects in virtual patient populations. The Simulator incorporates databases containing human physiological, genetic and epidemiological information. It integrates this information with in vitro or clinical data to predict behavior in “real-world” populations. The Simulator can handle DDIs involving up to four drugs plus three metabolites. It accommodates simultaneous competitive enzyme and transporter inhibition, irreversible time-based enzyme inhibition, enzyme induction, and suppression.

How does PBPK modeling change the conduct of clinical trials?

Conducting clinical trials incurs immense costs. Thus, technologies that change clinical trial practices represent a sea change in drug development. Sponsors and regulatory agencies routinely use PBPK modeling and simulation to manage clinical trials. Substituting clinical DDI studies with informative ‘virtual’ trials can save millions of dollars and knock years off development time. These models address the concerns of regulatory reviewers. They can also answer ‘what-if ’questions designed to test the limits of safety.

From regulatory science to regulatory policy?

Regulatory agencies around the globe are embracing model-based approaches to drug development, including PBPK. FDA Office of Clinical Pharmacology (OCP) scientists have affirmed several uses for PBPK. First, it can help optimize trial designs. Second, PBPK models aid predicting the impact of intrinsic and extrinsic factors on pharmacokinetics. Third, they are a useful tool for developing dosing recommendations for special populations. In a paper published last year, the FDA’s Dr. Vikram Sinha wrote that approximately 50 submissions to the agency in 2013 either requested advice on using PBPK or incorporated this approach in their approval filings. Most submissions used PBPK to predict DDIs and drug exposure in pediatric and organ-impaired patients.

Learn more about how Certara’s scientific consulting services can help you!

Here’s my webinar where I presented examples of the role of PBPK modelling in the regulatory approvals process. I hope that you’ll watch it and let me know what you think in the comments section!

Steve Toon

About the Author

Dr Stephen Toon is the Managing Director of Certara's Simcyp business unit. Steve received his pharmacy degree from the University of Bath and his PhD in pharmacokinetics from the University of Manchester. following a period at the University of Washington, he founded Medeval, a clinical pharmacology CRO, which was acquired by ICON in 2003. He has published over 50 articles, abstracts and chapters in books.