I recently got the chance to attend the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition in San Diego, California. It was a valuable opportunity to see some truly innovative scientific approaches to the toughest challenges in drug development. Pediatric drug development, in particular, remains a top challenge for the pharmaceutical industry as noted during a symposium, “Coming of Age? PBPK in Infants and Young Children.”
PBPK modeling & simulation “comes of age” for pediatric drug development
In pediatric drug development, uncertainties persist around key system parameters, including the ontogeny of metabolic enzymes (Barrett et al., 2012). Physiologically-based pharmacokinetic (PBPK) models leverage prior systems knowledge and in vitro derived attributes of drug candidates. Over the past several years, there has been an increasing use of PBPK modeling and simulation (M&S) to understand the observed pharmacokinetic variability which may occur due to intrinsic and extrinsic factors or predict them quantitatively (Huang et al 2013). An especially powerful approach combines ‘bottom-up’ PBPK models with ‘top-down’ population pharmacokinetic models that analyze clinical data (Tsamandouras, 2013).
Improving the development and labeling of drugs for pediatric use
This symposium brought four different groups (“Clinicians”, “Regulators”, “Pharmaceutical Industry” and “M&S Community”) to present the latest efforts in improving development and labeling of drugs for pediatric use. The panelists gave their perspectives on incorporating PBPK into pediatric drug models and highlighted the remaining challenges (particularly on oral drug absorption modeling) and the current achievements (on defining ontogeny functions).
Dr. Robert Bies, Disease Modeling Director at Indiana University School of Medicine, and Prof. Amin Rostami, Director of Scientific R&D at Certara, moderated the symposium. It featured presentations by Dr. Trevor Johnson, Principal Scientist at Certara, Dr. Joseph Grillo, Associate Director for Labeling and Health Communication at the US FDA, Dr. Alexander Vinks, Director at Cincinnati Children’s Hospital Medical Center, and Michael Zientek, Senior Principal Scientist at Pfizer, Inc.
The take home messages for applying PBPK in pediatric development:
- Several obstacles prevent wider application of PBPK modeling and simulation in pediatric drug development. One of the biggest obstacles is the gap in knowledge of developmental aspects related to the physiology and biology defining the handling of drugs in pediatrics— particularly those related to enzymes and transporters in the liver and gut wall.
- Clinicians frequently employ off-label administration and dose adjustment of drugs in pediatrics due to a dearth of clinical data. PBPK methods can help fill this information void. While this approach provides evidence that may not be as robust as clinical studies, it can provide a knowledge base for prescribers by integrating ALL available data.
- The biggest boost for increasing the confidence in PBPK M&S is to apply models for several drugs rather than using the observed data of one drug to develop the PBPK model. The ability to do EXTERNAL validation is essential for these models.
PBPK modeling and simulation using the Simcyp Simulator
Working at Certara— a leader in model-based drug development— and as a parent, I’m very interested in technology that supports developing safe and effective medications for kids. Certara’s Simcyp Pediatric Simulator is a tool that can help determine safe dosing without exposing children to experimental drugs. It allows pharmacokinetic behavior to be modeled in neonates, infants and children. This provides valuable information relevant to first-time dosing decisions and the design of pediatric clinical studies.
The Simcyp Pediatric Simulator includes a full physiologically-based pharmacokinetic (PBPK) model together with extensive libraries on demographics, developmental physiology and the ontogeny of drug elimination pathways. It allows population variability in pharmacokinetics to be simulated over any age range and potential drug-drug interactions (DDIs) to be quantified. Predictions can be made either from in vitro data or from adult in vivo values by retrograde modeling.
Learn more about PBPK in pediatric drug development
I particularly enjoyed Trevor Johnson’s talk, “PBPK in Pediatric Drug Development: Developing the Models, Refining the System Parameters.” He has graciously allowed me to share his slides with our blog readers. I hope that you’ll check it out and let me know what you think!
In addition, you might be interested in watching a short webinar on this topic by my colleague, Dr. JF Marier.