On 2022 年 12 月 7 日, Simcyp led a live panel discussion on the benefits of using modeling & simulation, specifically physiologically-based pharmacokinetics (PBPK), for two key vulnerable populations—pregnancy and pediatrics. Hosted by Simcyp’s Mark Lovern, panelists were:
- Ping Zhao, Senior Program Officer, Bill & Melinda Gates Foundation. Prior to joining BMGF, Dr Zhao spent 9 years at FDA, serving as an expert reviewer, leading the agency’s first PBPK program, reviewing more than 200 PBPK submissions in IND/NDA/BLAs, and championing PBPK regulatory research.
- Saskia de Wildt, Professor and chair of Clinical Pharmacology, Radboud University. A pediatric intensivist, Dr. de Wildt has published over 190 peer-review international papers and received over 8 million euros in Principal Investigator research funding, with a specific focus on individualized drug therapy in children and pregnant women.
- Susan Cole is an Expert Pharmacokinetics Assessor and leads the Clinical Pharmacology group in the Innovative Medicine Group at the MHRA, the UK Regulatory Agency. Prior to joining the MHRA in 2012, Sue worked for 26 years at Pfizer in the UK in the field of Drug Metabolism and Pharmacokinetics.
- Karen Rowland Yeo, SVP of Client & Regulatory Strategy at Simcyp.
Overview of Conversation
Because drug dosing information in pediatrics and pregnant women is often insufficient or scarce, sub-optimal use of medicines is common. Robust PBPK models have the potential to enhance dose selection in these situations. While PBPK modeling has gained momentum in commercial drug development for pediatrics, its potential to support dose selection in investigator-initiated research or clinical care in both children and pregnant women has not been fully explored. Furthermore, PBPK modeling is generally underutilized in global health, where children and pregnant women are important target populations. A major roadblock to the use of PBPK in these settings is the gap between the quantitative pharmacology community and healthcare professionals who make recommendations for dosing in children and pregnant women in real-life scenarios or investigators who design clinical studies.
- Dr. de Wildt spoke of the challenges and opportunities in developing drugs for children. Children are not small adults, so drug developers and prescribers need to understand and include factors around the actual disease, as well as ontogeny, pathophysiology, and demographics, versus simple allometric extrapolation from adult data. It can be difficult to recruit and run studies, for logistical reasons. Parents and children often will participate if they understand the need for data and to help others. For older medicines that are given off label, companies are challenged to find the budget to invest in the studies that would enable proper dosing recommendations.
- Children may need different doses of medicine, different sizes of devices, or different types of therapy at each stage of growth. Growth, maturation, and environmental factors, along with disease and genetic factors directly affect drug performance in children. Factors such as kidney function, brain volume, blood flow, and absorption, distribution, metabolism, and excretion (ADME) are non-linear during the neonate to small child period. Organ maturation has a significant effect on drug metabolism and excretion.
- Even though drugs are needed to treat both acute and chronic conditions, pregnant patients have largely been left out of drug development. This results in critical healthcare issues, including incorrect and potentially dangerous dosing, impact on both/either the mother and the fetus, and denial of important medications for people in need.
- For pregnant and lactating women, drug labels remain largely uninformative for healthcare providers, leaving the benefit-risk assessment and dosing up to the prescriber. For example, in the UK, there are only five medicines licensed for use in pregnancy. PBPK modeling represents a useful way to determine if dose adjustments may be required.
- Dr. Zhao was asked about the vulnerabilities of pregnant and pediatrics patients in the developing world, where the problems are significantly amplified due to demographics, the social environment, and the prevalence of co-morbidity. He noted that the pregnant and children under 5 years of age are truly neglected—a key focus of his work—and the need to raise awareness around the impact.
- Dr. Yeo discussed how we can leverage in vitro data to simulate how the drug behaves in the body, creating virtual populations – including pregnant mothers and children. PBPK can also be used to account for the developmental changes that occur during the growth and development of pediatric patients. For pregnancy, we need to assess the importance of the drug for the mother, alongside potential toxicity to the fetus. This will change throughout the gestational period, from placental transfer to lactation.
- Ms. Cole spoke about the increased drive from all regulatory agencies to use modeling and simulation in drug development, mentioning the recent ICH MIDD roadmap initiative as an example. Recognizing the growth of PBPK applications, she noted that modeling can reduce the amount of data needed to inform dosing based on sparse sampling and the PBPK model for these special populations. She also spoke of the importance of model verification and qualification for building confidence. To this point, Dr. Yeo agreed that collaborations and communication with regulators (and clinical stakeholders) on model qualification is critical for efficient use of these models and that there are significant ongoing efforts. Dr. Yeo recognized that more data are required to populate the virtual models. Despite this, she suggests that many of the drug and virtual physiology models are ready to be used, and she encouraged all stakeholders to apply these models to address their questions in R&D and to inform efficient clinical study design.
- Dr. Zhao spoke about the industrialization and acceptance of PBPK for informing and replacing certain drug-drug interaction (DDI) studies and the sophistication of commercially available software products. He believes that we can build on that DDI success in special populations, pointing out that there are many publications and case studies in pediatrics, and some in pregnancy as well. PBPK applications are increasing, with our knowledge and acumen increasing all the time. Innovation by software developers towards more user-friendly interfaces would further enable efficient use of PBPK to inform optimal drug therapy in special populations.
- Dr. de Wildt pointed out that it is important to inform and involve all stakeholders, including healthcare providers and patients and parents in discussions on the value, but also limitations of PBPK for dosing guidelines in special populations. They may worry about the confidence in the models and the potential risks to the patient.
A full recording of the Linked-In Live event may be accessed at: