Karen Yeo, PhD, on the clinical utility of PBPK modeling in obstetric antidepressant dosing

While PBPK (physiologically based pharmacokinetic) modeling has established a foundation for predicting drug exposure in virtual populations, its application in specific therapeutic areas like antenatal and postnatal depression is revealing the necessity of individualized care. Karen Yeo, PhD, Senior vice president, Client & Regulatory Strategy, Certara UK, recently discussed how this quantitative framework can address the "one-dose-fits-all" limitation, particularly for medications metabolized by the highly variable CYP2D6 enzyme.

Navigating the variability of CYP2D6

The enzyme CYP2D6 plays a critical role in metabolizing many commonly prescribed antidepressants, yet its presence and activity vary significantly across the population. Yeo noted that approximately 10% of people lack the enzyme entirely, while 5% possess a "super gene" leading to ultra-rapid metabolism. This genetic variability is further complicated by the physiological shifts of pregnancy.

“The other thing to say as well is that this enzyme changes as you go from trimester 1 up to trimester 3, and you can end up with 3 times the amount of CYP2D6 that you had before getting pregnant,” Yeo explained. This dramatic increase means that plasma levels can fluctuate significantly, potentially leaving depression undertreated as the drug is cleared more rapidly. Conversely, those with lower enzyme activity may experience drug levels that are too high, increasing the risk of adverse effects, Yeo noted.

Bridging the gap between clinical studies and reality

Traditional clinical studies in pregnant populations are often limited by small subject sizes, making it difficult to capture the full spectrum of genetic and physiological diversity. Yeo’s team utilizes PBPK modeling to fill these gaps, providing clinicians and patients with the data needed to make informed, phenotype-based dosing decisions.

“This is where I think it's important for the patients and prescribers to make decisions about whether they want an individualized dose, depending on their CYP2D6 status, and also as they go from trimester 1 to trimester 3,” Yeo stated.

Assessing fetal exposure via innovative tools

A primary concern in obstetric prescribing is the risk-benefit ratio of maternal treatment versus fetal exposure. To address this, Certara integrates PBPK modeling with advanced in vitro tools like organ-on-a-chip technology. This combination allows researchers to predict how much of a drug is transferred across the placenta.

“Importantly, using our approach in conjunction with some in vitro tools like organ-on-a-chip... we can actually predict the exposures in the fetus as well to determine how much drug they're getting,” Yeo said. This predictive capability supports clinicians in making case-by-case decisions, ensuring the mother receives an effective dose while minimizing potential risks to the developing baby.

Reference:

Fitch J. Karen Yeo, PhD, on leveraging PBPK modeling for drug dosing in pregnancy. Published April 2, 2026. Accessed April 24, 2026. https://www.contemporaryobgyn.net/view/karen-yeo-phd-on-leveraging-pbpk-modeling-for-drug-dosing-in-pregnancy