085: Predicting Metoprolol Exposure-Response in Pregnant Population Using Physiologically-based Pharmacokinetic Modeling

Statement of Purpose, Innovation or Hypothesis: Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict (1) the maternal and umbilical metoprolol exposure during pregnancy, (2) the effect of metoprolol on maternal heart rate.

Description of Methods & Materials: Metoprolol transplacental permeability was predicted using its physicochemical properties and incorporated into the Physiologically Based Pharmacokinetic (PBPK) model [1]. A pharmacodynamic for the heart rate was developed for the non-pregnant population and applied to the pregnant population. Model predictions were compared to the observed data after administration of a single oral dose of 100 mg metoprolol [2].

Data & Results: The observed metoprolol concentration profiles in non-pregnant and pregnant subjects agreed with the 5th–95th prediction interval from the PBPK simulations. The calculated transplacental clearance (0.156 L/h/mL of placenta volume) predicted an average umbilical cord-to-maternal plasma ratio of 1.0, which agrees well with clinical observations. Likewise, the reduction in the heart rate reflecting the lower exposure during pregnancy agreed with the available observed data at 33-38 weeks of gestation.

Interpretation, Conclusion or Significance: The developed maternal PBPK model adequately predicted the observed exposure-response of metoprolol in the pregnant population. Using a verified population-based PBPK model provides valuable insights into the disposition of drug concentrations in special individuals that are otherwise difficult to study. In addition, offers the possibility of supplementing sparse samples obtained in vulnerable populations with additional knowledge, informing the dosing adjustment and study design, as well as improving the efficacy and safety of drugs in target populations.

Disclosures: Both authors are employees by Certara UK.

Citations/References: [1] Abduljalil et al., Drug Metab Dispos. 2022 Apr;50(4):386-400. [2] Hogstedt et l., Eur J Clin Pharmacol (1993) 44:243-246.

Additional Information/Authors: None