Khaled Abduljalil, Trevor N Johnson, Masoud Jamei
Certara UK Limited, Simcyp Division, Sheffield, United Kingdom
Objectives: Physiologically based pharmacokinetic (PBPK) models can integrate both the drug characteristics and the underlying physiology, along with its variability within a population to predict drugs kinetics. Once the model performance is verified for a particular drug in a specific population, it can be assessed with increased confidence in another population with different characteristics. The objective of this work is to use PBPK modelling approach to predict the impact of pregnancy on propranolol pharmacokinetics taking into account the influence of time-varying physiological changes in the system parameters using the Simcyp Pregnancy population [1,2,3].
Methods: A compound model for prpranolol was developed and the Sim-Pregnancy population was used from the library within the Simcyp Simulator V19. A full Maternal-Placental-Fetal PBPK model that includes placenta as a 3-comparment permeability limited organ and 14 compartments for different fetal organs was used within the Simulator. A full PBPK model using the Rodgers & Rowland’s method [4] was used to model the drug distribution. The Advanced Dissolution, Absorption and Metabolism (ADAM) absorption model was used to describe the absorption process in the mother. The In Vitro-In Vivo Extrapolation (IVIVE) approach was used to describe propranolol elimination mediated by CYP2D6 and CYP1A2. The model was used to predict propranolol PK in 6 trials of 10 pregnant women after being verified for non-pregnant women aged between 20 – 45 years after 10mg intravenous infusion over 10 minutes or 120 mg oral administration [5]. The predicted propranolol pharmacokinetics parameters were compared to clinical observations [5]. Sensitivity analysis was used to optimize placental clearance on both maternal (CLPD,M) and fetal (CLPD,F) sides as well as the fetal clearance to describe reported umbilical concentrations [6].
Results: The Maternal-Placental-Fetal PBPK model was able to predict propranolol pharmacokinetics in pregnant women 32-36 gestational weeks. The optimized placental clearance values were 0.02 L/h/mL of placental volume for CLPD,M and CLPD,F, and 1 L/h/Fetal body weight for fetal metabolic clearance. During pregnancy, the predicted/observed ratios were 0.91, 1.01, 0.98, and 1.03 for elimination rate, half-life, AUC∞, and CLiv, respectively after intravenous administration and 1.08, 0.92, and 1.61 for elimination rate, half-life, and AUC∞, respectively after oral administration.
Conclusions: PBPK models offer an approach to investigate the drug exposure during pregnancy and inter-subject variability using prior drugs physicochemical properties and system (mother and fetus) parameters. The developed model can be used to explore the impact of other scenarios affecting maternal exposure, such as drug-drug interactions, dose modification, CYP2D6 phenotypes and/or incorporating metabolites data. In terms of fetal exposure, the model can also be used to predict drug exposure in individual organs relevant for risk assessment.
References:
[1] Abduljalil K et al. Clin Pharmacokinet. 2012;51(6):365-96.
[2] Abduljalil K, et al. Clin Pharmacokinet 2018;57(9):1149–1171
[3] Abduljalil K, et al. Clin Pharmacokinet 2019. PMID 29987449
[4] Rodgers T et al. J Pharm Sci. 2006;95(6):1238-57.
[5] O’Hare MF et al. Eur J Clin Pharmacol. 1984;27(5):583-7
[6] Smith MT et al. Eur J Clin Pharmacol. 1983;24(6):727-237
Reference: PAGE () Abstr 9243 [www.page-meeting.org/?abstract=9243]
Poster: Drug/Disease Modelling - Absorption & PBPK