Challenges Related to Acquisition of Physiological Data for Physiologically Based Pharmacokinetic (PBPK) Models in Postpartum, Lactating Women and Breastfed Infants—A Contribution from the ConcePTION Project

Physiologically based pharmacokinetic (PBPK) modelling is a bottom-up approach to predict pharmacokinetics in specific populations based on population-specific and medicine-specific data. Using an illustrative approach, this review aims to highlight the challenges of incorporating physiological data to develop postpartum, lactating women and breastfed infant PBPK models. For instance, most women retain pregnancy weight during the postpartum period, especially after excessive gestational weight gain, while breastfeeding might be associated with lower postpartum weight retention and long-term weight control. Based on a structured search, an equation for human milk intake reported the maximum intake of 153 mL/kg/day in exclusively breastfed infants at 20 days, which correlates with a high risk for medicine reactions at 2–4 weeks in breastfed infants. Furthermore, the changing composition of human milk and its enzymatic activities could affect pharmacokinetics in breastfed infants. Growth in breastfed infants is slower and gastric emptying faster than in formula-fed infants, while a slower maturation of specific metabolizing enzymes in breastfed infants has been described. The currently available PBPK models for these populations lack structured systematic acquisition of population-specific data. Future directions include systematic searches to fully identify physiological data. Following data integration as mathematical equations, this holds the promise to improve postpartum, lactation and infant PBPK models.</p

Generic PBPK template for predicting drug concentration time profiles in human breast milk (D3.6)

This deliverable described in the present report reports on the development, evaluation and application of a generic Physiologically-based pharmacokinetic modelling (PBPK) template: To predict medicine concentration time profiles in human milk; To calculate milk-associated medicine doses ingested by neonates and infants

PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia

Sildenafil is a potent vasodilator and phosphodiesterase type five inhibitor, commercially known as Revatio® and approved for the treatment of pulmonary arterial hypertension. Maternal administration of sildenafil during pregnancy is being evaluated for antenatal treatment of several conditions, including the prevention of pulmonary hypertension in fetuses with congenital diaphragmatic hernia. However, determination of a safe and effective maternal dose to achieve adequate fetal exposure to sildenafil remains challenging, as pregnancy almost always is an exclusion criterion in clinical studies. Physiologically-based pharmacokinetic (PBPK) modelling offers an attractive approach for dose finding in this specific population. The aim of this study is to exploit physiologically-based pharmacokinetic modelling to predict the required maternal dose to achieve therapeutic fetal exposure for the treatment congenital diaphragmatic hernia. A full-PBPK model was developed for sildenafil and N-desmethyl-sildenafil using the Simcyp simulator V21 platform, and verified in adult reference individuals, as well as in pregnant women, taking into account maternal and fetal physiology, along with factors known to determine hepatic disposition of sildenafil. Clinical pharmacokinetic data in mother and fetus were previously obtained in the RIDSTRESS study and were used for model verification purposes. Subsequent simulations were performed relying either on measured values for fetal fraction unbound (fu = 0.108) or on values predicted by the simulator (fu = 0.044). Adequate doses were predicted according to the efficacy target of 15 ng/mL (or 38 ng/mL) and safety target of 166 ng/mL (or 409 ng/mL), assuming measured (or predicted) fu values, respectively. Considering simulated median profiles for average steady state sildenafil concentrations, dosing regimens of 130 mg/day or 150 mg/day (administered as t.i.d.), were within the therapeutic window, assuming either measured or predicted fu values, respectively. For safety reasons, dosing should be initiated at 130 mg/day, under therapeutic drug monitoring. Additional experimental measurements should be performed to confirm accurate fetal (and maternal) values for fu. Additional characterization of pharmacodynamics in this specific population is required and may lead to further optimization of the dosing regimen

Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling—A Contribution from the ConcePTION Project

Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for “non-lactating” adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage

PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia

Sildenafil is a potent vasodilator and phosphodiesterase type five inhibitor, commercially known as Revatio® and approved for the treatment of pulmonary arterial hypertension. Maternal administration of sildenafil during pregnancy is being evaluated for antenatal treatment of several conditions, including the prevention of pulmonary hypertension in fetuses with congenital diaphragmatic hernia. However, determination of a safe and effective maternal dose to achieve adequate fetal exposure to sildenafil remains challenging, as pregnancy almost always is an exclusion criterion in clinical studies. Physiologically-based pharmacokinetic (PBPK) modelling offers an attractive approach for dose finding in this specific population. The aim of this study is to exploit physiologically-based pharmacokinetic modelling to predict the required maternal dose to achieve therapeutic fetal exposure for the treatment congenital diaphragmatic hernia. A full-PBPK model was developed for sildenafil and N-desmethyl-sildenafil using the Simcyp simulator V21 platform, and verified in adult reference individuals, as well as in pregnant women, taking into account maternal and fetal physiology, along with factors known to determine hepatic disposition of sildenafil. Clinical pharmacokinetic data in mother and fetus were previously obtained in the RIDSTRESS study and were used for model verification purposes. Subsequent simulations were performed relying either on measured values for fetal fraction unbound (fu = 0.108) or on values predicted by the simulator (fu = 0.044). Adequate doses were predicted according to the efficacy target of 15 ng/mL (or 38 ng/mL) and safety target of 166 ng/mL (or 409 ng/mL), assuming measured (or predicted) fu values, respectively. Considering simulated median profiles for average steady state sildenafil concentrations, dosing regimens of 130 mg/day or 150 mg/day (administered as t.i.d.), were within the therapeutic window, assuming either measured or predicted fu values, respectively. For safety reasons, dosing should be initiated at 130 mg/day, under therapeutic drug monitoring. Additional experimental measurements should be performed to confirm accurate fetal (and maternal) values for fu. Additional characterization of pharmacodynamics in this specific population is required and may lead to further optimization of the dosing regimen