Nina Nauwelaerts (1), Neel Deferm (1), Julia Macente (1), Bart Lammens (2), Karel Allegaert (1), Thomas Bouillon (2, 3), Anne Smits (1), Pieter Annaert (1,2)
(1) KU Leuven, (2) BioNotus, (3) IntiQuan (current affiliation)
Objectives:
Sildenafil and bosentan are used as combined therapy for pulmonary arterial hypertension (PAH). Since pregnancy is contra-indicated for women with PAH [1], there is a huge knowledge gap regarding the safety of sildenafil and bosentan during pregnancy and lactation [2,3]. Only a single case report measured sildenafil levels in human milk, and no information was found for bosentan [4]. We have recently reported on a single mother-infant pair exposed to sildenafil and bosentan during lactation (manuscript accepted). The objective of this study was to use these data to verify a Physiologically-Based Pharmacokinetic (PBPK) model to predict exposure to sildenafil and bosentan in human milk, and subsequent systemic infant exposure.
Methods:
The PBPK model was built in PK-Sim® (Open Systems Pharmacology, v 9.1) and MoBi. A previously developed PBPK model for bosentan (unpublished data) was combined with a published PBPK model for sildenafil [5]. Co-administration of sildenafil and bosentan results in drug-drug interactions (DDI), i.e. CYP3A4 induction by bosentan [6] and OATP1B1/3 inhibition by sildenafil [7]. The combined administration of both medicines was simulated using a virtual population (n=100) and compared to observed data [8].
The PBPK model was extended with a breast compartment, including a subcompartment representing the human milk [9]. Transfer of medicines between the breast intracellular and human milk was parametrized by a secretion clearance (CLsec) and a reuptake clearance (CLre), based on physicochemical properties [10]. CLsec was further fitted to (sparse) human milk data from one sampling day from our case report. A lactating population (n=100) was used to simulate the steady-state plasma and human milk concentrations after oral administration of sildenafil (20 mg, 3x/day) and bosentan (125 mg, 2x/day). The predictive performance was evaluated using (sparse) human milk data from the other sampling day and the reported concentration range for sildenafil [4]. The milk-to-plasma ratio was calculated based on the area under the curve (AUC).
The daily infant dosages (DIDs) were calculated based on a human milk intake of 150 mL/kg/day. The DIDs were compared to maternal doses for sildenafil (0.72 mg/kg/day) and bosentan (3.01 mg/kg/day), and to usual therapeutic infant doses for sildenafil (1.50 mg/kg/day) and bosentan (4.00 mg/kg/day). Finally, the systemic exposure in the breastfed infant was simulated using a pediatric population (0-12 months, n=1200).
Results:
The median fold errors on the AUClast and maximum plasma concentration (Cmax) for co-administered sildenafil and bosentan were 0.74 and 1.09 for sildenafil, and 0.84 and 0.97 for bosentan [8].
For the lactation PBPK model, CLsec and CLre were 244.4 mL/h and 962.1 mL/h for sildenafil and 3187 mL/h and 1893 mL/h for bosentan. The (sparse) observed data for sildenafil and bosentan from both sampling days fall within the 5th-95th percentile of the population simulation. Average steady-state human milk concentration was 3.5 µg/L for sildenafil, which falls within the reported concentration range (1.64-4.49 µg/L) [4], and 53 µg/L for bosentan. The milk-to-plasma ratio was 0.75% for sildenafil and 0.11% for bosentan.
DID for sildenafil (0.53 µg/kg/day) and bosentan (7.9 µg/kg/day) were small compared to maternal (0.07% and 0.3%) and usual therapeutic infant (0.04% and 0.2%) doses. Infant systemic exposure relative to maternal exposure was 1.3% for sildenafil, and 7.2% for bosentan.
Conclusion:
PBPK modelling was successfully used to predict the transfer of sildenafil and bosentan into human milk, although further verification of the predictive performance is required. Ongoing efforts aim to determine the permeability coefficients across the blood-milk barrier in mammary epithelial cells. Application to other medicines aims to develop a generic in vitro/in silico workflow. To conclude, this study shows the potential of PBPK modelling to fill the knowledge gap regarding the safety of medicines in lactating women and their infants.
Acknowledgement:
This work has received support from the EU/EFPIA Innovative Medicines Initiative [2] Joint Undertaking ConcePTION grant No. 821520. The research leading to these Results was conducted as part of the ConcePTION consortium. This abstract only reflects the personal views of the stated authors. Nina Nauwelaerts received a PhD fellowship from the Research Foundation—Flanders (1S50721N).
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Reference: PAGE 30 (2022) Abstr 10148 [www.page-meeting.org/?abstract=10148]
Poster: Drug/Disease Modelling - Absorption & PBPK