Eef Hoeben (1), Pieter Annaert (2), Kristel Van Calsteren (3), Sigrid Conings (3), Karel Allegaert (3), Jan Deprest (3) and Francesca M Russo (3)
(1) BioNotus GCV, Galileilaan 15, 2845 Niel, Antwerp, Belgium, (2) Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium, (3) Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium.
Objectives: Sildenafil (SIL) is a selective phosphodiesterase 5 (PDE5) inhibitor. It is currently being administered to pregnant patients with pulmonary hypertension and is under evaluation as a treatment for several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction. The trans-placental passage of SIL was studied in an ex-vivo human placenta perfusion experiment1. The objective of this analysis was to develop a model describing the ex-vivo transfer of SIL through the human placenta and to estimate the trans-placental transfer parameters (i.e. diffusion (CLcot), placental elimination (kPE) and placental partition coefficient (Kppl)) of SIL from this ex-vivo human placenta perfusion experiment.
Methods: Six placentas were collected after term delivery from healthy volunteers, cannulated and dually perfused. Antipyrine (AP), a small non-protein bound molecule that passes the placental barrier by passive diffusion, was used as internal control. SIL and AP were added to the maternal circulation at 50 ng/mL (i.e. therapeutic concentration (TC); N=3) and 500 ng/mL (i.e. maximum tolerated concentration (MC); N=3) for SIL and at 100 mg/mL (N=6) for AP. Samples were collected from both fetal and maternal reservoir at different time points and were analyzed for SIL, its desmethyl metabolite (DM)-SIL and AP by validated LC-MSMS or -UV methods. Transfer of SIL and AP across the placenta was modelled as a cotyledon split into maternal (M) and fetal (F) compartments2. Data were analyzed by a non-linear mixed effects modeling approach, using NONMEM software3. Inter-individual variability (IIV) was evaluated using an exponential error model and residual error (RE) was described using a proportional model. The FOCE method with interaction was used for estimation of model parameters, i.e. CLcot, kPE and Kppl, IIV and RE.
Results: SIL crossed the placenta at both (TC and MC) concentrations. Both maternal and fetal levels reached a plateau at 90-120 min. The FM ratios at equilibrium (150 min) were 0.83 (0.71–1.00) for TC and 0.93 (0.70-1.04) for MC. DM-SIL was not detected in any sample, suggesting negligible placental CYP3A-mediated metabolism. A 4-compartment transport model provided an adequate description of the observed ex-vivo data of SIL and AP in the fetal and maternal reservoir. The trans-placental transfer parameters of SIL and AP were estimated with acceptable precision. There was considerable IIV on the trans-placental parameters, especially on CLcot, which might be explained by the possible contribution of other factors like drug transporters, metabolism (other than CYP3A-mediated) and/or protein binding. The estimated kPE was small and may represent leakage and/or metabolism via other pathway(s).
Conclusion: SIL crosses the term placenta ex-vivo. The trans-placental transfer parameters could be estimated from the ex-vivo human placenta perfusion experiment using the developed model. The estimated values of these parameters will be implemented in a pregnant-physiologically based pharmacokinetic (p-PBPK) model in order to be able to predict the PK profiles of SIL in the fetus.
References:
[1] Russo FM, Conings S, Annaert P, Van Mieghem T, Allegaert K, Deprest J, Van Calsteren K. 474: Placenta transfer of sildenafil citrate in the ex-vivo human cotyledon perfusion model. Abstract. American Journal of Obstetrics & Gynecology 2017. 216:S280 Manuscript under revision.
[2] Mendes MDS, Hirt D, Vinot C, Valade E, Lui G, Pressiat C, Bouazza N, Foissac F, Blanche S, Le MP, Peytavin G, Treluyer J-M, Urien S and Benaboud S. Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models. British Journal of Clinical Pharmacology, 81:646-657, 2015.
[3] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 27 (2018) Abstr 8455 [www.page-meeting.org/?abstract=8455]
Poster: Drug/Disease Modelling - Other Topics