Maïlys De Sousa Mendes
Paris V University
Pregnant women and foetuses are exposed to numerous drugs. However they are orphan populations regarding to safety and efficacy. Therefore the prediction of maternal and foetus drug exposures prior to administration would be highly useful. A physiologically based pharmacokinetic (PBPK) model for nevirapine (NVP), which is metabolized by CYP3A4, 2B6 and 2D6 pathways was developed to predict maternal and foetal pharmacokinetics (PK).
The model was developed in non-pregnant and pregnant women. All physiological and enzymatic changes that could impact NVP pharmacokinetics were taken into account. Transplacental parameters estimated from ex-vivo human placenta perfusion experiments were included in this PBPK modelTo validate the model, observed maternal and cord blood concentrations were compared to predicted concentrations [1]. The impact of foetal clearance on foetal PK was also investigated.
By implementing physiological changes including CYP3A4, 2D6 and 2B6 inductions we predicted a clearance increase of 21 % in late pregnancy. The PBPK model successfully predicted the disposition for non-pregnant and pregnant populations. Parameters obtained from the ex-vivo experiments allowed to predict NVP concentrations that matched observed cord blood concentrations. The foetal-to-maternal area under the curve ratio (0-24h interval) was 0.77. Foetal metabolism had not significant effect on foetal PK.
The PBPK approach is a useful tool to quantify a priori drug exposure during pregnancy for metabolized drugs and can be applied to evaluate alternative dosing regimens to optimise drug therapy. This approach, including ex-vivo human placental perfusion parameters, is a promising approach to predict human foetal exposure.
References:
[1] Benaboud S, Ekouévi DK, Urien S, Rey E, Arrivé E, Blanche S, Gray G, Sim KL, Avit D, McIntyre J, Nerrienet E, Dabis F, Tréluyer J-M, Hirt D. Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates. Antimicrob Agents Chemother. 2011 Jan;55(1):331–7.
Reference: PAGE 25 (2016) Abstr 5761 [www.page-meeting.org/?abstract=5761]
Poster: Drug/Disease modeling - Absorption & PBPK