CT-006 - APPLICATION OF PBPK TO ASSESS THE IMPACT OF UGT1A1 GENOTYPE ON DOLUTEGRAVIR EXPOSURE IN PREGNANT WOMEN AND FETUSES

J. Ning¹, A. Pansari¹, K. Yeo², A. Heikkinen¹, C. WAITT³, L. Almond⁴; ¹Certara UK, ²Certara UK Ltd, Simcyp Division, ³University of Liverpool, ⁴Certara UK (Simcyp).

Background: A major concern of drug use in pregnant women is transplacental drug transfer leading to fetal drug exposure which may cause potential toxicity to the developing fetus. Dolutegravir, an HIV integrase strand transfer inhibitor [1], is primarily metabolized by UGT1A1. The objective of this work was to predict maternal and fetal disposition of dolutegravir during pregnancy using a PBPK modelling approach accounting for the various UGT1A1 genotypes.

Methods: A PBPK model for dolutegravir was developed and verified in non-pregnant subjects using the Simcyp Simulator V22. The model was then extended to include a permeability limited placental model using a virtual pregnancy population that considers gestational-dependent increase in UGT1A1 activity, in addition to other physiological changes. The transplacental passive permeability clearance (CLPDM/PDF) of 0.00155 L/h/mL of placenta volume was scaled from the published ex vivo cotyledon perfusion data [2]. The maternal and umbilical cord PK of dolutegravir were verified against the observed data [3-5]. The model was then applied to predict the maternal and fetal exposure of UGT1A1 extensive metabolizers (EMs) and poor metabolizers (PMs) following 50 mg QD dolutegravir orally over 14 days at gestational weeks (GWs) of 17 and 40.

Results: The simulated dolutegravir exposure in non-pregnant subjects, pregnant subjects and the fetus were within 1.6-fold of observed data [1, 3-5]. The predicted cord to maternal ratio (GW of 38) of 1.30 (range: 0.69-2.39) was reasonably consistent with observed ratios of 1.21 (range: 0.51-2.11) [5] and 1.25 [3]. Predicted dolutegravir PK parameters in UGT1A1 EMs and PMs (Table 1) show that the AUC of dolutegravir in both maternal plasma and umbilical cord at GW 17 and 40 in UGT1A1 PMs that is ~1.6-fold higher in PMs than in UGT1A1 EMs. The predicted cord to maternal ratio in UGT1A1 PMs is comparable to UGT1A1 EMs at GW 17 and 40.

Conclusion: PBPK modelling can be used to assess untested scenarios that are difficult to investigate clinically, such as the impact of phenotypes on drug exposure in pregnant women and their fetuses.

[1] NDA204790
[2] Freriksen Clin Pharmacol Ther. 2020 Jun;107(6):1352-1361
[3] Mulligan AIDS. 2018 Mar 27;32(6):729-737
[4] Bollen Clin Infect Dis. 2021 Jan 23;72(1):121-127
[5] Waitt PLoS Med. 2019 Sep 20;16(9):e1002895