P0671 Supporting vedolizumab treatment throughout pregnancy: Insights from a population pharmacokinetic model
Authors: Duvnjak Z , Steenholdt C , Skejø C , Baunwall S M D , Widigson E S K , Korgaard J , Klassen R A , Bolstad N , Kjeldsen J , Poulsen A , Kievit L , Larsen L , Munkholm P , Svenningsen L , Haderslev K V , Wildt S , Vind I , Kelsen J , Abrantes J A , Michelet R , Huisinga W , Kloft C , Julsgaard M 
Published: January 2025

Abstract

Background
The pharmacokinetic (PK) profile of vedolizumab during pregnancy is not fully characterised, though concentrations have been reported to drop1.To minimise transplacental transfer, discontinuation in the 3rd trimester has been suggested, but this may lead to flare in IBD in pregnancy and postpartum2. This study aimed to characterise changes in vedolizumab PK in pregnancy using mathematical modelling and to explore dosing scenarios to guide decisions on 3rd-trimester dosing.

Methods
A multicenter, prospective, observational study was conducted recruiting pregnant women with IBD receiving vedolizumab. Pre-pregnancy patient characteristics were recorded. Vedolizumab dosing regime, vedolizumab trough concentrations, presence of vedolizumab antidrug antibodies, clinical and biochemical data were assessed before vedolizumab administrations and at delivery. Vedolizumab data were analysed using a nonlinear mixed-effects PK modelling approach. As a starting point for pregnancy model development, a PK model of vedolizumab from the drug development program based on 2554 patients was used3. Employing the final model, different dosing scenarios were simulated. Underexposure to vedolizumab was defined as concentrations ≤ 10 mg/L4.

Results
From 39 pregnant women, 136 vedolizumab measurements were analysed. The developed PK model comprised 2 disposition compartments with linear and target-mediated elimination pathways, and it incorporated the impact of pre-pregnancy patient characteristics e.g. albumin levels, body weight and disease status, as well as a gestation-dependent decrease in albumin due to plasma expansion and additional increase in elimination in the 3rd trimester. Trough vedolizumab concentrations were observed to drop during pregnancy, especially in the 3rd trimester (Figure 1: dosing interval of every 8 weeks). The median trough concentrations (pre-pregnancy albumin of 40 g/L) decreased by 10%, 20%, 30% and 40% until weeks 10, 23, 32 and 36 of gestation, respectively. Vedolizumab concentrations were lower for patients with lower pre-pregnancy albumin. Changes in the vedolizumab PK profile in pregnancy for two dosing scenarios are shown in Figure 2. If the dose scheduled in the 3rd trimester is skipped, the duration of the vedolizumab underexposure is prolonged in ≥ 50% of the patients, depending on the delivery time, to 6-10 weeks (Figure 2a) and 2-6 weeks (Figure 2b).

Conclusion
Vedolizumab concentrations progressively decrease in pregnancy, especially in the 3rd trimester, resulting in underexposure to the drug if not dosed throughout pregnancy, including the last trimester. These results underscore the importance of continuing vedolizumab throughout pregnancy to maintain disease remission in pregnancy and post-partum.

References
1.Prentice R, Flanagan E, Wright EK, et al. Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero. Clin Gastroenterol Hepatol. Published online March 2024:S1542356524002520. doi:10.1016/j.cgh.2024.02.0252.
2.Torres J, Chaparro M, Julsgaard M, et al. European Crohn’s and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. J Crohns Colitis. 2023;17(1):1-27. doi:10.1093/ecco-jcc/jjac1153.
3.Rosario M, Dirks NL, Gastonguay MR, et al. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther. 2015;42(2):188-202. doi:10.1111/apt.132434.
4.Verstockt B, Mertens E, Dreesen E, et al. Influence of Drug Exposure on Vedolizumab-Induced Endoscopic Remission in Anti-Tumour Necrosis Factor [TNF] Naïve and Anti-TNF Exposed IBD Patients. J Crohns Colitis. 2020;14(3):332-341. doi:10.1093/ecco-jcc/jjz151.