Xiaoning Wang1, Jin Zhou1, Bill Poland2, Shuang Xu2, Ana Ruiz-Garcia1
1Gilead Sciences, Inc., 2Certara
Introduction: Seladelpar is a once-daily (QD) oral peroxisome proliferator–activated receptor delta (PPARd) agonist indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA [1]. Objectives: To develop a population pharmacokinetics (PK) model of seladelpar in healthy participants, patients with hepatic impairment of various aetiologies, and patients with PBC, and to evaluate the effects of intrinsic and extrinsic factors on seladelpar PK parameters. Methods: Data were pooled from 8 Phase 1 and 4 Phase 2/3 studies of seladelpar in healthy participants, patients with hepatic impairment of various aetiologies, and patients with PBC. The population PK analysis was conducted in NONMEM v7.4 [2]. Population and individual model parameters were estimated using the first-order conditional estimation with eta-epsilon interaction (FOCE-I). A full covariate modelling approach was implemented to evaluate covariate effects. Covariates were retained in the final model if they resulted in a seladelpar exposure change of <80% or >125% compared with the reference. The performance of the final model was evaluated with diagnostic plots and predictive checks. Monte Carlo simulations were conducted using the final population PK model parameters. A virtual population was created by resampling with replacement from the 255 PBC patients included in the population PK analysis population. The simulation was performed with seladelpar 10 mg QD to evaluate the steady-state exposure metrics. Results: The analysis dataset included a total of 4781 PK observations of seladelpar from 488 healthy participants, patients with hepatic impairment, and patients with PBC. Seladelpar PK were characterised by a 2-compartment population PK model with sequential zero-order release and first-order absorption. For a 72.6-kg patient with PBC, the apparent clearance (CL/F) and apparent central volume (V/F) (relative standard error [RSE]) were estimated at 12.6 L/h (3.31%) and 84.4 L (3.66%), respectively. The total apparent volume of distribution was 110.3 L. The final model included the covariate effects of body weight, food intake, patient status, and hepatic impairment. The effects of body weight were included using allometric scaling with fixed coefficients (0.75 for clearance, 1 for central volume). Hepatic impairment increased the bioavailability of seladelpar and decreased the apparent clearance and volume of distribution. As a result, steady-state area under the concentration curves (AUC [90% CI]) were predicted to increase by 13% (2%–25%) for patients with PBC and Child-Pugh (CP) class A without portal hypertension; 54% (32%–75%) for patients with PBC and CP class A with portal hypertension; 48% (29%–66%) for patients with PBC and CP class B. The increase of AUC was 145% (116%–176%) for patients with PBC and CP class C based on limited data. Seladelpar administration with food was predicted to reduce the steady-state maximum observed concentration (Cmax [90% CI]) by 23% (15%–31%). Relative bioavailability (90% CI) was 15% (11%–19%) lower in healthy participants when compared with patients with PBC. Other covariates, including age, sex, baseline laboratory values (eg, alkaline phosphatase, albumin), CYP2C9 phenotype, concomitant proton pump inhibitor (PPI) use, and concomitant UDCA use, did not result in seladelpar exposure change of more than 10% compared with the reference and were not retained in the final model. Conclusion: The population PK model developed herein adequately described seladelpar concentrations over time in healthy participants, patients with hepatic impairment, and patients with PBC. The model-predicted increase of seladelpar exposure from CP class A status (with or without portal hypertension) was modest. There was no clinically relevant effect on the exposure based on food intake. Other covariates, including age, sex, and concomitant PPI use, were not significant or clinically relevant. These findings further support the use of seladelpar 10 mg QD dosing in patients with PBC with CP class A cirrhosis, and without regard to food or PPI use.
[1] Seladelpar. Summary of product characteristics. European Medicines Agency. Gilead Sciences Inc.; 2025. [2] Beal S.L., Sheiner L.B., Boeckmann A.J., & Bauer R.J. (Eds). NONMEM 7.4 users guides (ICON plc, Gaithersburg, MD, 1989–2018).
Reference: PAGE 33 (2025) Abstr 11771 [www.page-meeting.org/?abstract=11771]
Poster: Drug/Disease Modelling - Other Topics