Population pharmacokinetics and pharmacokinetics-pharmacodynamics analyses of elafibranor to support dose selection in primary biliary cholangitis

This publication present the research behind the global regulatory success of elafibranor (Iqirvo®), a first-in-class PPAR-α/δ agonist for the treatment of primary biliary cholangitis (PBC).

PBC is a rare, autoimmune chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. If left untreated, the disease can progress to liver failure, making early and effective management critical.

While ursodeoxycholic acid (UDCA) remains the standard first-line treatment, there is a vital need for second-line therapies for patients who have an inadequate response or are unable to tolerate UDCA.

By integrating data from 17 clinical trials, our team used quantitative modeling to bridge the gap between complex drug exposure and clinical response. This approach not only confirmed the efficacy of the 80 mg/day dose but also demonstrated that no dose adjustments were necessary across diverse patient subpopulations. 

Key highlights: 

• Robust modeling: Our team developed population PK models using data from 894 patients to characterize the PK of elafibranor and its active metabolite, GFT1007.
• Exposure-response link: PKPD modeling established a clear relationship between drug exposure (total AUC during a dosing interval at steady state) and reductions in biochemical markers such as alkaline phosphatase (ALP).
• Dose confirmation: Simulations confirmed that 80 mg/day achieves near-maximum effect, with ~91% of patients predicted to reach a ≥15% relative decrease in ALP at Week 52.
• Consistent efficacy: Analysis showed that covariates, such as body weight or age, did not have a clinically meaningful impact on response, supporting a flat-dosing regimen.

Karl Brendel and Marion Dehez from Ipsen, and the University of Ljubljana in collaboration with our consultants Qing Xi Ooi, Stijn van Beek, Jurij Aguiar Zdovc, and Maddlie Bardol provided the essential dose justification for recent approvals by U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

This work exemplifies the power of model-informed drug development (MIDD) and pharmacometrics in accelerating the path from early development to regulatory approval, ultimately bringing a first-in-class treatment to the PBC community more efficiently and offering a vital new pathway for patients who previously had few treatment options.