Population pharmacokinetic analysis of elafibranor and metabolite GFT1007 to support exposure-response characterization and dose selection in patients with primary biliary cholangitis
Stijn van Beek (1), Qing Xi Ooi (1), Karl Brendel (2), Marion Dehez (2)
(1) Pharmetheus AB, Uppsala, Sweden, (2) Ipsen, Les Ulis, France
Objectives: Elafibranor is a dual peroxisome proliferator-activated receptor α/δ agonist. It is an orally administered, liver-targeted drug candidate developed for the treatment of primary biliary cholangitis (PBC), which is a rare, chronic cholestatic liver disease. A population analysis was conducted with the aim of characterizing the pharmacokinetic (PK) characteristics of elafibranor and its main active metabolite GFT1007, and to evaluate the impact of covariates.
Methods: The data for this analysis originated from 13 Phase I studies, 2 Phase II studies, and 2 Phase III studies. In these studies, the dose levels ranged from 5 mg to 360 mg and the regimens ranged from single dosing to daily dosing for over a year.
Separate population PK models for elafibranor and GFT1007 were developed. A sequential method typically used for PK-pharmacodynamic model development[1,2] and parent-metabolite modeling was considered, but not pursued as the graphical analysis suggested that limited GFT1007 formation is dependent on the systemic elimination of elafibranor. A simultaneously estimated joint model for elafibranor and GFT1007 was not feasible due to the extremely long estimation time of the model. The influence of covariates was evaluated using the stepwise covariate model building procedure. The PK analysis was performed using NONMEM version 7.5.0. PK simulations were conducted using the mrgsolve package in R and the effect of covariates on PK was illustrated using the forest plots.
Results: 12,205 and 10,592 concentration observations from 892 and 894 adult subjects, including 130 patients with PBC, for elafibranor and GFT1007, respectively, were included in the analysis.
Both elafibranor absorption and GFT1007 formation were described by a sequential zero-order and first-order process after a short lag time and their dispositions follow a two-compartment kinetic with a linear elimination process. The absorption of elafibranor and formation of GFT1007 were associated with large inter-individual variability, inter-occasion variability (elafibranor only), and residual unexplained variability relative to the disposition process. A more than proportional decrease in elafibranor exposure with lower doses was observed. However, between 50–360 mg/day, the PK of elafibranor is expected to be linear.
The elafibranor-GFT1007 dynamics were characterized by limited GFT1007 formation that is dependent on the systemic elimination of elafibranor, as evident by:
- GFT1007 elimination half-life (median 10.7 95% confidence interval [9.84, 11.9] hours) being shorter compared to elafibranor (59.7 [52.1, 67.3] hours)
- Plateauing GFT1007 concentrations that seem invariant to the continued increase in elafibranor concentrations over time
- GFT1007 having a much higher Cmax and similarly short time to Cmax compared to elafibranor, already after administration of the first dose
Based on the PK simulations, the time to steady state was predicted to be around 12 days for elafibranor and 2 days for GFT1007. Following elafibranor administration at the proposed dose level of 80 mg, exposure to GFT1007 in patients with PBC is higher than their exposure to elafibranor. At steady state, Cmax is approximately 8 times higher, AUC 5 times larger, and Cmin 1.5 times higher for GFT1007 compared to elafibranor.
Conclusions: The PK of elafibranor and GFT1007 is characterized by a highly variable absorption and the disposition is two-compartmental and linear. For the proposed dose of 80 mg/day, the PK of elafibranor and GFT1007 is expected to be linear. The elafibranor-GFT1007 dynamics were atypical whereby only limited GFT1007 formation seems dependent on the systemic elimination of elafibranor. Following elafibranor administration of 80 mg/day, exposure to GFT1007 in patients with PBC is much higher than their exposure to elafibranor. Then, assuming equipotency for elafibranor and GFT1007, the pharmacodynamic effect is likely to be driven more by GFT1007 than elafibranor.
References:
[1] Zhang L, Beal SL, Sheiner LB. Simultaneous vs. Sequential Analysis for Population PK/PD Data I: Best-Case Performance. J Pharmacokinet Pharmacodyn. 2003 Dec;30(6):387-404.
[2] Zhang L, Beal SL, Sheiner LB. Simultaneous vs. Sequential Analysis for Population PK/PD Data II: Robustness of Methods. J Pharmacokinet Pharmacodyn. 2003 Dec;30(6):405-16.
*Analysis and publication sponsor: Ipsen; included studies sponsor: GENFIT
