Yesong Shin, Dongwoo Chae, Kyungsoo Park
Brain Korea 21 FOUR Project for Medical Science, Yonsei University,Seoul,South Korea
Objectives: Leflunomide is an immunosuppressive drug indicated for the treatment of rheumatoid arthritis (RA). Leflunomide is characterized by high protein binding and long half-life. Due to enterohepatic circulation(EHC) of A771726, multiple peaks are observed in the concentration-time profile, which may contribute to its long half-life (∼2 weeks). For this reason, FDA recommended a loading dose of 100mg Q.D. for 3 days to reach rapid steady-state concentration level. While the pharmacokinetics (PK) of its active metabolite A771726 reportedly show large interindividual variability [1,2], no efficient dose individualization strategy is currently in use. The goal of this study was to develop a population PK model for leflunomide and propose an optimal dosing strategy in RA patients.
Methods: Data was collected in two phase 1 clinical trials . The study subjects’ age was 25.2±3.8 years and weights 71.2±8.9kg. Through these studies, A771726 plasma concentration data were collected from 50 healthy male volunteers. A single oral dose of 40 mg was given under fasting condition. We first developed a conventional PK (CPK) model, and subsequently elaborated the model by adding a gallbladder compartment to accommodate enterohepatic circulation (EHC) of leflunomide. We assumed that the gallbladder emptying period for bile release occurred at every mealtime. Multiple dose simulations were performed to determine the optimal dosing regimen that minimizes the error between the target and predicted concentrations.
Results: The data were best described by a two compartment model with first order absorption and EHC, with allometric scaling of CL and V by body weight. Here, enterohepatic recycling was parameterized with the rate constant of drug accumulation into the gallbladder (K24) and the duration of drug release into the gut (T41). The typical parameter estimates were 1.61 h-1 for the absorption rate constant (KA), 6.83 L for central compartment volume(V2), 2.27 L for peripheral compartment volume(V3), 0.593 L/h for inter-compartment clearance(Q), 0.0273 L/h for systemic clearance (CL), 4 h for T41, and 0.0116 h-1 for K24. The inter-individual variability estimates (CV%) were 107.2% for KA, 24.7% for V2, and 27.22% for CL. No significant covariate was found other than body weight, which was incorporated into CL and V with power coefficients of 0.75 and 1, respectively. Multiple dose simulations based on the final model suggested that to attain target concentration, the loading dose should be increased by 15 mg for every 10 kg increase in body weight.
Conclusions: The population PK model incorporating EHC well described the pharmacokinetic profile of A771726. Based on extensive model simulations, we propose a personalized dosing scheme for RA patients based on body weight. The large inter-individual variability of KA could be due to pharmacogenetic differences, such as that related to ABCG2 [3,4], or could be due to our use of a common KA for both initial drug absorption and EHC-mediated reabsorption. A yet another possibility could be a complex absorption mechanism that cannot be adequately captured by simple first order kinetics. The use of Physiologically Based Finite Time Pharmacokinetic (PBFTPK) model might be a possible solution in this case [5]. Notwithstanding these limitations, our work is the first step towards dose optimization of leflunomide and is expected to reduce the incidence of adverse events related to inappropriate dosing.
References:
[1] AM Hopkins, MD Wiese, SM Proudman, CE O’Doherty, DJR Foster, and RN Upton. Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients. CPT Pharmacometrics Syst Pharmacol. 2015 Jun; 4(6): 362–371.
[2] Bohanec Grabar P, Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis. Drug Metab Dispos. 2009 Oct;37(10):2061-8. doi: 10.1124/dmd.109.027482. Epub 2009 Jul 6.
[3] W. Weber, L.H. The population approach: Measuring and managing variability in response, concentration and dose; COST B1 medicine: European cooperation in the field of scientific and technical research, Brussels: European Commission: 1997; pp 238–244.
[4] W. Weber, L.H. Use of a population approach to the development of leflunomide: A new disease-modifying drug in the treatment of rheumatoid arthritis; Hoechst Marion Roussel. COST B1 medicine, Geneva: 1997; pp 239–244
[5] Chryssafidis P, Tsekouras AA, Macheras P. Re-writing oral pharmacokinetics
using physiologically based finite time pharmacokinetic (PBFTPK) models.
Pharm. Res. 2022;39
Reference: PAGE 30 (2022) Abstr 9959 [www.page-meeting.org/?abstract=9959]
Poster: Drug/Disease Modelling - Absorption & PBPK