Population pharmacokinetics of FM101 in healthy volunteers and long-term safety prediction: phase 1 study
Hongjae Lee (1, 2), Heungjo Kim (1, 2), Jangyoun Hwang (1, 2, 3), Ji Yong Kim (3), Saehan Kang (3), Min Jung Chang (1, 2, 4)
(1) Department of pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea, (2) Department of Pharmaceutical Medicine and Regulatory, Yonsei University, Incheon, Republic of Korea, (3) Future Medicine Co., Ltd., Republic of Korea (4) Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon, Republic of Korea
Introduction/Objectives: Non-alcoholic steatohepatitis is a chronic liver disease characterized by hepatic steatosis, inflammation, and fibrosis. Currently, there are no approved pharmacological therapies highlighting the need for novel therapeutic strategies [1].
Adenosine and its receptor play crucial roles in regulating energy metabolism and immune response. The A3 adenosine receptor inhibits the cyclic adenosine monophosphate-protein kinase A pathway resulting in the regulation of mitochondrial electron transport chain and apoptosis [2]. FM101, the drug of interest in this study, is a biased agonist of A3 adenosine receptor with potential therapeutic effects on non-alcoholic steatohepatitis. Regarding the involvement of A3 adenosine receptor in energy metabolism and immune response regulation, strong preclinical data exists based on multiple mechanisms of action for FM101, including inflammation, fibrosis, and lipid accumulation [3]. To investigate the effects of FM101 on liver mitochondria and NASH severity, phase 2 clinical trial is to be conducted.
To ensure its safety and efficacy in clinical trials, the optimized dosage should be recommended. Therefore, in this study, we aimed to present the pharmacokinetic model of FM101 in phase 2 1 clinical trial and to assure the validity of the trial design of phase 2 clinical trial.
Methods: We developed population pharmacokinetic (PK) modeling of FM101 in healthy subjects from single and multiple ascending dose phase 1 trials conducted from January 2019 to August 2019. Each subject in this study received FM101 oral doses. The pharmacokinetic blood samples of single ascending dose part were collected at predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 15, 24, 36, 48, and 72 hours postdose of FM101 75, 150, 300, 600, 1200, and 2400 mg each. For multiple ascending dose part, the pharmacokinetic blood samples for the 150 mg qd cohort were collected at predose and 1, 2, 4, 6, 8, 12, and 24 hours after the first dose on day 1, at predose on day 3 to day 7 and 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours after the last dose on day 7. For the 600 mg bid cohort, blood samples were collected before the morning dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 15, and 24 hours after the morning dose of day 1, before the morning dose on day 3 to day 7, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 15, 24, and 48 hours after the morning dose on day 7. MonolixSuite2023R1 (Lixoft, Antony, France) was used to develop population PK modeling of FM101 phase 1 clinical trial data. One- and two-compartments with zero- and first-order absorption models were tested as a potential FM101 structural model. Based on the structural model selected, covariate screening was performed for all collected covariates (body mass index, weight, and gender). With the inclusion of selected covariates, the final model for FM101 was evaluated through goodness-of-fit plots, visual predictive check, and bootstrap. Simulation was performed to confirm the safety of FM101 phase 2 clinical trial design.
Results: In total, 1020 FM101 concentrations of 54 healthy subjects from FM101 phase 1 clinical trial were collected. A two-compartment model with zero-order absorption best described the FM101 pharmacokinetics in healthy subjects. As a result of covariate screening, we found that the clearance (CL/F) increased as the weight increased and if the gender of the subject was male. The central volume of distribution (V1/F) also increased as the weight of subject increased. The dose of 300 mg bid for 13 weeks in different weights and gender were simulated. The final model was as follows:
CL/F = 87.08*[(Wt/75.4)^1.23]*exp(0.24*SEX; male = 1, female = 0) L/h
V1/F = 294.28*[(Wt/75.4)^1.58] L
The simulation results confirmed that the accumulation of FM101 did not occur with a dose of 300 mg bid within 13 weeks duration regardless of gender and weight.
Conclusions: The results of FM101 modeling and simulations suggest that the administration of FM101 300 mg bid for 13 weeks does not cause accumulation of FM101 in the body and thus the dosing scenario is safe to be implemented in the phase 2 trial.
References:
[1] Vlad R et al. (2010). A position statement on NAFLD/NASH based on the EASL 2009 special conference.
[2] György H et al. (2013). Adenosine: An endogenous regulator of innate immunity.
[3] Park JS et al. (2021). Biased agonism of Adenosine a3 receptor signaling confers protection from non-aloholic steatohepatitis. 2021 fall international convention of the pharmaceutical society of Korea.