Sungyeun Bae (1) Jae-Yong Chung (2,3) In-Jin Jang (1) SeungHwan Lee (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea (2) Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea (3) Department of Clinical Pharmacology and Therapeutics, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
Objectives:
MIT-001 is a potent mitochondrial-targeting antioxidant targeting various inflammatory diseases. Utilizing pharmacokinetic (PK) and safety data from previous clinical trials in healthy subjects and patients with pharmacodynamic data from the animal model, we aimed to develop a population PK model for intravenous (IV) MIT-001 to provide an evidence for selection of appropriate doses in later trials.
Methods:
PK data from two phase 1 clinical trials with healthy male adults and two phase 2 clinical trials with patients were used (NONMEM v 7.4.3). The base model was developed including an evaluation of 1-, 2-, and 3-compartment models. Various elimination models such as linear elimination, Michaelis-Menten kinetics, and elimination with autoinhibition were evaluated. Covariate analysis included age, height, body weight, aspatate transaminase (AST), alanine transaminase (ALT), serum creatinine, sex, and disease status (patient/healthy). Models were evaluated using objective function value, goodness of fit (GOF) plots, visual predictive check, and bootstrap analysis. The GOF plots included observed values versus individual (IPRED) and population (PRED) predicted concentrations, conditional weighted residuals (CWRES) versus PRED or time. The final model was used to simulate exposures for various doses (MIT-001 IIV 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100 mg twice weekly). The PK data of 500 virtual subjects were simulated using the final model. Whether the PK profile after repeated IV infusion of MIT-001 was within the minimum effective dose observed in non-clinical study and maximum tolerable dose defined in the previous phase 1 clinical studies was identified.
Results:
A total of 2,785 concentration-time data from 161 subjects (89 healthy subjects and 72 patient) were included for the model development. For improvement of the modeling process, log-transformed MIT-001 concentration with an additive residual error model was implemented. The 3-compartment model with linear elimination best described the PK profile of MIT-001. The autoinhibition effect was applied as the PK profile of MIT-001 appeared to be underestimated after multiple dose. The disease status was a significant covariate on V1, and was included in the final model. The GOF plots showed that the model-predicted concentrations were generally in agreement with the observed concentrations. In addition, the median, 5th, and 95th percentile of data was well captured by the 90% confidence interval of the respective predictive percentile for overall data. The simulated PK profile showed that about 80% of subjects were expected to reach effective exposure after twice weekly repeated dose of 20 mg for 5 weeks. Furthermore, more than 85% of subjects were expected to be tolerable at dose of 60 mg.
Conclusions:
The overall PK profiles of IV MIT-001 was well explained by a 3-compartment model with first-order elimination with autoinhibition. Considering results of the non-clinical study and the previous clinical trials, the dose range of 20-60 mg is recommended for the following clinical trials.
Reference: PAGE 32 (2024) Abstr 10940 [www.page-meeting.org/?abstract=10940]
Poster: Drug/Disease Modelling - Safety