Wenjun Chen, Zourong Ruan, Honggang Lou, Bo Jiang
Center of Clinical Pharmacology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
Objectives:
TLL-018 is a novel selective Janus Kinase 1 / Tyrosine Kinase 2 inhibitor which is being developed for the treatment of several inflammatory diseases. TLL-018 was evaluated in early phase clinical trials as an oral immediate-release (IR) formulation and the extended-release (ER) formulation was expected to be developed. This study aims to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics (PK) of TLL-018 IR formulation in humans based on the in vitro and in vivo PK data of animals, and to use the validated PBPK model of IR formulation to predict the in vivo plasma concentration curves of TLL-018 ER formulations according to the in vitro dissolution profiles and the in vivo concentration data in dog.
Methods:
The physicochemical and physiological parameters of TLL-018, including molecular weight, solubility, lipophilicity, permeability, pKa, plasma protein binding rate, and blood/plasma ratio were used to establish a PBPK model in mouse firstly. These parameters were mainly gained from the in vitro experiments, or predicted by ADMET Predictor® (Version 10.2, Simulations Plus, Inc., CA, United States). Plasma concentration-time curves in mice by intravenous injection and oral administration of TLL-018 were used for model validation and optimization. The PBPK model in mouse was then sequentially extrapolated to rat and dog, and the model was verified and optimized using the measured PK data in these animals. Furthermore, the PBPK model was extrapolated to human to predict the PK of TLL-018 IR formulation in human. After establishing the PBPK model of the IR formulation of TLL-018 in human, the in vitro dissolution profiles of the ER formulations were used in the model to predict the PK of different ER formulations in humans. In addition, the in vitro-in vivo correlation (IVIVC) for TLL-018 ER formulations in dog was used to predict the PK of TLL-018 ER formulations in human. The model predictions were validated based on the measured results of an ER formulation (Formulation A).
Results:
Advanced Compartmental Absorption and Transit (ACAT) model built in GrastroPlus software, consisting of nine compartments corresponding to different segments of the digestive tract, was used for absorption. All tissues were represented by a perfusion-limited model. The established PBPK model proved to be effective in describing the observed plasma concentrations of TLL-018 in animals. The simulated plasma profiles aligned well with the observed data. For intravenous administration, the area under the plasma concentration-time curve (AUC) predicted by the PBPK model were all within ±15% of the measured value. For oral administration, the prediction result of the low dose group was better than that of the high dose group. The predicted Cmax, Tmax and AUC of human IR formulation extrapolated from animal PBPK model were all within the two-fold of the observed value. Furthermore, the concentration-time curves of TLL-018 ER formulations were simulated by the optimized PBPK model combining with in vitro dissolution profiles or IVIVC obtained from dog. The prediction errors of Cmax, Tmax and AUC for ER Formulation A were all less than 20%.
Conclusions:
PBPK model played a significant role in the development of new drug TLL-018 and the selection of ER formulations.
References:
[1] Mohamed MF, Trueman S, Othman AA, Han JH, Ju TR, Marroum P. Development of In Vitro-In Vivo Correlation for Upadacitinib Extended-Release Tablet Formulation. AAPS J. 2019 Oct 25;21(6):108.
[2] Investigator’s brochure of TLL-018.
[3] Agoram, B., W. S. Woltosz and M. B. Bolger, 2001. Predicting the impact of physiological and biochemical processes on oral drug bioavailability.
Reference: PAGE 32 (2024) Abstr 10818 [www.page-meeting.org/?abstract=10818]
Poster: Drug/Disease Modelling - Absorption & PBPK