(W1130-10-65) Development and Validation of a Physiologically Based Pharmacokinetic Model of Tofacitinib in Mice to Predict Dosing in Higher Animal Species

Purpose: The physiologically based pharmacokinetic (PBPK) model, a mechanistic quantitative framework, is established mainly based on physiological organ sizes, blood flow rates, tissue-to-plasma partition coefficient (K _p), elimination mechanisms, etc. It can provide insight into drug concentration–time profiles in various tissues and build the relationship between dose and pharmacokinetic (PK) profiles in specific tissues to further assess the pharmacological effects. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. A black-box warning was issued by the USFDA to Tofacitinib tablet products, which decreases its benefit-to-risk ratio. Efforts have been made by our research group to formulate tofacitinib as protein nanoparticles and target it to the intestine, to increase its action locally thereby limiting systemic exposure. Tofacitinib is primarily metabolized by cytochrome P450 (CYP450) 3A4 (CYP3A4) followed by CYP450 2C19 (CYP2C19), with minimal metabolism through glucuronidation or other conjugation pathways. In developing a new targeted dosage form, dose selection is a critical criterion while designing and conducting studies in an animal model. Therefore, it is crucial to develop a robust PBPK model of tofacitinib in mice to accurately predict the dose in animal studies of different species. This study aims to develop and validate a robust PBPK model of tofacitinib in mice by utilizing in vitro, and in vivo data, and subsequently predicting disposition in other species.

Methods: Model development and verification were conducted using GastroPlus®9.8.3 (Academic License-Simulation Plus Inc., Lancaster, CA). Several features of the GastroPlus®9.8.3 were used to achieve the study objectives. The study outlines a stepwise approach for PBPK simulation that involves learning and confirming phases. Besides the data obtained from the literature, the ADMET Predictor® module (version 10.4) was used to obtain in silico estimates of key physiochemical and biopharmaceutical properties from the structure. PKPlus® (version 2.5) was used to predict and build the disposition model using intravenous administration data of tofacitinib in mice. The Advanced Compartmental Absorption and Transit model was used to describe the in vivo dissolution and intestinal absorption of tofacitinib after oral administration of 20 mg/kg mg tofacitinib (suspension form) to mice.

Results: The study presents a PBPK modeling approach for tofacitinib. The PBPK model was developed in a stepwise manner, beginning with the modeling of tofacitinib in silico physicochemical and ADME prediction. The intravenous data used for developing the disposition model was well-fitted using a 2-compartmental model (AIC: -13.716; Objective weighing function: 1/Yhat^2). For the PBPK model, observed v/s predicted ratios of AUC (0.927) and C_max (1.133) were within the two-fold limit (Fig 1). This framework provides a standardized approach to PBPK modeling that can be used across different drug development programs and supports model-informed prediction of the bioavailability of tofacitinib in different higher species of animals like rats, dogs, and humans.

Conclusion: In the present work, the PBPK model of tofacitinib in mice was developed. The framework includes a step wise approach to PBPK modeling. This model could be applied to accurately predict the dose of tofacitinib in different species like rats, dogs, and humans.

References: 1. Tse, S.; Dowty, M.E.; Menon, S.; Gupta, P.; Krishnaswami, S. Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug Exposure and Support Dosing Recommendations for Potential Drug-Drug Interactions or in Special Populations: An Example Using Tofacitinib. J. Clin. Pharmacol. 2020, 60, 1617–1628, doi:10.1002/JCPH.1679.
2. Dixit, A.; Mallurwar, S.R.; Sulochana, S.P.; Zainuddin, M.; Mullangi, R. Determination of Tofacitinib in Mice Whole Blood on Dried Blood Spots Using LC-ESI-MS/MS: Application to Pharmacokinetic Study in Mice. Drug Res. (Stuttg). 2019, 69, 330–336, doi:10.1055/A-0677-3066/ID/R2018-06-1642-0020/BIB.

Acknowledgements: The authors are thankful to Simulations Plus for providing the academic license of GastroPlus®9.8.3 (Academic License-Simulation Plus Inc., Lancaster, CA)