Prediction of potential drug-drug interaction of tofacitinib and ritonavir using a population modeling approach with allometric scaling method
Sung-yoon Yang1, Bui Thi Tham1, Hyunjung Lee2, HyungJun Kim1, YuJoung Choi1, Jeongmin Ha1, Lien Thi Ngo1*, Hwi-yeol Yun1*, Jung-woo Chae1*
Affiliation 1: College of pharmacy, Chungnam National university Affiliation 2: Department of Bio-AI Convergence, Chungnam National University
Objectives: Tofacitinib (TOF) is a small molecule Janus kinase (JAK) inhibitor that is used in the treatment of rheumatoid arthritis (RA) by blocking the activity of JAK enzymes, and the metabolism is primarily mediated by Cytochrome P450 (CYP) 3A4 enzyme [1]. Ritonavir (RITO), is an anti-HIV agent and a potent CYP3A4 inhibitor to increase the exposure of other CYP3A4 substrates [2]. Considering its CYP3A4-mediated pathway, the co-administration of RITO with TOF might cause potential drug-drug interaction (DDI). The purpose of this study is to evaluate the potential DDI between RITO and TOF and predict PK DDI in human. Firstly, we conducted a PK study to investigate the DDI profile between these two drugs in rats. Secondly, a population PK model was developed to describe the PK of TOF and the effects of RITO on TOF PK profiles. Thirdly, we extrapolated the PK parameters of TOF in the presence/absence of RITO coadministration from rats into human using allometric scaling methods. By using population model-based approach, the DDI profiles between RITO and TOF was simulated in humans.
Methods: An animal study was conducted to obtain DDI PK profile between RITO and TOF in rats. Rats were randomly assigned into three groups and were pre-treated with RITO for four consecutive days (GR1 control group, GR2 and GR3 pretreated with RITO 10 and 20 mg/kg/day, respectively). On the fifth day, each rat received 10 mg/kg dose of TOF following the administration of RITO. Plasma samples were collected at pre-determined time points after the administration of TOF and stored at -80 °C before the analysis. The plasma concentrations of TOF in rats were determined using a validated LC-MS/MS method. The area under the curve (AUC) and maximum concentration of the drug (Cmax) of TOF were calculated by non-compartmental analysis (NCA), then were compared between the groups using statistical methods. Simultaneously, a compartmental model approach performed on NONMEM (7.5.1. version) was used to characterize PK of TOF and examine the effects of RITO on PK parameters of TOF. Then, PK parameters of TOF were extrapolated from rats into humans using allometric scaling method. Applying the model-based approach, the PK DDI between RITO and TOF was simulated in humans. The dosing scenarios included in the simulation were A) TOF 5 mg twice daily, without or with RITO [JW1] 100 mg/day and 200 mg/day, B) TOF 10 mg twice daily, without or with RITO at doses of 100 mg/day and 200 mg/day at the steady-state condition of TOF. By comparing the PK profiles of TOF in the presence/absence of RITO, the DDI profiles were assessed.
Results: NCA results showed that RITO exerts a statistically significant increase in AUC and Cmax of TOF in rat plasma (p<0.01). The PK of TOF in rats was well described by one-compartment model with first-order elimination and first-order absorption kinetics. The final model was developed by incorporating dose of RITO as a covariate through its CYP3A4-mediated interaction onto clearance. The covariate effects of RITO on clearance of TOF were modeld using a Michaelis Menten equation. The extrapolated PK parameters (the apparent clearance and volume of distribution) for human were estimated as 34.4 L/hr and 107.5 L, respectively and absorption rate constant (Ka) was obtained from another source since Ka is highly dependent on species [3]. In human, CL/F of TOF was significantly decreased to 12.4L/hr and 6.7 L/hr in the presence of RITO at doses of 100 mg/day and 200 mg/day. As a result, the presence of RITO at doses of 100 mg/day and 200 mg/day increases the exposure of TOF compared to when TOF was administered alone.
Conclusions: In conclusion, we investigated the potential for drug-drug interactions between TOF and RITO in humans using a population model-based approach and allometric scaling method. RITO substantially increases the exposure of TOF, which warrants caution and further investigation when considering the combination of these two drugs in clinical practice.
References:
[1] Xie, R.; Deng, C.; Wang, Q.; Kanik, K.S.; Nicholas, T.; Menon, S. Population Pharmacokinetics of Tofacitinib in Patients with Psoriatic Arthritis. Int J Clin Pharmacol Ther 2019, 57, 464–473, doi:10.5414/CP203516.
[2] Hull, M.W.; Montaner, J.S.G. Ritonavir-Boosted Protease Inhibitors in HIV Therapy. Annals of Medicine 2011, 43, 375–388, doi:10.3109/07853890.2011.572905.
[3] Xie, R.; Deng, C.; Wang, Q.; Kanik, K.S.; Nicholas, T.; Menon, S. Population Pharmacokinetics of Tofacitinib in Patients with Psoriatic Arthritis. Int J Clin Pharmacol Ther 2019, 57, 464–473, doi:10.5414/CP203516.