The Effects of Ritonavir on the Pharmacokinetics of Tofacitinib in Rats

Background and Objective: Tofacitinib (TOF), an oral Janus kinase inhibitor used to treat rheumatoid arthritis (RA), is extensively metabolized by cytochrome P450 (CYP) 3A4. Ritonavir (RTV), a protease inhibitor, is commonly used as a pharmacokinetic (PK) enhancer due to its potent CYP3A4 inhibitory effects. Considering the prevalence of comorbidities in RA patients, it is possible to use TOF and RTV concurrently, raising concerns about potential drug-drug interactions (DDIs). The current study aims to assess the potential DDIs between RTV and TOF. Methods: An in vivo rat study was conducted to investigate the impacts of RTV on the PK of TOF. Rats were randomly divided into three groups: vehicle, RTV 10 mg/kg, and RTV 20 mg/kg, each undergoing four days of pretreatment. On the test day, TOF (10 mg/kg) was administered following co-administration of the respective RTV doses. Blood samples were collected at the pre-specified time points. Plasma concentrations of TOF were quantified using liquid chromatography coupled with mass spectrometry, and PK parameters were analyzed using non-compartmental analysis. Results: RTV (10 and 20 mg/kg) increased the area under the curve of TOF by 2.53-fold (95% CI: 1.64-3.43) and 5.39-fold (95% CI: 4.47-6.33), respectively, and the maximum concentration by 1.47-fold (95% CI: 0.99-2.00) and 2.86-fold (95% CI: 2.39-3.37), respectively. Whereas the half-life (t_1/2) remained unchanged. Conclusions: RTV substantially increased TOF exposure in rats. These results suggest the need for dose adjustments of TOF during co-administration with RTV in clinical settings. Further clinical research is needed to confirm these findings.