Evaluation Of The Effect Of Filgotinib On The Pharmacokinetics Of Rosuvastatin, Atorvastatin, And Pravastatin

Background: Filgotinib is an orally administered small molecule that preferentially inhibits Janus kinase 1 and is approved for use in Europe and Japan in adult patients with rheumatoid arthritis (RA) who have had an inadequate response to conventional therapies. Patients with RA are at a higher risk of cardiovascular morbidity and mortality relative to the general population1. Thus, it is important to understand potential drug-drug interactions of filgotinib with lipid-lowering agents such as statins. Based on in vitro studies, filgotinib is not expected to significantly increase exposure of statins via inhibition of the organic anion transporting peptide (OATP) at clinically relevant exposures. Hence, in Phase 2 and Phase 3 clinical studies, statins were allowed for use with filgotinib. A post-hoc analysis showed no increase in statin-induced AEs such as muscle or liver toxicities when statins were coadministered with filgotinib (“Concomitant Use of Statins in Filgotinib-Treated Patients with Rheumatoid Arthritis: A Post Hoc Analysis”, submitted to EULAR 2021). Objectives: The objectives of this study (NCT04608344) were to evaluate the effect of filgotinib on the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin, which are sensitive substrates for the OATP-1B1/1B3, and the short-term safety of administering filgotinib with or without statins. Methods: This was an open-label, randomized, two-way, crossover study in healthy adult volunteers (n = 27). Study participants received a single dose of atorvastatin (ATV 40 mg) and a single dose of a cocktail of pravastatin (PRA 40 mg)/rosuvastatin (ROS 10 mg), on two different occasions with washout in between, alone or in combination with filgotinib (200 mg QD for 11 days). Serial pharmacokinetic sampling was performed and pharmacokinetic parameters for each statin were calculated. Safety was assessed throughout the study. An analysis of variance using a mixed-effects model was applied to the natural logarithmic transformation of pharmacokinetic parameters (Cmax and AUCinf) for ATV, 2-OH-ATV (active metabolite of ATV), PRA, and ROS. Geometric-least squares means (GLSM) ratios and 90% confidence intervals (90% CI) of pharmacokinetic parameters were estimated for each analyte and were compared against pre-specified lack of pharmacokinetic alteration boundaries of 70 to 143%. Results: Of the 27 enrolled participants, 25 participants completed all study treatments. Most AEs and laboratory abnormalities were Grade 1 or 2 in severity; 1 participant discontinued due to a Grade 3 increase in creatine kinase and 1 participant discontinued due to difficulty in blood draws. Following coadministration of filgotinib with ATV, relative to ATV alone, ATV AUCinf was unaffected (GLSM ratio (90% CI): 0.91 (0.84, 0.99)), but ATV Cmax was slightly reduced (GLSM ratio (90% CI): 0.82 (0.69, 0.98)). 2-OH-ATV exposure (Cmax and AUCinf) were unaffected (GLSM ratio (90% CI): 0.98 (0.81, 1.18) for Cmax and 1.12 (1.02, 1.22) for AUCinf), and were within the pre-specified lack-of-effect bounds. Following coadministration with filgotinib, PRA AUCinf was unaffected (GLSM ratio (90% CI): 1.22 (1.06, 1.42)), but PRA Cmax was slightly higher (1.25 (1.01, 1.54)). ROS exposure (Cmax and AUCinf) were moderately higher upon coadministration with filgotinib (GLSM ratio (90% CI): 1.68 (1.43, 1.97) for Cmax and 1.42 (1.30, 1.56) for AUCinf), and these changes in rosuvastatin exposure are not considered to be clinically relevant. Conclusion: All study treatments were generally well tolerated. Co-administration with filgotinib did not have a clinically meaningful impact on the exposure of ATV, PRA, and ROS. These data support concomitant use of filgotinib with OATP substrates such as statins. References: [1]Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016;37(29): 2315-2381. Disclosure of Interests: Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Cara Nelson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Qi Gong Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Muhsen Alani Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Thomas Tarnowski Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Ahmed A. Othman Shareholder of: Gilead Sciences, Employee of: Gilead Sciences