Assessment of the Effect of Filgotinib on the Pharmacokinetics of Atorvastatin, Pravastatin, and Rosuvastatin in Healthy Adult Participants

Abstract

Filgotinib, an oral Janus kinase-1 preferential inhibitor, is approved in Europe and Japan for adults with rheumatoid arthritis. Patients with rheumatoid arthritis are at higher risk of cardiovascular morbidity/mortality; thus, it is important to understand potential drug-drug interactions of filgotinib with lipid-lowering agents. This open-label, randomized, 2-way crossover study evaluated the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin with and without filgotinib coadministration. Healthy participants (N = 27) received single doses of atorvastatin (40 mg) and of a pravastatin (40 mg)/rosuvastatin (10 mg) cocktail-alone or with filgotinib (200 mg once daily for 11 days)-on 2 different occasions with washout in between. Serial pharmacokinetic blood samples were collected, and safety was assessed. Pharmacokinetic parameters were evaluated using 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratio of the test treatment (statin coadministration with filgotinib) vs statin alone, with prespecified lack-of-interaction bounds of 0.70 to 1.43. Coadministration of filgotinib did not affect atorvastatin area under the plasma concentration-time curve extrapolated to infinity (AUC_inf ; [GLSM ratios (90% CI): 0.91 (0.84-0.99)]), but maximum concentration [C_max ] was slightly lower [0.82 (0.69-0.99)]. The exposure of 2-hydroxy-atorvastatin was unaffected (GLSM ratios [90% CI], 0.98 [0.81-1.19] for C_max ; 1.11 [1.02-1.22] for AUC_inf ). Pravastatin AUC_inf was also unaffected (GLSM ratios, 1.22 [1.05-1.41], but C_max was slightly higher 1.25 [1.01-1.54]). Rosuvastatin exposure was moderately higher with filgotinib coadministration-GLSM ratios (90% CI), 1.68 (1.43-1.97) for C_max ; 1.42 (1.30-1.57) for AUC_inf -but this was not considered clinically relevant. These results indicate that filgotinib has no clinically meaningful effect on exposure of atorvastatin, pravastatin, or rosuvastatin.

Keywords: clinical pharmacology; drug-drug interactions; pharmacokinetics and drug metabolism; pharmacology; rheumatology.

Figure 1

Study schematic for (A) sequence AB and (B) sequence BA. Samples collected during intensive PK sampling. PK, pharmacokinetics.

Figure 2

Mean (± SD) plasma concentrations of (A) atorvastatin, (B) 2‐hydroxy‐atorvastatin, (C) pravastatin, and (D) rosuvastatin with or without coadministration with filgotinib. 2‐hydroxy‐atorvastatin is an active metabolite of atorvastatin. Gray horizontal lines indicate lower limit of quantitation. H, hours; SD, standard deviation.

Figure 3

Effect of filgotinib on exposures of atorvastatin, 2‐hydroxy‐atorvastatin, pravastatin, and rosuvastatin. Dashed vertical lines indicate prespecified boundaries (0.70‐1.43). AUC_inf, area under the curve from time 0 extrapolated to infinity; CI, confidence interval; C_max, maximum observed concentration; PK, pharmacokinetics.