Background/Purpose:

Filgotinib is a potent and selective JAK1 inhibitor in clinical development for treatment of inflammatory diseases, including rheumatoid arthritis and inflammatory bowel diseases. Filgotinib does not inhibit or induce CYP or UGT metabolic enzymes in vitro, and did not alter the pharmacokinetics (PK) of midazolam, a sensitive CYP3A substrate, in healthy subjects. In order to support the use of filgotinib in fertile women, this Phase I study was conducted to rule out unanticipated interactions of filgotinib on the PK of a representative oral contraceptive (OC), levonorgestrel (LEVO)/ethinyl estradiol (EE).

Methods:

This was an open-label, randomized, two-way crossover study in healthy female subjects. Subjects received a single dose of LEVO (150 ug)/EE (30 ug) alone (Treatment A; reference), or in combination with multiple-dose filgotinib (200 mg once daily; 15 days; Treatment B; test). PK sampling was performed for 120 hours following administration of the OC, and safety was assessed throughout the study. An analysis of variance using a mixed-effects model was applied to the natural logarithmic transformation of PK parameters (AUC and C_max) for EE and LEVO. Geometric-least squares means (GLSM) ratios and 90% confidence intervals (90%CI) of PK parameters were estimated for the test vs reference treatments, and were compared against pre-specified lack of PK alteration boundaries of 70 to 143%. The PK of filgotinib was evaluated as well, and compared against historical values.

Results:

The study enrolled 24 subjects. All subjects completed study treatments; 1 subject discontinued after the last PK draw, due to withdrawal of consent. The mean (range) age of subjects was 37 (21-45) years, 21 (87.5%) were white, and 24 (100%) were of Hispanic or Latino ethnicity.

Coadministration of OC with filgotinib resulted in comparable exposures of LEVO and EE. The GLSM ratios (90%CI) for AUC_inf, AUC_last and C_max of LEVO were 94.9 (90.2, 99.8), 94.2 (89.1, 99.6) and 105 (94.8, 117), respectively; corresponding values for EE were 114 (109, 118), 113 (109, 117) and 114 (106, 122). The GLSM ratios (90%CI) were contained within the pre-specified lack of interaction bounds (70‑143%), indicating a lack of interaction of filgotinib on OC. Exposures of filgotinib were consistent with historical data.

Study treatments were generally well tolerated; 3 (12.5%) and 6 (25.0%) of subjects experienced an adverse event (AE) during Treatments A and B, respectively. No serious or severe AEs occurred; all AEs reported were Grade 1 (mild). Of the AEs reported only one (headache) was recorded as related to study drug (during Treatment B), and it was not distinctly attributed to LEVO/EE versus filgotinib. All laboratory abnormalities were Grade 1, and there were no clinically significant trends in laboratory abnormalities, vital sign measurements, or ECG recordings.

Conclusion:

Co-administration with filgotinib did not alter the PK of levonorgestrel/ethinyl estradiol. Hormonal contraceptives can be allowed as an effective contraception method for subjects on filgotinib treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lack-of-drug-drug-interaction-between-filgotinib-a-jak-1-selective-inhibitor-and-a-representative-hormonal-contraceptive-medication-levonorgestrelethinyl-estradiol/