Background/Purpose: Nintedanib is a tyrosine kinase inhibitor that has been approved for the treatment of SSc-ILD. As nintedanib may cause fetal harm, patients taking nintedanib should avoid pregnancy. The combination of ethinylestradiol and levonorgestrel is a commonly used oral contraceptive. We investigated the pharmacokinetics (PK) of the combination of ethinylestradiol and levonorgestrel alone and with nintedanib at steady-state in female patients with SSc-ILD.

Methods: We conducted an open-label, two-period, fixed-sequence, drug–drug interaction study (NCT03675581). Female patients aged ≥18 years, with SSc (based on 2013 ACR/EULAR criteria) and ≥10% extent of fibrotic ILD on a high-resolution computed tomography (HRCT) scan were eligible to participate. In Period 1, patients received a single tablet containing 30 μg ethinylestradiol and 150 μg levonorgestrel (reference treatment) ≥3 days before the first administration of nintedanib in Period 2. In Period 2, patients received a second tablet containing 30 μg ethinylestradiol and 150 μg levonorgestrel after continuous intake of nintedanib 150 mg bid for ≥10 consecutive days (test treatment). The primary PK endpoints were the areas under the concentration–time curve of ethinylestradiol and levonorgestrel in plasma over the time interval from 0 to the last quantifiable data point (AUC_0-tz) and the maximum measured concentrations of ethinylestradiol and levonorgestrel in plasma (C_max). The areas under the concentration–time curve of ethinylestradiol and levonorgestrel in plasma over the time interval from 0 extrapolated to infinity (AUC_0-∞) were secondary PK endpoints. The relative exposure to ethinylestradiol and levonorgestrel when administered alone versus in combination with nintedanib was assessed using an ANOVA model.

Results: PK data were analyzed from 15 treated patients. Plasma concentration–time profiles of ethinylestradiol and levonorgestrel were similar after administration alone or after administration of nintedanib 150 mg bid for ≥10 consecutive days (Figure). Total exposure to ethinylestradiol (AUC_0-tz and AUC_0-∞) was similar when ethinylestradiol and levonorgestrel were administered alone or after multiple administrations of nintedanib and peak exposure to ethinylestradiol (C_max) slightly increased (by approximately 16%) after multiple administrations of nintedanib (Table). No differences in total or peak exposure to levonorgestrel (AUC_0-tz or C_max) were observed when ethinylestradiol and levonorgestrel were administered alone or after multiple administrations of nintedanib (Table).

Conclusion: PK results indicate that there is no relevant effect of nintedanib 150 mg bid on the plasma exposure to ethinylestradiol and levonorgestrel in female patients with SSc-ILD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/drug-drug-interaction-study-of-nintedanib-ofev-and-the-combination-of-ethinylestradiol-and-levonorgestrel-microgynon-in-patients-with-systemic-sclerosis-associated-interstitial-lung-di/