A Drug-Drug Interaction Study to Investigate the Effect of Nintedanib on the Pharmacokinetics of Microgynon (Ethinylestradiol and Levonorgestrel) in Female Patients with Systemic Sclerosis-Associated Interstitial Lung Disease

Abstract

Background and objectives: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD), idiopathic pulmonary fibrosis, and other chronic fibrosing ILDs with a progressive phenotype. As nintedanib may cause foetal harm, patients taking nintedanib should avoid pregnancy. The objective of this study was to investigate the effect of nintedanib co-administration on the pharmacokinetics of Microgynon (ethinylestradiol and levonorgestrel) in female patients with SSc-ILD.

Methods: This was an open-label, two-period, fixed-sequence, drug-drug interaction study. Female patients with SSc and ≥ 10% extent of fibrotic ILD on a high-resolution computed tomography scan were eligible to participate. In Period 1, patients received one Microgynon tablet (ethinylestradiol 30 μg and levonorgestrel 150 μg) ≥ 3 days before the first administration of nintedanib in Period 2. In Period 2, patients received one Microgynon tablet following intake of nintedanib 150 mg twice daily for ≥ 10 consecutive days. The primary pharmacokinetic endpoints were the areas under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 to the last quantifiable data point (AUC0-tz) and the maximum measured concentrations of ethinylestradiol and levonorgestrel in plasma (Cmax). The secondary pharmacokinetic endpoint was the area under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 extrapolated to infinity (AUC0-∞). The relative exposures of ethinylestradiol and levonorgestrel when administered alone and in combination with nintedanib were assessed using an ANOVA model.

Results: Seventeen patients were treated. Pharmacokinetic data from 15 patients were analysed. Plasma concentration-time profiles of ethinylestradiol and levonorgestrel were similar following administration of Microgynon before and after administration of nintedanib for ≥ 10 consecutive days. Adjusted geometric mean (gMean) ratios [90% confidence intervals (CIs)] for AUC0‒tz (101.4% [92.8, 110.7]) and AUC0‒∞ (101.2% [94.0, 109.1]) indicated that there was no difference in total ethinylestradiol exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for Cmax of ethinylestradiol (116.7% [90% CI 107.6, 126.5]) indicated an increase in peak exposure in the presence of nintedanib. Adjusted gMean ratios [90% CIs] for AUC0-tz (96.4% [91.5, 101.6]) and Cmax (100.9% [89.9, 113.2]) indicated that there was no difference in total or peak levonorgestrel exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for AUC0‒∞ of levonorgestrel indicated a decrease in total exposure in the presence of nintedanib (88.1% [90% CI 80.0, 97.0]).

Conclusion: Pharmacokinetic data indicate that there is no relevant effect of nintedanib on plasma exposure to ethinylestradiol and levonorgestrel in female patients with SSc-ILD.

Trial registration: Clinicaltrials.gov NCT03675581.

Conflict of interest statement

MCV reports grants from BI, Ferrer and Janssen-Cilag; fees for serving as an advisor or review panel member for BI and Janssen-Cilag; and speaker fees from BI, Janssen-Cilag, Novartis, Roche. AG-D-C reports consultancy fees from BI and Janssen. MK reports grants from BI and Roche and consultancy fees from BI, Galapagos, Roche. MA, KM, SRM, SW and MG are employees of BI.

© 2021. The Author(s).

Figures

Fig. 1

Study design. aPatients received nintedanib 150 mg bid for ≥10 consecutive days prior to Microgynon administration in Period 2. Patients received nintedanib 150 mg bid over a period of ≥14 days to approximately 28 days. bBlood samples for PK evaluation were collected on the days of Microgynon administration (pre- and post-dose) and on the following 2 days. EOT end of treatment, PK pharmacokinetic, bid twice daily

Fig. 2

Geometric mean plasma concentration–time profiles of ethinylestradiol after single-dose administration of Microgynon before (Period 1) and after administration of nintedanib 150 mg bid for ≥ 10 consecutive days (Period 2), plotted on a semi-logarithmic scale

Fig. 3

Geometric mean plasma concentration–time profiles of levonorgestrel after single-dose administration of Microgynon before (Period 1) and after administration of nintedanib 150 mg bid for ≥ 10 consecutive days (Period 2), plotted on a semi-logarithmic scale