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

Autor: Martina Gahlemann, Alfredo Guillén-Del-Castillo, Michael Kreuter, Salome R. Mack, Mandy Avis, Sven Wind, Kristell Marzin, Madelon C. Vonk
Přispěvatelé: Institut Català de la Salut, [Vonk MC] Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands. [Guillén-Del-Castillo A] Unitat de Malalties Autoimmunes Sistèmiques, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Kreuter M] Center for Interstitial and Rare Lung Diseases, Pneumology and Respiratory Care Medicine, Thoraxklinik, University of Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany. [Avis M] Boehringer Ingelheim B.V., Alkmaar, The Netherlands. [Marzin K, Mack SR] Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany, Vall d'Hebron Barcelona Hospital Campus
Rok vydání: 2022
Předmět:
medicine.medical_specialty
Indoles
Cmax
Antineoplastic Agents
Levonorgestrel
Ethinyl Estradiol
enfermedades de la piel y tejido conjuntivo::enfermedades del tejido conjuntivo::esclerodermia sistémica [ENFERMEDADES]
Gastroenterology
Idiopathic pulmonary fibrosis
chemistry.chemical_compound
Pharmacokinetics
Ethinylestradiol
Internal medicine
medicine
Humans
Pharmacology (medical)
Drug Interactions
Original Research Article
Pharmacology
Scleroderma
Systemic
Farmacocinètica
business.industry
Interstitial lung disease
Middle Aged
medicine.disease
Confidence interval
United States
Europe
Drug Combinations
chemistry
Contraceptive Agents
Hormonal
Area Under Curve
Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma
Systemic [DISEASES]
Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5]
Esclerosi sistemàtica progressiva
Pulmons - Malalties - Complicacions
Nintedanib
Female
business
Lung Diseases
Interstitial
medicine.drug
Zdroj: European Journal of Drug Metabolism and Pharmacokinetics, 47, 1, pp. 81-89
European Journal of Drug Metabolism and Pharmacokinetics, 47, 81-89
European Journal of Drug Metabolism and Pharmacokinetics
Scientia
ISSN: 0378-7966
Popis: Contains fulltext : 248967.pdf (Publisher’s version ) (Open Access) 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 (AUC(0-tz)) and the maximum measured concentrations of ethinylestradiol and levonorgestrel in plasma (C(max)). 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 (AUC(0-∞)). 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 AUC(0‒tz) (101.4% [92.8, 110.7]) and AUC(0‒∞) (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 C(max) 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 AUC(0-tz) (96.4% [91.5, 101.6]) and C(max) (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 AUC(0‒∞) 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.
Databáze: OpenAIRE
Externí odkaz: