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Relationship between nintedanib exposure and adverse events in patients with idiopathic pulmonary fibrosis

Ulrike Schmid, Benjamin Weber, Claudia Dallinger, Luca Richeldi, Christoph Hallmann, Ganesh Raghu, Matthias Freiwald
European Respiratory Journal 2016 48: OA4963; DOI: 10.1183/13993003.congress-2016.OA4963
Ulrike Schmid
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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Benjamin Weber
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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Claudia Dallinger
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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Luca Richeldi
National Institute for Health Research Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
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Christoph Hallmann
Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany
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Ganesh Raghu
Pulmonary and Critical Care Medicine, University of Washington, Seattle, WAUnited States
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Matthias Freiwald
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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Abstract

Background: In the TOMORROW and INPULSIS® trials, nintedanib 150 mg twice daily (bid) reduced disease progression versus placebo in patients with idiopathic pulmonary fibrosis (IPF). Based on study protocol, adverse events were managed by treatment interruption and dose reduction.

Aim: To explore the relationship between nintedanib exposure and adverse events of diarrhea and liver enzyme elevations.

Methods: Data from 1403 patients with IPF who received nintedanib doses of 50-150 mg bid (N=895) or placebo (N=508) for up to 52 weeks in the TOMORROW trial (Phase II) or one of the two INPULSIS trials (Phase III) were analyzed. The relationship between exposure and the probability of experiencing diarrhea or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevation of ≥ 3x upper limit of normal (ULN) was investigated by parametric time-to-first event modeling. Observed and PK model predicted pre-dose plasma concentrations at steady-state were selected as exposure metrics.

Results: A reliable association between nintedanib exposure and risk of diarrhea could not be established; results indicated that dose was a better predictor of diarrhea than exposure. A weak relationship between nintedanib exposure and ALT and/or AST elevations was found, with a trend towards increased risk with increasing exposure based on limited data (41 events).

Conclusions: Together with the previously presented exposure-efficacy analyses, the current analyses provide a modelling framework for a quantitative benefit-risk assessment in patients with IPF with altered nintedanib exposure due to comedication or patient characteristics.

  • Idiopathic pulmonary fibrosis
  • Treatments
  • Interstitial lung disease
  • Copyright ©the authors 2016
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Relationship between nintedanib exposure and adverse events in patients with idiopathic pulmonary fibrosis
Ulrike Schmid, Benjamin Weber, Claudia Dallinger, Luca Richeldi, Christoph Hallmann, Ganesh Raghu, Matthias Freiwald
European Respiratory Journal Sep 2016, 48 (suppl 60) OA4963; DOI: 10.1183/13993003.congress-2016.OA4963

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Relationship between nintedanib exposure and adverse events in patients with idiopathic pulmonary fibrosis
Ulrike Schmid, Benjamin Weber, Claudia Dallinger, Luca Richeldi, Christoph Hallmann, Ganesh Raghu, Matthias Freiwald
European Respiratory Journal Sep 2016, 48 (suppl 60) OA4963; DOI: 10.1183/13993003.congress-2016.OA4963
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