Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function
Authors Kunz C, Luedtke D, Unseld A, Hamilton A, Halabi A, Wein M, Formella S
Received 11 August 2015
Accepted for publication 4 December 2015
Published 18 March 2016 Volume 2016:11(1) Pages 585—595
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Dr Richard Russell
Christina Kunz,1 Doreen Luedtke,1 Anna Unseld,2 Alan Hamilton,3 Atef Halabi,4 Martina Wein,5 Stephan Formella6
1Translational Medicine and Clinical Pharmacology, 2Global Biometrics and Clinical Applications, Boehringer Ingelheim Pharma GmbH and Co KG, Biberach, Germany; 3Boehringer Ingelheim, Burlington, ON, Canada; 4CRS Clinical Research Services Kiel GmbH, Kiel, 5Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH and Co KG, Biberach, 6Medicine Coordination, Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim, Germany
Purpose: In two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled β2-agonist for treatment of COPD, were investigated.
Subjects and methods: The first trial included eight subjects with mild hepatic function impairment (Child–Pugh A), eight subjects with moderate impairment (Child–Pugh B), and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min-1) and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 µg olodaterol administered with the Respimat Soft Mist inhaler.
Results: Olodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0–4) for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%–125%) and 105% (79%–140%), respectively. Corresponding values for dose-normalized maximum concentration (Cmax) were 112% (84%–151%) (mild impairment) and 99% (73%–135%) (moderate impairment). The geometric mean ratio (90% confidence interval) of AUC0–4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%–195%), and for Cmax was 137% (84%–222%). There was no significant relationship between creatinine clearance and AUC0–4 or Cmax. Renal clearance of olodaterol was reduced to 20% of normal in severe renal impairment.
Conclusion: Mild to moderate hepatic function impairment or severe renal function impairment did not result in a clinically relevant increase of olodaterol systemic exposure after a single inhaled dose.
Keywords: chronic obstructive pulmonary disease, exposure, olodaterol, long-acting β2-agonist, hepatic impairment, renal impairment
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