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01-05-2007 | Original Research Article

Steady-State Pharmacokinetics of Roflumilast and Roflumilast N-Oxide in Patients with Mild and Moderate Liver Cirrhosis

Authors: Robert Hermann, Dr Nassr Nassr, Gezim Lahu, Éva Péterfai, Dietrich Knoerzer, Rolf Herzog, Karl Zech, Christian de Mey

Published in: Clinical Pharmacokinetics | Issue 5/2007

Abstract

Background

Roflumilast and its primary N-oxide metabolite are targeted Phosphodiesterase 4 (PDE4) inhibitors with similar in vivo potency. Roflumilast is being developed for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease and asthma.

Objective

To investigate the effects of mild and moderate liver cirrhosis on the steady-state pharmacokinetics of roflumilast and roflumilast N-oxide.

Methods

Patients with mild (n = 8, Child-Pugh A) and moderate (n = 8, Child-Pugh B) liver cirrhosis and healthy subjects (n = 8) matched with patients with cirrhosis with regard to sex, age and bodyweight received oral roflumilast 25Cμg once daily for 14 days. Blood samples were collected for 24 hours after the last dose on day 14. Steady-state plasma concentrations of roflumilast and roflumilast N-oxide were determined using a validated high-performance liquid chromatography with tandem mass spectrometry assay. The pharmacokinetics were compared between groups using ANOVA.

Results

In patients with liver cirrhosis, the average total exposure (area under the plasma concentration-time curve from 0 to 24 hours [AUC₂₄]) of roflumilast was ≈51% (Child-Pugh A) and 92% (Child-Pugh B) higher than in healthy subjects. In contrast, roflumilast maximum plasma concentration (C_max) was unaltered in Child-Pugh A patients and was increased by 27% in Child-Pugh B patients. Changes in the AUC₂₄ of roflumilast N-oxide were less distinct, with 24% and 41% increases and corresponding C_max increases of 26% and 40% in Child-Pugh A and B patients, respectively, compared with healthy subjects. Overall, changes in average potency-corrected exposure to the sum of the free fractions of both compounds were estimated to result in ≈26% and 46% increases in total PDE4 inhibitory capacity (tPDE4i) in Child-Pugh A and B patients, respectively, relative to healthy subjects. Roflumilast was well tolerated.

Conclusions

Mild and moderate liver cirrhosis resulted in distinct alterations of exposure to roflumilast but only in modest alterations of exposure to roflumlast N-oxide. The integrated exposure-weighted assessment of the observed pharmacokinetic changes of roflumilast and roflumilast N-oxide (tPDE4i) indicates modest average exposure increases to the sum of both compounds. These findings and the favourable tolerability profile suggest that roflumilast can be safely used in patients with mild and moderate liver cirrhosis without special precautions or dose adjustment.

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Title: Steady-State Pharmacokinetics of Roflumilast and Roflumilast N-Oxide in Patients with Mild and Moderate Liver Cirrhosis
Authors: Robert Hermann
Dr Nassr Nassr
Gezim Lahu
Éva Péterfai
Dietrich Knoerzer
Rolf Herzog
Karl Zech
Christian de Mey
Publication date: 01-05-2007
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 5/2007
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200746050-00003

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Steady-State Pharmacokinetics of Roflumilast and Roflumilast N-Oxide in Patients with Mild and Moderate Liver Cirrhosis

Abstract

Background

Objective

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objective

Methods

Results

Conclusions

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