Steady-State Pharmacokinetics of Roflumilast and Roflumilast N-Oxide in Patients with Mild and Moderate Liver Cirrhosis
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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.
To investigate the effects of mild and moderate liver cirrhosis on the steady-state pharmacokinetics of roflumilast and roflumilast N-oxide.
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.
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 (Cmax) 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 Cmax 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.
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.
KeywordsLiver Cirrhosis Roflumilast Trimetazidine Hepatic Function Impairment Pharmacokinetic Parameter Estimate
This study was sponsored by ALTANA Pharma AG (Konstanz, Germany). The authors thank the clinical team at the Drug Research Center in Balatonfüred, Hungary, for technical assistance in the conduct of the study and Mrs Sabine Berger, Exploratory Medicine, ALTANA Pharma AG (Konstanz, Germany) for clinical monitoring of the study. The authors thank pharm-analyt Labor GmbH (Baden, Austria) for performing the bioanalytical assays of roflumilast and roflumilast N-oxide, and Medical Laboratory Bremen GmbH (Bremen, Germany) for analysing monoethylglycinexylidide and lidocaine. The authors acknowledge Dr Angela Schilling and Dr Kathy B. Thomas (Medical Writing, ALTANA Pharma AG, Konstanz, Germany) for helpful suggestions during the preparation of the article.
The authors Dr Robert Hermann, Dr Nassr Nassr, Gezim Lahu, Dr Dietrich Knoerzer, Rolf Herzog and Dr Karl Zech are employees of ALTANA Pharma AG (Konstanz, Germany). Dr Christian de Mey and Dr Éva Péterfai have assumed the roles of the principal investigator and the clinical investigator, respectively, as representatives of contract research organisations for the present study. As such, they have relationships involving commercial interests with the sponsor of this study. Beyond the scope of the present study, Dr Christian de Mey also serves as a consultant for ALTANA Pharma AG.
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