title: Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis.
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 250 microg 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 [AUC(24)]) of roflumilast was approximately 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 AUC(24) 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 approximately 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 roflumilast 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.
authors.affiliation: Exploratory Medicine, ALTANA Pharma AG, Konstanz, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Hermann
authors.forename: Nassr
authors.initials: N
authors.lastname: Nassr
authors.forename: Gezim
authors.initials: G
authors.lastname: Lahu
authors.forename: Eva
authors.initials: E
authors.lastname: Péterfai
authors.forename: Dietrich
authors.initials: D
authors.lastname: Knoerzer
authors.forename: Rolf
authors.initials: R
authors.lastname: Herzog
authors.forename: Karl
authors.initials: K
authors.lastname: Zech
authors.forename: Christian
authors.initials: C
authors.lastname: de Mey
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000009:adverse effects / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D019540:Area Under Curve; D001549:Benzamides / Q000009:adverse effects / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D003521:Cyclopropanes / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; C424423:Roflumilast; C517734:roflumilast N-oxide