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Letter to the Editor| Volume 34, ISSUE 8, P1839-1841, August 2012

Dear Dr. Walson

Published:July 06, 2012DOI:https://doi.org/10.1016/j.clinthera.2012.06.015
Dear Dr. Walson
Previous ArticlePhase I, Multicenter, Randomized, Open-Label Study Evaluating the Pharmacokinetics and Safety Profile of Repeated Once-Daily Doses of Intravenous Esomeprazole in Children 0 to 17 Years of Age
Next ArticleThe authors respond
      In the January 2012 issue of Clinical Therapeutics, we were pleased to see the article on a new treatment of chronic obstructive pulmonary disease, roflumilast, by Pinner et al,
      • Pinner N.A.
      • Hamilton L.A.
      • Hughes A.
      Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease.
      Clin Ther. 2012; 34: 56-66
      titled “Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease.” Since roflumilast was recently approved, the review is especially timely for educating readers on this drug. In support of this, we would like the published information to be as accurate as possible. Please consider the following inaccuracies in the article:
      • 1
        Page 57, column 2, line 40: Based on the cited references,
        • Bethke T.D.
        • Bohmer G.M.
        • Hermann R.
        • et al.
        Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.
        J Clin Pharmacol. 2007; 47: 26-36
        , 
        • Bethke T.D.
        • Lahu G.
        High absolute bioavailability of the new oral phosphodiesterase-4 inhibitor roflumilast.
        Int J Clin Pharmacol Ther. 2011; 49: 51-57
        , 
        • Huennemeyer A.
        • Hauns B.
        • David M.
        • et al.
        Pharmacokinetics and safety of roflumilast, a once-daily, oral, selective PDE4 inhibitor, and its active metabolite roflumilast N-oxide in healthy subjects.
        J Allergy Clin Immunol. 2004; 113 (Abstract)
        , 
        • Manegold A.
        • Hauns B.
        • David M.
        • et al.
        Pharmacokinetic characteristics of roflumilast administered in gradually increasing doses of 500 μg to 1000 μg are dose-linear in healthy subjects.
        Eur Respir J. 2002; 20 (Abstract): S108
        the t½ for roflumilast N-oxide should be 20 to 23 hours, not 20 to 22 hours as reported in the article.
      • 2
        Page 58, column 1, lines 19 to 22: The sentence “Long-acting bronchodilators, theophylline (2 weeks), and inhaled and/or oral corticosteroids were discontinued before inclusion in the study” should read, “Long-acting bronchodilators, theophylline (2 weeks), and inhaled and/or oral corticosteroids (4 weeks) were discontinued before inclusion in the study,” to accurately report the design of the study
        • Grootendorst D.C.
        • Gauw S.A.
        • Verhoosel R.M.
        • et al.
        Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD.
        Thorax. 2007; 62: 1081-1087
        and to be consistent within the sentence, given that weeks of discontinuation necessary in patients taking theophylline (2 weeks) was reported earlier in the sentence.
      • 3
        Page 58, column 2, lines 9 to 13: The sentence “Of note, inflammation worsened during the placebo arm of the study, with increases in sputum neutrophils, eosinophils, neutrophil elastase, and α2-macroglobulin above baseline values” omits eosinophil cationic protein (ECP), interleukin (IL)-8, and lactoferrin, which the cited reference
        • Grootendorst D.C.
        • Gauw S.A.
        • Verhoosel R.M.
        • et al.
        Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD.
        Thorax. 2007; 62: 1081-1087
        reported as also increased above baseline values. No explanation is given as to why these measures were omitted.
      • 4
        Page 58, Table I:
        • a
          The table title claims that the table summarizes ranges of reported pharmacokinetic data for roflumilast and roflumilast N-oxide in healthy adult subjects following a single 500-μg oral dose and cites 4 articles reporting such data. However, no explanation is given as to why 6 articles already cited in the review that also reported similar data
          • Böhmer G.M.
          • Gleiter C.H.
          • Morike K.
          • et al.
          No dose adjustment on coadministration of the PDE4 inhibitor roflumilast with a weak CYP3A, CYP1A2, and CYP2C19 inhibitor: an investigation using cimetidine.
          J Clin Pharmacol. 2011; 51: 594-602
          , 
          • Lahu G.
          • Huennemeyer A.
          • von Richter O.
          • et al.
          Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          J Clin Pharmacol. 2008; 48: 1339-1349
          , 
          • Lahu G.
          • Nassr N.
          • Herzog R.
          • et al.
          Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.
          J Clin Pharmacol. 2011; 51: 586-593
          , 
          • Nassr N.
          • Huennemeyer A.
          • Herzog R.
          • et al.
          Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.
          Br J Clin Pharmacol. 2009; 68: 580-587
          , 
          • Nassr N.
          • Lahu G.
          • Hunnemeyer A.
          • et al.
          Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast.
          J Clin Pharmacol. 2007; 47: 660-666
          , 
          • von Richter O.
          • Lahu G.
          • Huennemeyer A.
          • et al.
          Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          Clin Pharmacokinet. 2007; 46: 613-622
          were omitted from the table. Although the inclusion of these 6 studies would not substantially change the reported pharmacokinetic parameter ranges, the authors provide no explanation as to why these studies were omitted.
        • b
          One of the data sources for the table reports pharmacokinetic parameters for roflumilast and roflumilast N-oxide in the fed and fasted states,
          • Hauns B.
          • Hermann R.
          • Hunnemeyer A.
          • et al.
          Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects.
          J Clin Pharmacol. 2006; 46: 1146-1153
          but the table reports only parameters from the fasted state. Although the additional inclusion of the fed-state parameters would not substantially change the reported pharmacokinetic parameter ranges, the authors provide no explanation as to why these parameters were omitted.
        • c
          The inclusion of data from the 6 omitted references
          • Böhmer G.M.
          • Gleiter C.H.
          • Morike K.
          • et al.
          No dose adjustment on coadministration of the PDE4 inhibitor roflumilast with a weak CYP3A, CYP1A2, and CYP2C19 inhibitor: an investigation using cimetidine.
          J Clin Pharmacol. 2011; 51: 594-602
          , 
          • Lahu G.
          • Huennemeyer A.
          • von Richter O.
          • et al.
          Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          J Clin Pharmacol. 2008; 48: 1339-1349
          , 
          • Lahu G.
          • Nassr N.
          • Herzog R.
          • et al.
          Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.
          J Clin Pharmacol. 2011; 51: 586-593
          , 
          • Nassr N.
          • Huennemeyer A.
          • Herzog R.
          • et al.
          Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.
          Br J Clin Pharmacol. 2009; 68: 580-587
          , 
          • Nassr N.
          • Lahu G.
          • Hunnemeyer A.
          • et al.
          Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast.
          J Clin Pharmacol. 2007; 47: 660-666
          , 
          • von Richter O.
          • Lahu G.
          • Huennemeyer A.
          • et al.
          Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          Clin Pharmacokinet. 2007; 46: 613-622
          and from the fed state
          • Hauns B.
          • Hermann R.
          • Hunnemeyer A.
          • et al.
          Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects.
          J Clin Pharmacol. 2006; 46: 1146-1153
          in Table I results in the following revisions to the summarized parameters: roflumilast Cmax, 3.9–8.3 µg/L; roflumilast N-oxide Cmax, 8.4–13.1 µg/L; roflumilast N-oxide AUC, 305–780 µg · h/L; roflumilast t½, 10.3–33.1 hours; roflumilast N-oxide t½, 19.6–44.0 hours; and roflumilast Tmax, 0.9–2.0 hours.
      • 5
        Page 59, Table II:
        • a
          Although each study of each drug measures AUC differently, the authors give no indication as to what kind of AUC parameter is being reported in each case. In Table II, multiple different AUC parameters are reported (AUC0–tlqc [erythromycin
          • Lahu G.
          • Huennemeyer A.
          • Herzog R.
          • et al.
          Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          Int J Clin Pharmacol Ther. 2009; 47: 236-245
          ], AUC0-infinity [ketoconazole,
          • Lahu G.
          • Huennemeyer A.
          • von Richter O.
          • et al.
          Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          J Clin Pharmacol. 2008; 48: 1339-1349
          rifampicin,
          • Nassr N.
          • Huennemeyer A.
          • Herzog R.
          • et al.
          Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.
          Br J Clin Pharmacol. 2009; 68: 580-587
          and montelukast
          • Böhmer G.M.
          • Nassr N.
          • Wenger M.
          • et al.
          The targeted oral, once-daily phosphodiesterase 4 inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions.
          J Clin Pharmacol. 2009; 49: 389-397
          ], AUCinfinity [fluvoxamine
          • von Richter O.
          • Lahu G.
          • Huennemeyer A.
          • et al.
          Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          Clin Pharmacokinet. 2007; 46: 613-622
          and enoxacin
          • Lahu G.
          • Nassr N.
          • Herzog R.
          • et al.
          Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.
          J Clin Pharmacol. 2011; 51: 586-593
          ], AUClast [cimetidine
          • Böhmer G.M.
          • Gleiter C.H.
          • Morike K.
          • et al.
          No dose adjustment on coadministration of the PDE4 inhibitor roflumilast with a weak CYP3A, CYP1A2, and CYP2C19 inhibitor: an investigation using cimetidine.
          J Clin Pharmacol. 2011; 51: 594-602
          and magnesium hydroxide/aluminium hydroxide
          • Nassr N.
          • Lahu G.
          • Hunnemeyer A.
          • et al.
          Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast.
          J Clin Pharmacol. 2007; 47: 660-666
          ], and AUCτ [budesonide
          • Hermann R.
          • Siegmund W.
          • Giessmann T.
          • et al.
          The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide.
          J Clin Pharmacol. 2007; 47: 1005-1013
          ]), but no indication is given as to whether these parameters were directly comparable among drugs, as is implied by the table.
        • b
          The following values are incorrectly reported based on the cited references
          • Lahu G.
          • Nassr N.
          • Herzog R.
          • et al.
          Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.
          J Clin Pharmacol. 2011; 51: 586-593
          , 
          • von Richter O.
          • Lahu G.
          • Huennemeyer A.
          • et al.
          Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          Clin Pharmacokinet. 2007; 46: 613-622
          , 
          • Lahu G.
          • Huennemeyer A.
          • Herzog R.
          • et al.
          Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide.
          Int J Clin Pharmacol Ther. 2009; 47: 236-245
          and should be revised: roflumilast + enoxacin AUC, +56%; roflumilast + fluvoxamine t½, 32 hours; roflumilast N-oxide + enoxacin AUC, +23%; roflumilast N-oxide + erythromycin t½, 16 hours; roflumilast N-oxide + fluvoxamine t½, 35 hours.
        • c
          Table II incorrectly states that montelukast was administered as a single dose, whereas the data reported correspond to steady-state montelukast administration.
          • Böhmer G.M.
          • Nassr N.
          • Wenger M.
          • et al.
          The targeted oral, once-daily phosphodiesterase 4 inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions.
          J Clin Pharmacol. 2009; 49: 389-397
      • 6
        Page 60, column 1, line 30: The increase in tPDE4i activity with enoxacin was incorrectly reported as 27% and should be 25%.
        • Lahu G.
        • Nassr N.
        • Herzog R.
        • et al.
        Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.
        J Clin Pharmacol. 2011; 51: 586-593
      • 7
        Page 60, column 1, line 43: The decrease in roflumilast N-oxide AUC with rifampicin was incorrectly reported as 68% and should be 56%.
        • Nassr N.
        • Huennemeyer A.
        • Herzog R.
        • et al.
        Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.
        Br J Clin Pharmacol. 2009; 68: 580-587
      • 8
        Page 61, column 2, line 36: The description of the inclusion criteria for the M2-124 and M2-125 studies omits the requirement that patients must have had bronchitic symptoms, an important component of the study design.
        • Calverley P.M.
        • Rabe K.F.
        • Goehring U.M.
        • et al.
        Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.
        Lancet. 2009; 374: 685-694
      • 9
        Page 62, Table III:
        • a
          The population in the study by Rabe et al
          • Rabe K.F.
          • Bateman E.D.
          • O'Donnell D.
          • et al.
          Roflumilast–an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial.
          Lancet. 2005; 366: 563-571
          is incorrectly described as having had moderate COPD; patients were required to have had moderate to severe COPD.
        • b
          Study populations of the M2-112, M2-124, and M2-125 studies
          • Calverley P.M.
          • Rabe K.F.
          • Goehring U.M.
          • et al.
          Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.
          Lancet. 2009; 374: 685-694
          , 
          • Calverley P.M.
          • Sanchez-Toril F.
          • McIvor A.
          • et al.
          Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease.
          Am J Respir Crit Care Med. 2007; 176: 154-161
          are incorrectly described as having had severe COPD; patients were required to have had severe to very severe COPD.
        • c
          For the M2-127 and M2-128 studies,
          • Fabbri L.M.
          • Calverley P.M.
          • Izquierdo-Alonso J.L.
          • et al.
          Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials.
          Lancet. 2009; 374: 695-703
          under “Study Population,” the requirement of sputum production was omitted; the entry should read, “In addition, the tiotropium arm required the presence of chronic cough, sputum production, and frequent use of rescue inhalers.”
      • 10
        Page 63, column 1, lines 29 to 32: The following sentence is incorrect: “Patients in the M2-127 trial must not have had an exacerbation requiring systemic corticosteroids in the previous month, but this was not an exclusion criteria for the M2-128 trial.” Both trials excluded patients who had had an exacerbation in the previous month that required systemic corticosteroids.
        • Fabbri L.M.
        • Calverley P.M.
        • Izquierdo-Alonso J.L.
        • et al.
        Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials.
        Lancet. 2009; 374: 695-703
      • 11
        Page 64, column 1, lines 1 to 3: The sentence “In a subset of patients who reported weight loss as an adverse event, mean weight change was −6.26 kg” omits the context that, in this subset of patients, mean weight change with placebo was −4.47 kg, as reported in the cited reference.
        • Martinez F.J.
        • Rabe K.F.
        • Wouters E.F.M.
        • et al.
        Time course and reversibility of weight decrease with roflumilast, a phosphodiesterase 4 inhibitor.
        Am J Respir Crit Care Med. 2010; 181 (Abstract): A4441
      • 12
        Page 64, column 1, lines 19 to 23: The sentence “In documents submitted to the FDA, the suicide-related adverse events included 2 attempted and 3 completed suicides in roflumilast-treated patients and 1 attempted suicide in placebo-treated patients” omits the context that, of the 3 completed suicides in roflumilast-treated patients, 2 of those patients committed suicide >3 weeks after discontinuation of the study drug, as reported in the cited reference.
        Daxas (roflumilast) in chronic obstructive pulmonary disease FDA advisory committee briefing document.
        http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM207379.pdf
      • 13
        Page 64, column 2, lines 43 to 45: The authors call for studies that more fully assess drug interactions, but they do not cite 4 published drug-interaction studies that should have been found in their systematic review of the literature: roflumilast + warfarin (published June 2011),
        • McCracken N.
        • Lahu G.
        • Bethke T.D.
        Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects.
        Int J Clin Pharmacol Ther. 2011; 49: 388-396
        roflumilast + theophylline (published July 2011),
        • Böhmer G.
        • Gleiter C.H.
        • Hunnemeyer A.
        • Lahu G.
        • Bethke T.D.
        Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults.
        Int J Clin Pharmacol Ther. 2011; 49: 451-460
        roflumilast + formoterol (published June 2011),
        • de Mey C.
        • Nassr N.
        • Lahu G.
        No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study.
        BMC Clin Pharmacol. 2011; 11: 7
        and roflumilast + salbutamol (published November 2006).
        • Bethke T.D.
        • Giessmann T.
        • Westphal K.
        • et al.
        Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects.
        Int J Clin Pharmacol Ther. 2006; 44: 572-579
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      References

        • Pinner N.A.
        • Hamilton L.A.
        • Hughes A.
        Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease.
        Clin Ther. 2012; 34: 56-66
        View in Article
        • Bethke T.D.
        • Bohmer G.M.
        • Hermann R.
        • et al.
        Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.
        J Clin Pharmacol. 2007; 47: 26-36
        View in Article
        • Bethke T.D.
        • Lahu G.
        High absolute bioavailability of the new oral phosphodiesterase-4 inhibitor roflumilast.
        Int J Clin Pharmacol Ther. 2011; 49: 51-57
        View in Article
        • Huennemeyer A.
        • Hauns B.
        • David M.
        • et al.
        Pharmacokinetics and safety of roflumilast, a once-daily, oral, selective PDE4 inhibitor, and its active metabolite roflumilast N-oxide in healthy subjects.
        J Allergy Clin Immunol. 2004; 113 (Abstract)
        View in Article
        • Manegold A.
        • Hauns B.
        • David M.
        • et al.
        Pharmacokinetic characteristics of roflumilast administered in gradually increasing doses of 500 μg to 1000 μg are dose-linear in healthy subjects.
        Eur Respir J. 2002; 20 (Abstract): S108
        View in Article
        • Grootendorst D.C.
        • Gauw S.A.
        • Verhoosel R.M.
        • et al.
        Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD.
        Thorax. 2007; 62: 1081-1087
        View in Article
        • Böhmer G.M.
        • Gleiter C.H.
        • Morike K.
        • et al.
        No dose adjustment on coadministration of the PDE4 inhibitor roflumilast with a weak CYP3A, CYP1A2, and CYP2C19 inhibitor: an investigation using cimetidine.
        J Clin Pharmacol. 2011; 51: 594-602
        View in Article
        • Lahu G.
        • Huennemeyer A.
        • von Richter O.
        • et al.
        Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide.
        J Clin Pharmacol. 2008; 48: 1339-1349
        View in Article
        • Lahu G.
        • Nassr N.
        • Herzog R.
        • et al.
        Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.
        J Clin Pharmacol. 2011; 51: 586-593
        View in Article
        • Nassr N.
        • Huennemeyer A.
        • Herzog R.
        • et al.
        Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.
        Br J Clin Pharmacol. 2009; 68: 580-587
        View in Article
        • Nassr N.
        • Lahu G.
        • Hunnemeyer A.
        • et al.
        Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast.
        J Clin Pharmacol. 2007; 47: 660-666
        View in Article
        • von Richter O.
        • Lahu G.
        • Huennemeyer A.
        • et al.
        Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.
        Clin Pharmacokinet. 2007; 46: 613-622
        View in Article
        • Hauns B.
        • Hermann R.
        • Hunnemeyer A.
        • et al.
        Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects.
        J Clin Pharmacol. 2006; 46: 1146-1153
        View in Article
        • Lahu G.
        • Huennemeyer A.
        • Herzog R.
        • et al.
        Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide.
        Int J Clin Pharmacol Ther. 2009; 47: 236-245
        View in Article
        • Böhmer G.M.
        • Nassr N.
        • Wenger M.
        • et al.
        The targeted oral, once-daily phosphodiesterase 4 inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions.
        J Clin Pharmacol. 2009; 49: 389-397
        View in Article
        • Hermann R.
        • Siegmund W.
        • Giessmann T.
        • et al.
        The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide.
        J Clin Pharmacol. 2007; 47: 1005-1013
        View in Article
        • Calverley P.M.
        • Rabe K.F.
        • Goehring U.M.
        • et al.
        Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.
        Lancet. 2009; 374: 685-694
        View in Article
        • Rabe K.F.
        • Bateman E.D.
        • O'Donnell D.
        • et al.
        Roflumilast–an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial.
        Lancet. 2005; 366: 563-571
        View in Article
        • Calverley P.M.
        • Sanchez-Toril F.
        • McIvor A.
        • et al.
        Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2007; 176: 154-161
        View in Article
        • Fabbri L.M.
        • Calverley P.M.
        • Izquierdo-Alonso J.L.
        • et al.
        Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials.
        Lancet. 2009; 374: 695-703
        View in Article
        • Martinez F.J.
        • Rabe K.F.
        • Wouters E.F.M.
        • et al.
        Time course and reversibility of weight decrease with roflumilast, a phosphodiesterase 4 inhibitor.
        Am J Respir Crit Care Med. 2010; 181 (Abstract): A4441
        View in Article
      22. Daxas (roflumilast) in chronic obstructive pulmonary disease.
        http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM207379.pdf
        (Accessed February 8, 2012)
        View in Article
        • McCracken N.
        • Lahu G.
        • Bethke T.D.
        Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects.
        Int J Clin Pharmacol Ther. 2011; 49: 388-396
        View in Article
        • Böhmer G.
        • Gleiter C.H.
        • Hunnemeyer A.
        • Lahu G.
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      Article info

      Publication history

      Published online: July 06, 2012

      Identification

      DOI: https://doi.org/10.1016/j.clinthera.2012.06.015

      Copyright

      © 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.

      ScienceDirect

      Access this article on ScienceDirect

      Linked Article

      • Roflumilast: A Phosphodiesterase-4 Inhibitor for the Treatment of Severe Chronic Obstructive Pulmonary Disease
        Clinical TherapeuticsVol. 34Issue 1
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          Roflumilast is a newly approved phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of exacerbations.
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      • The authors respond
        Clinical TherapeuticsVol. 34Issue 8
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          We thank Dr. Laurenzi for his thorough review and critique of our recent article “Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease,” published in the January 2012 issue of Clinical Therapeutics.1 While several of the suggested changes are minor and would not substantially alter the findings, as stated by Dr. Laurenzi, we want to clarify and correct a few of the highlighted items. Items 1 to 7 and 9 are accurate, with the differences likely due to rounding (5b), attempts to provide representative data without being exhaustive (1, 3, 4a–c, 5a, and 9), and errors made while compiling the data (2, 5c, 6, and 7); therefore, we see no need to discuss them further in this response.
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