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Drug Interactions

Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects

T.D. Bethke, T. Giessmann, K. Westphal, A. Weinbrenner, B. Hauns, D. Hauschke, M. David, G. Lahu, K. Zech, R. Hermann and W. Siegmund

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Volume 44 p. 572 - 579

Abstract

T.D. Bethke, T. Giessmann, K. Westphal, A. Weinbrenner, B. Hauns, D. Hauschke, M. David, G. Lahu, K. Zech, R. Hermann and W. Siegmund

¹ALTANA Pharma AG, Konstanz, and ²Department of Clinical Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, University of Greifswald, Germany
Objective: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor under investigation for the treatment of chronic obstructive pulmonary disease and asthma. In clinical practice, the drug is likely to be co-administered with inhaled bronchodilating b2-adrenoceptor agonists. Therefore, this study investigated the pharmacokinetic characteristics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide when co-administered with orally inhaled salbutamol in healthy subjects. Methods: In this open, randomized clinical study, 12 healthy male subjects received repeated doses of oral roflumilast 500 µg once daily, orally inhaled salbutamol 200 µg 3 times daily, and a combination of both drugs over 7 days according to a 3-period, changeover design with 14 days washout between treatments. Results: Co-administration of roflumilast and salbutamol did not markedly change roflumilast or roflumilast N-oxide disposition. Point estimates (90% confidence intervals) of area under the curve from 0 – 24 h (AUC0–24) and maximum plasma concentration in steady state (Cmax,ss) for roflumilast with salbutamol versus roflumilast alone were 1.05 (0.94, 1.17) and 0.97 (0.84, 1.10); the respective point estimates (90% confidence intervals) for AUC0–24 and Cmax,ss of roflumilast N-oxide were 0.98 (0.91, 1.06) and 0.98 (0.92, 1.03). Roflumilast co-administration did not alter the pharmacokinetics of steady state salbutamol. The respective point estimates (90% confidence intervals) for AUC0–6 and Cmax,ss of salbutamol with roflumilast versus salbutamol alone were 1.10 (0.99, 1.21), 1.08 (0.91, 1.28). The combination of both drugs was well tolerated. Conclusion: There were no relevant pharmacokinetic interactions between roflumilast and salbutamol at therapeutically effective doses. Correspondence to:
Prof. Dr. W. Siegmund
Department of Clinical Pharmacology
Peter Holtz Research Center of Pharmacology and Experimental Therapeutics
Ernst Moritz Arndt University of Greifswald
Friedrich-Löffler-Straße 23d
17487 Greifswald, Germany
Email: [email protected]

Pharmacokinetics

Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide

G. Lahu, A. Huennemeyer, R. Herzog, N. McCracken, R. Hermann, M. Elmlinger and K. Zech

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Volume 47 p. 236 - 245

Abstract

G. Lahu¹,², A. Huennemeyer¹, R. Herzog¹, N. McCracken¹, R. Hermann³, M. Elmlinger¹ and K. Zech¹

¹Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, ²University of Tuebingen, Institute for Toxicology, Pharmacy and Chemistry, Tuebingen, and ³Clinical Research Appliance, Radolfzell, Germany
Objective: To investigate the effects of steady state erythromycin on the pharmacokinetics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide in healthy subjects. Both roflumilast and roflumilast N-oxide have similar intrinsic PDE4 inhibitory activity; the total PDE4 inhibition (tPDE4i) in humans is likely due to the combined effect of roflumilast and roflumilast N-oxide. Methods: Subjects (n = 16) received single oral roflumilast 500 µg once daily (Days 1 and 15), and repeated oral erythromycin 500 mg three times daily (Days 9 – 21). Percent ratios of Test/Reference (Reference: roflumilast alone; Test: roflumilast and steady-state erythromycin) were calculated for the geometric means and their 90% confidence intervals for systemic exposure (AUC), maximum concentration (C_max) (roflumilast and roflumilast N-oxide), and apparent clearance of roflumilast. Results: After co-administration of erythromycin and roflumilast, the mean AUC and C_max of roflumilast increased by 70% and 40%, respectively. The mean apparent clearance of roflumilast decreased from 8.2 l/h (Reference) to 4.8 l/h (Test). Steady-state erythromycin did not alter the mean AUC of roflumilast N-oxide, however, the mean C_max decreased by 34%. The AUC_{roflumilast N-oxide}/AUC_roflumilast ratio decreased from 10.6 (Reference) to 6.4 (Test). Co-administration of erythromycin and roflumilast did not influence the integrated total exposure to roflumilast and roflumilast N-oxide, i.e. mean tPDE4i. No clinically relevant adverse events were observed during the study. Conclusions: Co-administration of erythromycin (a moderate CYP3A4 inhibitor) and roflumilast does not require dose adjustment of roflumilast.Correspondence to:
G. Lahu; Nycomed GmbH, Department of Pharmacometrics and Pharmacokinetics, Byk-Gulden-Straße 2, 78467 Konstanz, Germany
Email: [email protected]

Bioavailability Section

High absolute bioavailability of the new oral phosphodiesterase-4 inhibitor roflumilast

T.D. Bethke and G. Lahu

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Volume 49 p. 51 - 57

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (51-57)

High absolute bioavailability of the new oral phosphodiesterase-4 inhibitor roflumilast

T.D. Bethke and G. Lahu

Nycomed GmbH, Konstanz, Germany
Objective: To establish basic intravenous (IV) pharmacokinetics of roflumilast (ROF) and its pharmacologically active metabolite roflumilast N-oxide (R-NO) and to determine the absolute bioavailability of ROF in humans. Materials: In a randomized, open-label, 2-period, 2-sequence crossover study 12 healthy male subjects were randomized to receive ROF either orally (PO) 500 µg (immediate release tablets) or single IV (150 µg over 15 min). Plasma concentrations were determined. Dose-adjusted point estimates and 90% confidence intervals (CI) were calculated for the ratio of the AUC time curves using a multiplicative model and parametric analysis. Results: After IV administration, clearance of ROF was 0.14 l/h/kg, volume of distribution (V_{d area}) 2.92 l/kg, and the terminal t_1/2 was 14.8 h. After PO administration, ROF was rapidly absorbed; the absolute bioavailability was 79%. The AUC of the R-NO metabolite generally exceeded that of ROF. After IV and PO administration, the metabolic ratios were 7.4 and 12.4, respectively. Dose-adjusted analysis of the R-NO AUC values indicate a 21% higher R-NO formation seen with PO vs. IV, suggesting entire first-pass conversion of ROF is to the active R-NO. Formation/clearance processes of the R-NO appear to be slow with an observed tmax of 6.9 – 8.8 h, and corresponding to apparent t_1/2 values of 22.7 h and 20.6 h, after IV and PO administration, respectively. Conclusion: ROF is rapidly absorbed after PO administration and exhibits high absolute bioavailability and low clearance pharmacokinetics. The total exposure of R-NO exceeds that of ROF by a factor of 12 after oral administration.Correspondence to:
Dr. T.D. Bethke
Medical Department
Nycomed Germany GmbH
Byk-Gulden-Straße 2
78467 Konstanz, Germany
Email: [email protected]

Original Research

Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects

N. McCracken, G. Lahu and T.D. Bethke

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Volume 49 p. 388 - 396

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (388-396)

Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects

N. McCracken, G. Lahu and T.D. Bethke

Nycomed GmbH, Konstanz, Germany
Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved for the treatment of severe COPD. The pharmacological effect is mediated mainly by its active metabolite roflumilast N-oxide. Objective: This doubleblind, 2-period cross-over study was conducted to investigate the potential effects of concomitant roflumilast on pharmacokinetics and pharmacodynamics of warfarin and vice versa. Materials and methods: A total of 24 healthy adults was enrolled into the study. Once-daily oral doses of roflumilast (500 μg) or placebo were given for 12 days, with subjects receiving both treatments one after the other; single oral doses of (R,S)-warfarin (25 mg) were administered on Day –14 and Day 8 of both periods. Warfarin enantiomer concentrations, prothrombin time (PT), and clotting factor activity (Factor VII, only) as well as concentrations of roflumilast and roflumilast N-oxide were measured in plasma. Results: There was no clinically relevant pharmacokinetic or pharmacodynamic interaction between warfarin and roflumilast. Exposure over 120 h (area under the curve, AUC_0–120) with “Test” (warfarin plus roflumilast) and “Reference” (warfarin plus placebo) treatment for Factor VII (geometric mean ratio 102.1% (90% confidence interval: 99.7 – 104.7%)) and excess AUC_0–120 for PT (99.3% (92.3 – 106.9%)) were unchanged. Conclusions: Pharmacokinetic parameters including maximum plasma concentration (C_max) and AUC_0–∞ of (R)-, (S)-warfarin, roflumilast, and roflumilast N-oxide were unaffected by co-administration.Correspondence to:
Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestr. 4, 78467 Konstanz, Germany
Email: [email protected]

Original Research

Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults

G. Böhmer, C.H. Gleiter, A. Hünnemeyer, G. Lahu and T.D. Bethke

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Volume 49 p. 451 - 460

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (451-460)

Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults

G. Böhmer¹, C.H. Gleiter¹, A. Hünnemeyer², G. Lahu² and T.D. Bethke²

¹Department of Clinical Pharmacology, University of Tübingen, Tübingen, and ²Nycomed GmbH, Konstanz, Germany
Objective: To investigate whether a pharmacokinetic drug-drug interaction exists between theophylline (THEO), a CYP1A2 substrate with a narrow therapeutic index, and the concomitant substrate roflumilast (ROF), a novel selective PDE4 inhibitor partially metabolized by CYP1A2. Materials and methods: In an open-label, 2-period, crossover study, Treatment A (oral ROF 500 μg q.d. on Days 6 – 10 in addition to oral THEO 375 mg b.i.d. on Days 1 – 10) and treatment B (oral ROF 500 μg q.d. on Days 1 – 5) were administered consecutively in random order to each of 24 healthy adult subjects. Both periods were separated by a wash-out phase of at least 10 days. Plasma samples for pharmacokinetic evaluation (AUC, C_max, t_1/2, t_max) including percent peak-trough fluctuation (%PTF) of THEO were taken. Point estimates and the 90% confidence interval of the geometric mean ratios were calculated for AUC and C_max and descriptive statistics for other pharmacokinetic parameters. Results: Concomitant administration of ROF did not alter pharmacokinetics of THEO. With coadministered THEO, only steady-state total exposure to ROF (AUC) was increased by 28% whereas other pharmacokinetic parameters (t_1/2, C_max, t_max) of ROF and of the active metabolite roflumilast-N-oxide (R-NO), its main contributor to the pharmacodynamic effects, remained unchanged. Conclusions: Neither ROF nor its main metabolite had any impact on the metabolism of the concomitant CYP1A2 substrate THEO in humans. Though co-administration of THEO resulted in a minor increase (28%) in total ROF exposure, no safety or tolerability concerns and no altered total PDE4 inhibition of both ROF and R-NO, were observed.Correspondence to:
Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestrasse 4
78467 Konstanz, Germany
Email: [email protected]

Original Research

Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study

T.D. Bethke, M. Hartmann, A. Hünnemeyer, G. Lahu and C.H. Gleiter

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Volume 49 p. 491 - 499

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (491-499)

Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study

T.D. Bethke¹, M. Hartmann¹, A. Hünnemeyer¹, G. Lahu¹ and C.H. Gleiter²

¹Nycomed GmbH, Konstanz, and ²Department of Clinical Pharmacology, University of Tübingen, Tübingen, Germany
Objective: Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved in the European Union for the treatment of severe COPD. Roflumilast and its metabolites are mainly (70% of total radioactivity) eliminated via the kidneys as glucuronides. The potential impact of renal impairment on the pharmacokinetics of roflumilast and its active main metabolite roflumilast N-oxide were characterized. Materials and methods: Patients (n = 12) with severe renal impairment (creatinine clearance CL_CR < 30 ml/ min/1.73 m²; otherwise healthy) and matched (sex, age, weight, and height) healthy control subjects (n = 12; CL_CR > 80 ml/min/1.73 m²) were enrolled into an open-label, parallelgroup study. Single dose (500 μg, p.o.) pharmacokinetics and safety/tolerability of roflumilast and roflumilast N-oxide were compared between both groups. Results: A minor decrease of exposure (area under the plasma concentration-time curve from time zero to infinity (AUC_0–∞), maximum plasma concentration (C_max)) and a small increase in elimination half-life (t_1/2) of roflumilast (–1%; –6%; +19%, respectively) and roflumilast N-oxide (–%; ND; +30%, respectively) were observed in renally impaired patients compared with healthy subjects. No relevant differences in safety and tolerability were observed between groups. Conclusions: The pharmacokinetic changes observed in patients with renal impairment are of small magnitude without clinical importance. A dose adjustment or a change in the administration interval of roflumilast is not necessary in patients with renal impairment.Correspondence to:
Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestrasse 4
78467 Konstanz, Germany
Email: [email protected]

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