The Experts below are selected from a list of 2463 Experts worldwide ranked by ideXlab platform
Gezim Lahu - One of the best experts on this subject based on the ideXlab platform.
-
Absence of pharmacokinetic interaction between Roflumilast and digoxin in healthy adults.
Journal of clinical pharmacology, 2012Co-Authors: Gabriel Eckermann, Nassr Nassr, Gezim Lahu, Thomas D. BethkeAbstract:Numerous interactions are known for digoxin, which is a drug with a narrow therapeutic index and a substrate of P-glycoprotein (P-gp). This study investigated potential effects of coadministration on pharmacokinetics and safety of both drugs when a single dose of digoxin was concomitantly administered with Roflumilast under steady-state conditions. Sixteen healthy male and female adults were randomly assigned in an open-label, crossover study to either of 2 treatment sequences that consisted of 2 treatment periods separated by a washout phase. Treatments were oral daily doses of Roflumilast for 14 days given concomitantly on days 1 and 14 with a single oral dose of digoxin or an oral dose of digoxin once on day 1. Plasma samples for pharmacokinetic evaluations of digoxin and Roflumilast concentrations with and without concomitant treatment were taken. The rate of digoxin absorption was slightly (15%) but statistically insignificantly increased, whereas the extent of absorption was not altered by concomitant medication with Roflumilast. Concomitant medication with digoxin did not significantly affect steady-state pharmacokinetics of either Roflumilast or its active metabolite Roflumilast N-oxide. Roflumilast is not an inhibitor of P-gp. No safety or tolerability concerns were detected with coadministration of Roflumilast and digoxin.
-
Pharmacokinetic evaluation of Roflumilast
Expert opinion on drug metabolism & toxicology, 2011Co-Authors: Gezim Lahu, Nassr Nassr, Andreas HünnemeyerAbstract:Introduction: Roflumilast is a selective PDE4 inhibitor recently approved for oral, once-daily treatment of severe chronic obstructive pulmonary disease (COPD). Clinical trials have demonstrated the effect of Roflumilast on reducing exacerbation frequency and improving lung function in COPD, while its mode of action may offer the potential to target the inflammatory processes underlying COPD. Roflumilast is, therefore, an important addition to current therapeutic options. It is catalyzed by cytochrome P450 (CYP) 1A2 and 3A4 to its active metabolite, Roflumilast N-oxide, which accounts for > 90% of Roflumilast total PDE4 inhibitory activity. Areas covered: This article reviews the pharmacokinetics of Roflumilast and considers the effects of co-administration with CYP inhibitors or inducers, and other medications commonly used in patients with COPD, on the pharmacokinetics of Roflumilast and Roflumilast N-oxide. Expert opinion: Roflumilast has novel anti-inflammatory activity in COPD that provides the physi...
-
effect of steady state enoxacin on single dose pharmacokinetics of Roflumilast and Roflumilast n oxide
The Journal of Clinical Pharmacology, 2011Co-Authors: Nassr Nassr, Gezim Lahu, Rolf Herzog, Martin Elmlinger, Peter Ruth, Markus Hinder, A HuennemeyerAbstract:Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). It is metabolized by CYP1A2 and CYP3A4 to its primary metabolite, Roflumilast N-oxide, through which >90% total PDE4 inhibitory activity (tPDE4i) is mediated. Fluoroquinolones, of which enoxacin is the most potent CYP1A2 inhibitor, are used to treat COPD exacerbations. This phase I, open, nonrandomized, fixed-sequence, 2-period study evaluated the effects of steady-state enoxacin on the single-dose pharmacokinetics of Roflumilast and Roflumilast N-oxide. Twenty healthy participants received Roflumilast, 500 μg once daily, on days 1 and 12, and enoxacin, 400 mg twice daily, on days 7 to 18. Pharmacokinetic profiles were obtained for days 1 to 6 and 12 to 1 9. The safety and tolerability of all treatments were also assessed. In 1 9 evaluable participants, coadministration led to 56% higher mean systemic exposure, 20% higher mean peak concentrations, and 36% lower mean apparent oral clearance compared with Roflumilast alone. For Roflumilast N-oxide, 23% higher mean systemic exposure and 14% lower mean peak concentrations were seen after coadministration. Roflumilast was well tolerated both alone and in combination with enoxacin. A weak interaction was shown between Roflumilast and enoxacin, as mean tPDE4i increased by 25%, but is unlikely to have clinical relevance.
-
Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase-4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model
Clinical Pharmacokinetics, 2010Co-Authors: Gezim Lahu, Karl Zech, N Mccracken, Andreas Hünnemeyer, Edgar Diletti, Martin Elmlinger, Peter Ruth, Axel FaciusAbstract:Background: Roflumilast is an oral, selective phosphodiesterase (PDE)-4 inhibitor in development for the treatment of chronic obstructive pulmonary disease (COPD). Both Roflumilast and its metabolite Roflumilast N -oxide have anti-inflammatory properties that contribute to overall pharmacological activity. Objectives: To model the pharmacokinetics of Roflumilast and Roflumilast N -oxide, evaluate the influence of potential covariates, use the total PDE4 inhibitory activity (tPDE4i) concept to estimate the combined inhibition of PDE4 by Roflumilast and Roflumilast N -oxide, and use individual estimates of tPDE4i to predict the occurrence of adverse events (AEs) in patients with moderate-to-severe COPD. Methods: We modelled exposure to Roflumilast and Roflumilast N -oxide (21 studies provided the index dataset and five separate studies provided the validation dataset), extended the models to COPD (using data from two studies) and assessed the robustness of the parameter estimates. A parametric bootstrap estimation was used to quantify tPDE4i in subpopulations. We established logistic regression models for each AE occurring in >2% of patients in a placebo-controlled trial that achieved a p-value of
-
No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine
Journal of clinical pharmacology, 2010Co-Authors: Gabriele M. Böhmer, Nassr Nassr, Christoph H. Gleiter, Klaus Mörike, Antje Walz, Gezim LahuAbstract:This nonrandomized, fixed-sequence, 2-period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor Roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received Roflumilast, 500 µg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of Roflumilast and its active metabolite Roflumilast N-oxide was performed, and the ratio of geometric means for Roflumilast alone and concomitantly with steady-state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to Roflumilast and Roflumilast N-oxide) was also calculated. Coadministration of steady-state cimetidine increased mean tPDE4i of Roflumilast and Roflumilast N-oxide by about 47%. The maximum plasma concentration (C(max)) of Roflumilast increased by about 46%, with no effect on C(max) of Roflumilast N-oxide. The increase in tPDE4i of Roflumilast and Roflumilast N-oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of Roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine.
T.d. Bethke - One of the best experts on this subject based on the ideXlab platform.
-
Lack of pharmacokinetic and pharmacodynamic interactions of Roflumilast with (R, S)-warfarin in healthy adult subjects.
International journal of clinical pharmacology and therapeutics, 2011Co-Authors: N Mccracken, G Lahu, T.d. BethkeAbstract:UNLABELLED 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, AUC0-120) 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 AUC0-120 for PT (99.3% (92.3 - 106.9%)) were unchanged. CONCLUSIONS Pharmacokinetic parameters including maximum plasma concentration (Cmax) and AUC0-∞ of (R)-, (S)-warfarin, Roflumilast, and Roflumilast N-oxide were unaffected by co-administration.
-
The oral, once-daily phosphodiesterase 4 inhibitor Roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide.
Journal of clinical pharmacology, 2007Co-Authors: Robert Hermann, Karl Zech, G Lahu, Werner Siegmund, Thomas Giessmann, Kristin Westphal, Anita Weinbrenner, Bernhard Hauns, Felix Reutter, T.d. BethkeAbstract:This open-label, randomized, 3-period crossover study evaluated the pharmacokinetic interaction potential of Roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral Roflumilast 500 μg, once daily, orally inhaled budesonide 800 μg, twice daily, and concomitant administration of both treatments for 7 days each. Roflumilast and Roflumilast N-oxide in plasma and budesonide serum levels were measured by specific assays. Geometric mean test/reference ratios of steady-state pharmacokinetic parameters were evaluated by analysis of variance. Safety and tolerability were monitored. Pharmacokinetic parameters of Roflumilast, Roflumilast N-oxide, and budesonide after coadministration of Roflumilast and budesonide were similar to those after mono-treatment. Compared with budesonide and Roflumilast mono-treatments, slightly lower maximum serum/plasma concentration (C max ) and area under the curve (AUC) values of Roflumilast N-oxide and budesonide (ranging from -8% to -16%) were observed with combined treatment. All test/reference ratios were within predefined equivalence acceptance ranges for Roflumilast AUC (0.80, 1.25) and C max (0.70, 1.43) and for Roflumilast N-oxide and budesonide AUC and C max (all 0.67, 1.50). Coadministration of Roflumilast and budesonide did not alter the steady-state disposition of each other and did not affect safety and tolerability of either drug.
-
dose proportional intraindividual single and repeated dose pharmacokinetics of Roflumilast an oral once daily phosphodiesterase 4 inhibitor
The Journal of Clinical Pharmacology, 2007Co-Authors: T.d. Bethke, Robert Hermann, Dietrich Knoerzer, Gabriele M. Böhmer, Klaus Mörike, Bernhard Hauns, Richard Fux, Michael David, Wilhelm Wurst, Christoph H. GleiterAbstract:Abstract The dose-proportional, intraindividual, single- and repeated-dose pharmacokinetics of Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2-period, 2-sequence crossover study, 15 subjects received immediate-release tablets of Roflumilast 250 or 500 microg as single (day 1) and as repeated, once-daily doses for 8 days (days 5-12). Dose-adjusted point estimates and 90% confidence intervals of test (500 microg)/reference (250 microg) ratios for AUC and Cmax of Roflumilast and its pharmacologically active N-oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both Roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of Roflumilast and Roflumilast N-oxide. Repeated oral dosing with Roflumilast 250 and 500 microg once daily was well tolerated.
-
Roflumilast an oral anti inflammatory treatment for chronic obstructive pulmonary disease a randomised controlled trial
The Lancet, 2005Co-Authors: Klaus F Rabe, Dirk Bredenbroker, Eric D. Bateman, Denis E Odonnell, Stephan Witte, T.d. BethkeAbstract:Summary Background Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation associated with chronic inflammation. There are few treatment options for the disease. This study assessed the efficacy and safety of Roflumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD. Methods This phase III, multicentre, double-blind, randomised, placebo-controlled study was undertaken in an outpatient setting. 1411 patients with COPD were randomly assigned Roflumilast 250 μg (n=576), Roflumilast 500 μg (n=555), or placebo (n=280) given orally once daily for 24 weeks. Primary outcomes were postbronchodilator FEV 1 and health-related quality of life. Secondary outcomes included other lung function parameters and COPD exacerbations. Analyses were by intention to treat. Findings 1157 (82%) patients completed the study; 32 (11%) withdrew from the placebo group, 100 (17%) from the Roflumilast 250 μg group, and 124 (22%) from the Roflumilast 500 μg group. Postbronchodilator FEV 1 at the end of treatment significantly improved with Roflumilast 250 μg (by 74 mL [SD 18]) and Roflumilast 500 μg (by 97 mL [18]) compared with placebo (p Interpretation Roflumilast is a promising candidate for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo. Long-term studies are needed to fully assess the effect on health-related quality of life.
-
Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high absolute bioavailability
Journal of Allergy and Clinical Immunology, 2004Co-Authors: M. David, Karl Zech, M. Seiberling, C. Weimar, T.d. BethkeAbstract:Abstract Rationale Roflumilast is a novel, potent, selective phosphodiesterase 4 (PDE4) inhibitor in clinical development for the treatment of COPD and asthma. In humans, Roflumilast is metabolized to the pharmacologically active compound Roflumilast N-oxide. This study determined the bioavailability of Roflumilast after oral administration and assessed pharmacokinetics of Roflumilast and its metabolite in healthy subjects. Methods In an open-label, randomized, 2-period crossover study, 12 healthy male subjects received single doses of oral Roflumilast 500μg and intravenous (iv) Roflumilast 150μg as 15min short-term infusion. Plasma concentrations of Roflumilast and Roflumilast N-oxide were measured by HPLC. Vital signs, ECG, clinical laboratory, and adverse events were recorded. Results After oral administration, the mean peak plasma concentration (C max ) and extent (AUC) of exposure to Roflumilast were 8.33μg/L (68% range: 5.79 – 11.98μg/L) and 37.22μgxh/L (25.20 – 54.98μgxh/L). Median t max (min.- max.) of oral Roflumilast was 0.88h (0.50 – 1.50h) and mean elimination half-life (t 1/2 ) was 15.70h (68% range: 12.38 – 19.90h). Roflumilast N-oxide showed 12-fold higher AUC and about 1.5-fold higher C max than Roflumilast. Median t max occurred at 4.00h (2.00 – 48.00h), and t 1/2 was prolonged to 20.6h (15.40 – 27.56h). Following iv administration of Roflumilast, the volume of distribution was 2.9L/kg suggesting pronounced tissue distribution. Absolute bioavailability of orally administered Roflumilast was 79%. Roflumilast was well tolerated independent of the route of administration. Conclusions High absolute bioavailability of Roflumilast after oral intake, formation of a pharmacologically active metabolite Roflumilast N-oxide, and long t 1/2 of both compounds favour once-daily administration of Roflumilast.
Karl Zech - One of the best experts on this subject based on the ideXlab platform.
-
Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase-4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model
Clinical Pharmacokinetics, 2010Co-Authors: Gezim Lahu, Karl Zech, N Mccracken, Andreas Hünnemeyer, Edgar Diletti, Martin Elmlinger, Peter Ruth, Axel FaciusAbstract:Background: Roflumilast is an oral, selective phosphodiesterase (PDE)-4 inhibitor in development for the treatment of chronic obstructive pulmonary disease (COPD). Both Roflumilast and its metabolite Roflumilast N -oxide have anti-inflammatory properties that contribute to overall pharmacological activity. Objectives: To model the pharmacokinetics of Roflumilast and Roflumilast N -oxide, evaluate the influence of potential covariates, use the total PDE4 inhibitory activity (tPDE4i) concept to estimate the combined inhibition of PDE4 by Roflumilast and Roflumilast N -oxide, and use individual estimates of tPDE4i to predict the occurrence of adverse events (AEs) in patients with moderate-to-severe COPD. Methods: We modelled exposure to Roflumilast and Roflumilast N -oxide (21 studies provided the index dataset and five separate studies provided the validation dataset), extended the models to COPD (using data from two studies) and assessed the robustness of the parameter estimates. A parametric bootstrap estimation was used to quantify tPDE4i in subpopulations. We established logistic regression models for each AE occurring in >2% of patients in a placebo-controlled trial that achieved a p-value of
-
Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase-4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model
Clinical pharmacokinetics, 2010Co-Authors: Gezim Lahu, Karl Zech, N Mccracken, Andreas Hünnemeyer, Edgar Diletti, Martin Elmlinger, Peter Ruth, Axel FaciusAbstract:Background: Roflumilast is an oral, selective phosphodiesterase (PDE)-4 inhibitor in development for the treatment of chronic obstructive pulmonary disease (COPD). Both Roflumilast and its metabolite Roflumilast N-oxide have anti-inflammatory properties that contribute to overall pharmacological activity.
-
Effects of rifampicin on the pharmacokinetics of Roflumilast and Roflumilast N‐oxide in healthy subjects
British journal of clinical pharmacology, 2009Co-Authors: Nassr Nassr, Robert Hermann, Rolf Herzog, Karl Zech, A Huennemeyer, Oliver Von Richter, Manuela Koch, Kevin Duffy, Gezim LahuAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rifampicin is an antibiotic that is used to treat pulmonary tuberculosis. It induces several cytochrome P450 (CYP) enzymes and some drug transporter proteins; its greatest effect is as an inducer of CYP3A4 in the liver and in the small intestine. • Mechanistic drug–drug interaction studies with prototypic CYP3A4 inducers provide essential information for clinical drug development of new chemical entities that are metabolized by the involved CYP450 enzymes. • Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor being developed for the treatment of chronic obstructive pulmonary disease. • The pharmacological effect is based on the total PDE4 inhibitory activity, which represents the combined PDE4 inhibitory activity of Roflumilast and its major active metabolite, Roflumilast N-oxide. • In patients with chronic obstructive pulmonary disease, pulmonary tuberculosis can be an accompanying disease. Thus, the drug–drug interaction between rifampicin and Roflumilast is of clinical relevance. WHAT THIS STUDY ADDS • The pharmacokinetics of Roflumilast and of its major pharmacologically active metabolite Roflumilast N-oxide is affected by co-administration of rifampicin. • The potent induction of CYP3A4 and other CYP450 enzymes (such as CYP2C19 and extrahepatic CYP1A1) by rifampicin has led to a 58% decrease in the total PDE4 inhibitory activity of Roflumilast. • Co-administration of rifampicin with Roflumilast may reduce the therapeutic efficacy of Roflumilast. AIMS To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of Roflumilast and Roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, Roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity. METHODS Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of Roflumilast 500 µg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5–15. Plasma concentrations of Roflumilast and Roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and Cmax of Roflumilast and Roflumilast N-oxide and for oral apparent clearance (CL/F) of Roflumilast were estimated. RESULTS During the steady-state of rifampicin, the AUC0–∞ of Roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); Cmax by 68% (0.32; CI 0.26, 0.39); for Roflumilast N-oxide, the AUC0–∞ decreased by 56% (0.44; CI 0.36, 0.55); Cmax increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48). CONCLUSIONS Co-administration of rifampicin and Roflumilast led to a reduction in total PDE4 inhibitory activity of Roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of Roflumilast.
-
Effect of Single and Repeated Doses of Ketoconazole on the Pharmacokinetics of Roflumilast and Roflumilast N-Oxide
Journal of clinical pharmacology, 2008Co-Authors: Gezim Lahu, Robert Hermann, Rolf Herzog, A Huennemeyer, N Mccracken, Oliver Von Richter, Karl ZechAbstract:Effects of single and multiple doses of oral ketoconazole on Roflumilast and its active metabolite, Roflumilast N-oxide, were investigated in healthy subjects. In study 1, subjects (n = 26) received oral Roflumilast 500 microg once daily for 11 days and a concomitant 200-mg single dose of ketoconazole on day 11. In study 2, subjects (n = 16) received oral Roflumilast 500 microg on days 1 and 11 and a repeated dose of ketoconazole 200 mg twice daily from days 8 to 20. Coadministration of single-dose ketoconazole with steady-state Roflumilast increased the AUC of Roflumilast by 34%; C(max) was unchanged. For Roflumilast N-oxide, AUC and C(max) decreased by 12% and 20%, respectively. Repeated doses of ketoconazole increased the AUC and C(max) of Roflumilast by 99% and 23%, respectively; for Roflumilast N-oxide, AUC was unchanged, and C(max) decreased by 38%. No clinically relevant adverse events were observed. Coadministration of ketoconazole and Roflumilast does not require dose adjustment of Roflumilast.
-
Single-Dose Pharmacokinetics of Roflumilast in Children and Adolescents
Journal of clinical pharmacology, 2008Co-Authors: Kathleen A. Neville, Gezim Lahu, Rolf Herzog, Karl Zech, Stanley J. Szefler, Susan M. Abdel-rahman, Thomas D. Bethke, Melanie Gleason, Gregory L. KearnsAbstract:Roflumilast is an orally administered phosphodiesterase 4 inhibitor that has potential for use in pediatric patients with asthma. The pharmacokinetics of Roflumilast and Roflumilast N-oxide were examined in adolescents and children with stable mild to moderate asthma in an open-label crossover study with age-stratification and 2 treatment periods (100-microg dose in period 1, 250-microg dose in period 2) separated by a washout period. Plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using standard noncompartmental methods and compared between study groups and within the entire cohort. Roflumilast was well tolerated. Linear relationships were evident for dose and area under the plasma drug concentration-time curve extrapolated to infinity for both Roflumilast (r(2) = 0.36, P < .01) and Roflumilast N-oxide (r(2) = 0.39, P < .01). With the exception of dose-normalized maximum plasma concentration (mean 1.1 and 0.8 microg/L per 1 microg/kg dose for adolescents and children, respectively), pharmacokinetic parameters for Roflumilast and Roflumilast N-oxide were not different between age groups and were similar to adults.
Robert Hermann - One of the best experts on this subject based on the ideXlab platform.
-
the targeted oral once daily phosphodiesterase 4 inhibitor Roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions
The Journal of Clinical Pharmacology, 2009Co-Authors: Gabriele M. Böhmer, Nassr Nassr, Gezim Lahu, Christoph H. Gleiter, Andreas Hünnemeyer, Marcus Wenger, Silke Templin, Robert HermannAbstract:This nonrandomized, fixed-sequence, 3-period study investigated potential pharmacokinetic interactions between the leukotriene receptor antagonist montelukast, approved for the treatment of asthma, and Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor in clinical development for asthma and chronic obstructive pulmonary disease. Pharmacokinetic interactions are of interest because both drugs may be coadministered and share a common metabolic pathway via cytochrome P450 3A. Single-dose montelukast (10 mg, po) was administered alone in period 1, followed by repeated once-daily Roflumilast alone (500 microg, po) for 12 days (period 2). In period 3, 500 microg qd Roflumilast was coadministered with 10 mg qd montelukast for 8 days. Different pharmacokinetic parameters were evaluated for montelukast alone, for steady-state Roflumilast and its pharmacologically active metabolite Roflumilast N-oxide alone, for single-dose montelukast when coadministered with steady-state Roflumilast, and for steady-state Roflumilast and its N-oxide metabolite when coadministered with steady-state montelukast. The AUC and Cmax of montelukast were modestly increased by 9% and 8%, respectively, when single-dose montelukast was coadministered with steady-state Roflumilast. The pharmacokinetics of Roflumilast and Roflumilast N-oxide in steady state remained unchanged when repeat-dose montelukast was coadministered at steady-state. Concomitant administration of both drugs was well tolerated. These findings suggest that no dose adjustment is warranted for either drug when Roflumilast and montelukast are coadministered.
-
Effect of repeated dose of erythromycin on the pharmacokinetics of Roflumilast and Roflumilast N-oxide.
International journal of clinical pharmacology and therapeutics, 2009Co-Authors: G Lahu, Robert Hermann, A Huennemeyer, R Herzog, N Mccracken, M Elmlinger, K ZechAbstract: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 ofRoflumilast decreased from 8.2 1/h (Reference) to 4.8 1/h (Test). Steady-state erythromycin did not alter the mean AUC ofRoflumilast 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 ofRoflumilast.
-
Effects of rifampicin on the pharmacokinetics of Roflumilast and Roflumilast N‐oxide in healthy subjects
British journal of clinical pharmacology, 2009Co-Authors: Nassr Nassr, Robert Hermann, Rolf Herzog, Karl Zech, A Huennemeyer, Oliver Von Richter, Manuela Koch, Kevin Duffy, Gezim LahuAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rifampicin is an antibiotic that is used to treat pulmonary tuberculosis. It induces several cytochrome P450 (CYP) enzymes and some drug transporter proteins; its greatest effect is as an inducer of CYP3A4 in the liver and in the small intestine. • Mechanistic drug–drug interaction studies with prototypic CYP3A4 inducers provide essential information for clinical drug development of new chemical entities that are metabolized by the involved CYP450 enzymes. • Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor being developed for the treatment of chronic obstructive pulmonary disease. • The pharmacological effect is based on the total PDE4 inhibitory activity, which represents the combined PDE4 inhibitory activity of Roflumilast and its major active metabolite, Roflumilast N-oxide. • In patients with chronic obstructive pulmonary disease, pulmonary tuberculosis can be an accompanying disease. Thus, the drug–drug interaction between rifampicin and Roflumilast is of clinical relevance. WHAT THIS STUDY ADDS • The pharmacokinetics of Roflumilast and of its major pharmacologically active metabolite Roflumilast N-oxide is affected by co-administration of rifampicin. • The potent induction of CYP3A4 and other CYP450 enzymes (such as CYP2C19 and extrahepatic CYP1A1) by rifampicin has led to a 58% decrease in the total PDE4 inhibitory activity of Roflumilast. • Co-administration of rifampicin with Roflumilast may reduce the therapeutic efficacy of Roflumilast. AIMS To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of Roflumilast and Roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, Roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity. METHODS Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of Roflumilast 500 µg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5–15. Plasma concentrations of Roflumilast and Roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and Cmax of Roflumilast and Roflumilast N-oxide and for oral apparent clearance (CL/F) of Roflumilast were estimated. RESULTS During the steady-state of rifampicin, the AUC0–∞ of Roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); Cmax by 68% (0.32; CI 0.26, 0.39); for Roflumilast N-oxide, the AUC0–∞ decreased by 56% (0.44; CI 0.36, 0.55); Cmax increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48). CONCLUSIONS Co-administration of rifampicin and Roflumilast led to a reduction in total PDE4 inhibitory activity of Roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of Roflumilast.
-
Effect of Single and Repeated Doses of Ketoconazole on the Pharmacokinetics of Roflumilast and Roflumilast N-Oxide
Journal of clinical pharmacology, 2008Co-Authors: Gezim Lahu, Robert Hermann, Rolf Herzog, A Huennemeyer, N Mccracken, Oliver Von Richter, Karl ZechAbstract:Effects of single and multiple doses of oral ketoconazole on Roflumilast and its active metabolite, Roflumilast N-oxide, were investigated in healthy subjects. In study 1, subjects (n = 26) received oral Roflumilast 500 microg once daily for 11 days and a concomitant 200-mg single dose of ketoconazole on day 11. In study 2, subjects (n = 16) received oral Roflumilast 500 microg on days 1 and 11 and a repeated dose of ketoconazole 200 mg twice daily from days 8 to 20. Coadministration of single-dose ketoconazole with steady-state Roflumilast increased the AUC of Roflumilast by 34%; C(max) was unchanged. For Roflumilast N-oxide, AUC and C(max) decreased by 12% and 20%, respectively. Repeated doses of ketoconazole increased the AUC and C(max) of Roflumilast by 99% and 23%, respectively; for Roflumilast N-oxide, AUC was unchanged, and C(max) decreased by 38%. No clinically relevant adverse events were observed. Coadministration of ketoconazole and Roflumilast does not require dose adjustment of Roflumilast.
-
Steady-State Pharmacokinetics of Roflumilast and Roflumilast N-Oxide in Patients with Mild and Moderate Liver Cirrhosis
Clinical Pharmacokinetics, 2007Co-Authors: Robert Hermann, Nassr Nassr, Gezim Lahu, Éva Péterfai, Dietrich Knoerzer, Rolf Herzog, Karl Zech, Christian MeyAbstract: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 [AUC_24]) 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 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 ≈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.
Nassr Nassr - One of the best experts on this subject based on the ideXlab platform.
-
Absence of pharmacokinetic interaction between Roflumilast and digoxin in healthy adults.
Journal of clinical pharmacology, 2012Co-Authors: Gabriel Eckermann, Nassr Nassr, Gezim Lahu, Thomas D. BethkeAbstract:Numerous interactions are known for digoxin, which is a drug with a narrow therapeutic index and a substrate of P-glycoprotein (P-gp). This study investigated potential effects of coadministration on pharmacokinetics and safety of both drugs when a single dose of digoxin was concomitantly administered with Roflumilast under steady-state conditions. Sixteen healthy male and female adults were randomly assigned in an open-label, crossover study to either of 2 treatment sequences that consisted of 2 treatment periods separated by a washout phase. Treatments were oral daily doses of Roflumilast for 14 days given concomitantly on days 1 and 14 with a single oral dose of digoxin or an oral dose of digoxin once on day 1. Plasma samples for pharmacokinetic evaluations of digoxin and Roflumilast concentrations with and without concomitant treatment were taken. The rate of digoxin absorption was slightly (15%) but statistically insignificantly increased, whereas the extent of absorption was not altered by concomitant medication with Roflumilast. Concomitant medication with digoxin did not significantly affect steady-state pharmacokinetics of either Roflumilast or its active metabolite Roflumilast N-oxide. Roflumilast is not an inhibitor of P-gp. No safety or tolerability concerns were detected with coadministration of Roflumilast and digoxin.
-
Pharmacokinetic evaluation of Roflumilast
Expert opinion on drug metabolism & toxicology, 2011Co-Authors: Gezim Lahu, Nassr Nassr, Andreas HünnemeyerAbstract:Introduction: Roflumilast is a selective PDE4 inhibitor recently approved for oral, once-daily treatment of severe chronic obstructive pulmonary disease (COPD). Clinical trials have demonstrated the effect of Roflumilast on reducing exacerbation frequency and improving lung function in COPD, while its mode of action may offer the potential to target the inflammatory processes underlying COPD. Roflumilast is, therefore, an important addition to current therapeutic options. It is catalyzed by cytochrome P450 (CYP) 1A2 and 3A4 to its active metabolite, Roflumilast N-oxide, which accounts for > 90% of Roflumilast total PDE4 inhibitory activity. Areas covered: This article reviews the pharmacokinetics of Roflumilast and considers the effects of co-administration with CYP inhibitors or inducers, and other medications commonly used in patients with COPD, on the pharmacokinetics of Roflumilast and Roflumilast N-oxide. Expert opinion: Roflumilast has novel anti-inflammatory activity in COPD that provides the physi...
-
effect of steady state enoxacin on single dose pharmacokinetics of Roflumilast and Roflumilast n oxide
The Journal of Clinical Pharmacology, 2011Co-Authors: Nassr Nassr, Gezim Lahu, Rolf Herzog, Martin Elmlinger, Peter Ruth, Markus Hinder, A HuennemeyerAbstract:Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). It is metabolized by CYP1A2 and CYP3A4 to its primary metabolite, Roflumilast N-oxide, through which >90% total PDE4 inhibitory activity (tPDE4i) is mediated. Fluoroquinolones, of which enoxacin is the most potent CYP1A2 inhibitor, are used to treat COPD exacerbations. This phase I, open, nonrandomized, fixed-sequence, 2-period study evaluated the effects of steady-state enoxacin on the single-dose pharmacokinetics of Roflumilast and Roflumilast N-oxide. Twenty healthy participants received Roflumilast, 500 μg once daily, on days 1 and 12, and enoxacin, 400 mg twice daily, on days 7 to 18. Pharmacokinetic profiles were obtained for days 1 to 6 and 12 to 1 9. The safety and tolerability of all treatments were also assessed. In 1 9 evaluable participants, coadministration led to 56% higher mean systemic exposure, 20% higher mean peak concentrations, and 36% lower mean apparent oral clearance compared with Roflumilast alone. For Roflumilast N-oxide, 23% higher mean systemic exposure and 14% lower mean peak concentrations were seen after coadministration. Roflumilast was well tolerated both alone and in combination with enoxacin. A weak interaction was shown between Roflumilast and enoxacin, as mean tPDE4i increased by 25%, but is unlikely to have clinical relevance.
-
No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine
Journal of clinical pharmacology, 2010Co-Authors: Gabriele M. Böhmer, Nassr Nassr, Christoph H. Gleiter, Klaus Mörike, Antje Walz, Gezim LahuAbstract:This nonrandomized, fixed-sequence, 2-period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor Roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received Roflumilast, 500 µg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of Roflumilast and its active metabolite Roflumilast N-oxide was performed, and the ratio of geometric means for Roflumilast alone and concomitantly with steady-state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to Roflumilast and Roflumilast N-oxide) was also calculated. Coadministration of steady-state cimetidine increased mean tPDE4i of Roflumilast and Roflumilast N-oxide by about 47%. The maximum plasma concentration (C(max)) of Roflumilast increased by about 46%, with no effect on C(max) of Roflumilast N-oxide. The increase in tPDE4i of Roflumilast and Roflumilast N-oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of Roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine.
-
the targeted oral once daily phosphodiesterase 4 inhibitor Roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions
The Journal of Clinical Pharmacology, 2009Co-Authors: Gabriele M. Böhmer, Nassr Nassr, Gezim Lahu, Christoph H. Gleiter, Andreas Hünnemeyer, Marcus Wenger, Silke Templin, Robert HermannAbstract:This nonrandomized, fixed-sequence, 3-period study investigated potential pharmacokinetic interactions between the leukotriene receptor antagonist montelukast, approved for the treatment of asthma, and Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor in clinical development for asthma and chronic obstructive pulmonary disease. Pharmacokinetic interactions are of interest because both drugs may be coadministered and share a common metabolic pathway via cytochrome P450 3A. Single-dose montelukast (10 mg, po) was administered alone in period 1, followed by repeated once-daily Roflumilast alone (500 microg, po) for 12 days (period 2). In period 3, 500 microg qd Roflumilast was coadministered with 10 mg qd montelukast for 8 days. Different pharmacokinetic parameters were evaluated for montelukast alone, for steady-state Roflumilast and its pharmacologically active metabolite Roflumilast N-oxide alone, for single-dose montelukast when coadministered with steady-state Roflumilast, and for steady-state Roflumilast and its N-oxide metabolite when coadministered with steady-state montelukast. The AUC and Cmax of montelukast were modestly increased by 9% and 8%, respectively, when single-dose montelukast was coadministered with steady-state Roflumilast. The pharmacokinetics of Roflumilast and Roflumilast N-oxide in steady state remained unchanged when repeat-dose montelukast was coadministered at steady-state. Concomitant administration of both drugs was well tolerated. These findings suggest that no dose adjustment is warranted for either drug when Roflumilast and montelukast are coadministered.
