Absence of pharmacokinetic interaction between roflumilast and digoxin in healthy adults.

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.

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 physician with a treatment option beyond bronchodilation. It can be co-administered with many medications commonly used by patients with COPD and its anti-inflammatory activity provides incremental benefits on top of existing therapies. Future research will further elucidate the impact of roflumilast on COPD and beyond, while alternative dosing regimens may offer a means to ameliorate transient tolerability issues.

No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study.

BACKGROUND: Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in chronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves lung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction effects between inhaled formoterol and oral roflumilast. METHODS: This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In Regimen A, healthy men were treated with roflumilast (500 µg tablet once daily; Day 2-18) and concomitant formoterol (24 µg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 µg twice daily; Day 2-18) and concomitant roflumilast (500 µg once daily; Day 9-18). Steady-state plasma pharmacokinetics of roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-τ) as well as pharmacodynamics - blood pressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood eosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8 (Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast plus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling days and Day 19. Adverse events were monitored throughout the study. RESULTS: Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic interactions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular parameters as measured by ZCG, and these parameters were not affected during concomitant administration. Formoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval, without changes in the heart rate-corrected QTc interval. There were small effects on the other pharmacodynamic assessments when roflumilast and formoterol were administered individually, but no interactions or safety concerns were seen after concomitant administration. No severe or serious adverse events were reported, and no adverse events led to premature study discontinuation. CONCLUSIONS: No clinically relevant pharmacokinetic or pharmacodynamic interactions were found when oral roflumilast was administered concomitantly with inhaled formoterol, including no effect on cardiac repolarisation. Roflumilast was well tolerated.

Supra-therapeutic doses of roflumilast have no effect on cardiac repolarization in healthy subjects.

OBJECTIVE: This study assesses the potential of the phosphodiesterase 4 inhibitor roflumilast to affect cardiac repolarization. METHODS: In this randomized, placebo-controlled study (n = 80), 40 healthy subjects received moxifloxacin 400 mg p.o. (positive control for prolongation of QT/heart-rate corrected QT [QTc]) and another 40 received placebo. After a 1-day washout, subjects received placebo or ascending doses of roflumilast 500 (therapeutic dose), 750 or 1000 µg/day p.o., for 14, 7 and 14 days, respectively. QT intervals were measured and corrected for heart rate with a Fridericia algorithm (QTc(F)). The primary endpoint was the largest mean time-matched change in QTc(F) from baseline (day 1). Safety and tolerability were monitored. RESULTS: Moxifloxacin gave a maximum time-matched change in QTc(F) versus baseline of 6.79 ms. Repeated administration of roflumilast 500 and 1000 µg resulted in maximum QTc(F) changes from baseline of -3.23 and -4.81 ms, respectively, confirming the absence of any QT/QTc prolongation at therapeutic and supra-therapeutic dosing. There were no changes in other electrocardiographic variables or time intervals, and roflumilast was well tolerated. CONCLUSIONS: Repeated administration of roflumilast at doses ≤ 1000 µg/day had no effect on cardiac repolarization or overall cardiac safety evaluations in healthy subjects. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN63818313

Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.

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 19. The safety and tolerability of all treatments were also assessed. In 19 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.

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.

Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.

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 microg 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 C(max) 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 AUC(0-infinity) of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); C(max) by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC(0-infinity) decreased by 56% (0.44; CI 0.36, 0.55); C(max) 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.

The targeted oral, once-daily phosphodiesterase 4 inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions.

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.

Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis.

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.

Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects.

AIMS: The aim of this study was to investigate the effects of roflumilast, an investigational PDE4 inhibitor for the treatment of COPD and asthma, on the pharmacokinetics of the CYP3A probe drug midazolam and its major metabolites. METHODS: In an open, randomized (for midazolam treatment sequence) study, 18 healthy male subjects received single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart) alone, repeated doses of roflumilast (500 microg once daily for 14 days) alone, and repeated doses of roflumilast together with single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart). RESULTS: A comparison of clearance and peak and systemic exposure to midazolam following administration of roflumilast indicated no effect of roflumilast dosed to steady state on the pharmacokinetics of midazolam. Point estimates (90% CI) were 0.97 (0.84, 1.13) for the AUC of i.v. midazolam and 0.98 (0.82, 1.17) for that of oral midazolam with and without roflumilast. CONCLUSIONS: Therapeutic steady state concentrations of roflumilast and its N-oxide do not alter the disposition of the CYP3A substrate midazolam in healthy subjects. This finding suggests that roflumilast is unlikely to alter the clearance of drugs that are metabolized by CYP3A4.

Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype.

The genotype responsible for more than 60-fold interindividual differences in human hepatic CYP1A2 constitutive expression is not understood. Resequencing the human CYP1A1_CYP1A2 locus (39.6 kb) in five major geographically isolated subgroups recently led to the identification of 85 single nucleotide polymorphisms (SNPs), 57 of which were double-hit SNPs. Here, we attempted to correlate the CYP1A2 genotype with a metabolic phenotype. We chose 16 SNPs (all having a minor allele frequency > or =0.05 in Caucasians) to genotype 32 DNA samples (26 Caucasians, six Ethiopians) in which CYP1A2 metabolism had previously been determined. From 280 subjects (five locations worldwide) that had been CYP1A2-phenotyped, we genotyped the 10 highest, 14 lowest and eight intermediate DNA samples. Although no SNP was significant (P<0.05), possibly due to the small sample size, we found a trend for several of the six SNPs across the CYP1A2 linkage disequilibrium block associated with the trait. Five CYP1A2 haplotypes were inferred, two of which had not previously been reported; haplotype 1A2H10 showed the greatest association with CYP1A2 activity. Regulatory sequences responsible for the large interindividual differences in hepatic CYP1A2 gene basal expression might reside, in part, with some of these CYP1A2 SNPS but, in large part, might be located either cis (in nearby sequences not yet haplotyped) or trans in that they are not linked to the gene. We conclude that no SNP or haplotype in the CYP1A2 gene has yet been identified that can unequivocally be used to predict the metabolic phenotype in any individual patient.

Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity.

BACKGROUND: The major drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 is genetically conserved. One outlier of Brazilian descent was found in a clinical pharmacokinetic trial exhibiting a 6-fold higher exposure than expected to an investigational drug, shown to be a CYP3A4 substrate. We aimed to investigate the genetic background of this finding. METHODS: The allelic variant of the CYP3A4 gene present in the outlier was sequenced, and the corresponding complementary deoxyribonucleic acid was expressed in yeast and human embryonic kidney cells. The outlier was phenotyped by use of intravenous administration of 1 mg midazolam. Analysis of phenotype and genotype correlation was carried out. The prevalence of the new allele was screened for in a white population. RESULTS: We identified a subject who heterozygously carried a novel CYP3A4 allele, named CYP3A4*20, with a premature stop codon yielding a truncated protein. Heterologous expression revealed that the CYP3A4.20 enzyme does not incorporate heme and thus is devoid of catalytic activity. CYP3A phenotyping in vivo showed that CYP3A4*20 exhibits a clear genotype-phenotype correlation, demonstrated by the subject's low systemic midazolam clearance (2.99 mL x min(-1) x kg(-1)). Genotyping of a white German population (n = 428) and relatives of the subject, as well as a review of published CYP3A4 sequencing data, suggests that CYP3A4*20 is a rare variant allele (<0.06% in white subjects). CONCLUSIONS: CYP3A4*20 represents the first CYP3A4 allele to be identified that has been shown to be devoid of functional activity. It causes an intermediate CYP3A4 metabolizer phenotype in a heterozygous carrier. Subjects of this genotype might be susceptible to side effects during drug therapy with substrates or inhibitors of CYP3A4.