Robert Hermann

Dose‐Proportional Intraindividual Single‐ and Repeated‐Dose Pharmacokinetics of Roflumilast, an Oral, Once‐Daily Phosphodiesterase 4 Inhibitor

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 μg 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 μg)/reference (250 μg) 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 μg once daily was well tolerated.

Influence of food intake on the bioavailability of thioctic acid enantiomers

Recent controlled clinical trials have demonstrated that long-term administration of 600 mg thioctic acid (TA, R(+)-TA, S([)-TA; a-lipoic acid), once daily, can improve symptoms of peripheral and autonomic neuropathy in patients with diabetes mellitus (Ziegler et al. 1995). In diabetic patients the bioavailability of drugs may be decreased by delayed gastric emptying (due to autonomic neuropathy) and the interaction of drugs with food retained in the stomach. Therefore, the present trial investigated whether a pharmacokinetic interaction between food and TA takes place.

Pharmacokinetics of Alpha-Lipoic Acid in Subjects With Severe Kidney Damage and End-Stage Renal Disease

In an open‐label, parallel‐group study involving 16 patients (8 with severely reduced renal function, 8 with end‐stage renal disease needing hemodialysis), the effect of renal function on the pharmacokinetics, metabolism, and safety and of alpha‐lipoic acid (thioctic acid) was evaluated by comparing the pharmacokinetic parameters with those of a reference group of 8 healthy subjects. Alpha‐lipoic acid 600 mg was administered orally once daily for 4 days, and the pharmacokinetic parameters were measured on days 1 and 4. The mean percentage of the administered dose excreted in urine as parent compound was 0.2 and 0.05 in healthy subjects and subjects with severely reduced renal function, respectively. Assuming a bioavailability of 30%, this represents 0.67% and 0.17% of the bioavailable amount of alpha‐lipoic acid, respectively. The percentage of total urinary recovered amounts of alpha‐lipoic acid and 5 of its metabolites was 12.0 on both days. The respective values for patients with severe kidney damage were 5.2% (day 1) and 6.4% (day 4). The total percentage of the administered dose removed by hemodialysis was 4.0 in patients with end‐stage renal disease. Renal clearance of alpha‐lipoic acid and its major metabolites, 6,8‐bismethylthio‐octanoic acid, 4,6‐bismethylthio‐hexanoic acid and 2,4‐bismethylthio‐butanoic acid, were significantly decreased in subjects with kidney damage compared to the reference group. Apparent total clearance of alpha‐lipoic acid was poorly correlated with creatinine clearance. There is strong evidence that alpha‐lipoic acid is mainly excreted by nonrenal mechanism or further degraded to smaller units in the catabolic process. The significantly increased area under the curve values of 4,6‐bismethylthio‐hexanoic acid and half‐lives of 2,4‐bismethylthio‐butanoic acid on both days in patients with severely reduced function and end‐stage renal disease were not considered to be clinically relevant. Although trough levels of both metabolites tend to increase slightly in these subjects, no accumulation effects were detected. We conclude that the pharmacokinetics of alphalipoic acid are not influenced by creatinine clearance and are unaffected in subjects with severely reduced kidney function or end‐stage renal disease. Hemodialysis did not significantly contribute to the clearance of alpha‐lipoic acid. Hence, dose adjustment of alpha‐lipoic acid is not necessary in patients with renal dysfunction.

Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: A randomized placebo-controlled trial

RATIONALEnRoflumilast, an investigational, targeted phosphodiesterase 4 inhibitor, reduces the in vitro and in vivo inflammatory activity of cells such as neutrophils, eosinophils, macrophages, and monocytes.nnnOBJECTIVESnThe aim of this study was to explore the anti-inflammatory properties of roflumilast in a human model of segmental bronchial endotoxin challenge.nnnMETHODSnIn a randomized, placebo-controlled, double-blind, single-center parallel-group study, 37 healthy subjects of either sex were treated for 28 days with either oral roflumilast 500 microg once daily or placebo. At day 29, a baseline bronchoalveolar lavage was performed, followed by segmental endotoxin challenge (4 ng/kg) and saline control challenge. After 24h, bronchoalveolar lavage fluid was sampled from the challenged segments and cells were counted and differentiated.nnnRESULTSnAfter endotoxin challenge, influx of total cells (difference from baseline) in bronchoalveolar lavage of roflumilast-treated subjects was 36% lower than with placebo (p=0.02). Correspondingly, the influx of neutrophils and eosinophils of roflumilast-treated subjects was 39% (p=0.02) and 74% (p=0.01) lower than with placebo, respectively. In contrast, endotoxin-induced influx of monocytes was not different between roflumilast- and placebo-treated subjects. No significant differences existed between the groups pertaining to endotoxin-induced influx of macrophages and lymphocytes. Roflumilast was well tolerated. No unexpected or serious treatment-emergent signs and symptoms were observed.nnnCONCLUSIONSnRoflumilast attenuated the endotoxin-induced influx of neutrophils and eosinophils into the airways. This study demonstrates the anti-inflammatory properties of roflumilast on bronchoalveolar granulocytes in endotoxin-induced airway inflammation in healthy subjects.

Adverse events and discomfort in studies on healthy subjects: the volunteer's perspective A survey conducted by the German Association for Applied Human Pharmacology

AbstractObjective: The various good clinical practice (GCP) guidelines do not define the volunteering subject as an active party. The present survey addresses the volunteers perception of study-related inconvenience and risk and its impact on their decision to enrol.nMethods: The survey consisted of a questionnaire to be filled out voluntarily and anonymously by healthy subjects who volunteered for enrolment in human pharmacology studies and who had participated in at least one previous study. Twenty-five categorised multiple-choice questions covered previous study experience, motives for volunteering, perception of and compliance with study directives and restrictions, past experience with adverse events, impact of the study environment on perceived well-being and the nature of adverse events likely to discourage them from enrolment.nResults: Seven centres contributed by providing at least 30 (range 30–100) evaluable questionnaires. The database consists of a total of 440 healthy subjects (30.5% females, 69.5% males), from 18 to over 60 years of age. Two hundred and seven subjects (47.1%) were company employees and 233 (52.9%) were external volunteers. Eighty nine percent only participated in studies at one particular centre. Some 53.3% indicated financial motives, 27.8% `contribution to an improvement of pharmacotherapy, 12.7% `social responsibility, while 6.2% indicated other motives, mainly the opportunity of a free medical check-up. Thirteen subjects (3%) admitted to not answering correctly to the recruitment questions; this limited reliability is suspected to be even larger when the answer might preclude enrolment. From the volunteers perspective, the environmental study conditions clearly appeared to have a highly relevant impact on their personal well-being. Some 17.1% of the subjects reported to have suffered adverse events occasionally and 2.7% frequently; but 14% admitted not reporting adverse events promptly and about 20% indicated that, with respect to previous adverse events, they first sought advice from other volunteers rather than from the investigator.nConclusions: Adverse events and inconveniences are inherent to nontherapeutic studies in healthy subjects. From the volunteers perspective it appears that the incidence of adverse experiences in such studies exceeds the reported frequencies from investigators considerably. This finding suggests that investigators are usually not aware or able to ascertain the true incidence of adverse events. The present survey also confirms that pertinent information on the personal history may be unreliable. Volunteers are reluctant to answer questions regarding, in particular, their smoking habits, caffeine and alcohol consumption. Regarding the matter of informed consent, a noteworthy contradiction between the volunteers attitude and behaviour became apparent. Although the volunteers admit that even rather minor adverse events ordinarily would discourage them, they still consent to enrolment. In view of this apparent contradiction, there is no alternative to the investigators personal responsibility to counsel and protect the subject. Surveys such as this one may contribute to the awareness that the explicitness of GCP guidelines merely define the format, but not the content quality of these fundamental ethical values, which remain the unique burden and challenge of the investigator.

Investigation of a Potential Food Effect on the Pharmacokinetics of Roflumilast, an Oral, Once‐Daily Phosphodiesterase 4 Inhibitor, in Healthy Subjects

This open, randomized, single‐dose crossover study investigated effects of a high‐fat meal on the pharmacokinetics of roflumilast and its major active N‐oxide metabolite. Twelve healthy subjects received oral roflumilast 500 μg (2 × 250 μg) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic profiling of roflumilast and N‐oxide. Geometric mean ratios (fed/fasted) for point estimates (PE) and 90% confidence intervals (CI) were calculated for AUC0‐last, AUC0‐∞, and Cmax of both compounds. After the meal, roflumilast Cmax (PE, 0.59; 90% CI, 0.49‐0.70) was modestly reduced; N‐oxide Cmax (PE, 0.95; 90% CI, 0.90‐1.01) was unchanged. Roflumilast tmax was delayed in fed state (2.0 ± 0.4 hours) versus fasted state (1.0 ± 0.2 hours); N‐oxide tmax was unaltered. No significant food effect on roflumilast AUC0‐last (PE, 1.04; 90% CI, 0.90‐1.21), AUC0‐∞ (PE, 1.12; 90% CI, 1.00–1.25), and respective N‐oxide AUCs (PE, 0.91; 90% CI, 0.79‐1.04; PE, 0.99; 90% CI, 0.92‐1.06) occurred. Because roflumilast N‐oxide is the major contributor to roflumilasts overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food.

Effect of Fluvoxamine on the Pharmacokinetics of Roflumilast and Roflumilast N -Oxide

ObjectiveTo investigate the effects of steady-state dosing of fluvoxamine, an inhibitor of cytochrome P450 (CYP) 1A2 and CYP2C19, on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor and its pharmacodynamically active metabolite roflumilast N-oxide.MethodsIn an open-label, non-randomised, one-sequence, two-period, two-treatment crossover study, 14 healthy subjects received a single oral dose of roflumilast 500μg on study day 1. After a 6-day washout period, repeated doses of fluvoxamine 50mg once daily were given from days 8 to 21. On day 15, roflumilast 500μg and fluvoxamine 50mg were taken concomitantly. Percentage ratios of test/reference (reference: roflumilast alone; test: roflumilast plus steady-state fluvoxamine) of geometric means and their 90% confidence intervals for area under the plasma concentration-time curve, maximum plasma concentration (roflumilast and roflumilast N-oxide) and plasma clearance of roflumilast were calculated.ResultsUpon co-administration with steady-state fluvoxamine, the exposure to roflumilast as well as roflumilast N-oxide increased by a factor of 2.6 and 1.5, respectively. Roflumilast plasma clearance decreased by a factor of 2.6, from 9.06 L/h (reference) to 3.53 L/h (test). The combined effect of fluvoxamine coadministration on roflumilast and roflumilast N-oxide exposures resulted in a moderate (i.e. 59%) increase in total PDE4 inhibitory activity.ConclusionCo-administration of roflumilast and fluvoxamine affects the disposition of roflumilast and its active metabolite roflumilast N-oxide most likely via a potent dual pathway inhibition of CYP1A2 and CYP2C19 by fluvoxamine. The exposure increases observed for roflumilast N-oxide are suggested to be attributable to CYP2C19 co-inhibition by fluvoxamine and thus, are not to be expected to occur when roflumilast is co-administered with more selective CYP1A2 inhibitors.

Steady-State Pharmacokinetics of Roflumilast and Roflumilast N-Oxide in Patients with Mild and Moderate Liver Cirrhosis

BackgroundRoflumilast 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.ObjectiveTo investigate the effects of mild and moderate liver cirrhosis on the steady-state pharmacokinetics of roflumilast and roflumilast N-oxide.MethodsPatients 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.ResultsIn patients with liver cirrhosis, the average total exposure (area under the plasma concentration-time curve from 0 to 24 hours [AUC24]) of roflumilast was ≈51% (Child-Pugh A) and 92% (Child-Pugh B) higher than in healthy subjects. In contrast, roflumilast maximum plasma concentration (Cmax) was unaltered in Child-Pugh A patients and was increased by 27% in Child-Pugh B patients. Changes in the AUC24 of roflumilast N-oxide were less distinct, with 24% and 41% increases and corresponding Cmax 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.ConclusionsMild 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.

The Oral, Once-Daily Phosphodiesterase 4 Inhibitor Roflumilast Lacks Relevant Pharmacokinetic Interactions With Inhaled Budesonide

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 (Cmax) 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 Cmax (0.70, 1.43) and for roflumilast N‐oxide and budesonide AUC and Cmax (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.

Phenotyping of N-acetyltransferase type 2 by caffeine from uncontrolled dietary exposure.

Background and objectiveThe standard approach for phenotyping of the human arylamine N-acetyltransferase 2 (NAT2) uses urinary caffeine metabolite ratios after a caffeine test dose taken in after methylxanthine abstinence. We tested whether these standardization measures were still needed when a more sensitive quantification technique was used.MethodsA new liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the quantification of the caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), and 1-methylurate (1U) was developed. Urine samples from 77 healthy volunteers collected before and 5–6xa0h after oral intake of 150–200xa0mg caffeine were analyzed. The lower limits of quantification were 0.1xa0µg/ml for caffeine, 1X, 1U, and AFMU, and 0.2xa0µg/ml for AAMU.ResultsThe urinary NAT2 ratios (AFMU+AAMU) / (AFMU+AAMU+1X+1U) before and after caffeine intake correlated well in 65 volunteers (r2=0.827; P<0.0001). In 12 participants (16%), metabolite concentrations in urine before caffeine intake were below the quantification limit. NAT2 genotyping, done in 41 volunteers for four SNPs, corroborated the phenotyping results.ConclusionNAT2 activity can be determined from a spontaneous urine probe in most subjects by quantification of caffeine metabolites arising from non-standardized dietary caffeine exposure using LC-MS/MS. This may facilitate the phenotyping procedure.