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PHARMACOKINETICS |
From the Department of Clinical Development Strategy (Dr Bethke), Department of Exploratory Medicine (Dr Hermann, Dr Hauns), Department of Metabolism and Pharmacokinetics (Dr David), Department of Pharmacometrics and Pharmacokinetics (Dr Knoerzer), and Department of Clinical Development Operations and Science (Dr Wurst), ALTANA Pharma AG, Konstanz, Germany, and the Department of Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany (Dr Böhmer, Dr Fux, Dr Mörike, Dr Gleiter).
Address for reprints: Dr Christoph H. Gleiter, Abteilung Klinische Pharmakologie, Universitätsklinikum Tübingen, Otfried-Müller-Str. 45, 72076 Tübingen, Germany; e-mail: christoph.gleiter{at}med.uni-tuebingen.de.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: roflumilast • phosphodiesterase 4 inhibitor • healthy subjects • COPD • asthma
Roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyridyl-4]-benzamide) is a targeted inhibitor of PDE4 for oral administration.11 Roflumilast has been shown to exert in vitro and in vivo various anti-inflammatory effects relevant to COPD and asthma.12-15 In several clinical studies with COPD and asthma patients, treatment with repeated oral doses of roflumilast 250 and 500 µg once daily showed statistically significant improvements in lung function as well as clinical symptoms and decreased inflammatory biomarkers in various compartments such as induced sputum, bronchoalveolar lavage fluid, and the systemic circulation.16-21
In humans, roflumilast is rapidly absorbed after oral administration, and the absolute bioavailability of a 500-µg immediate-release tablet is about 79%.22 In adults, the apparent terminal plasma disposition half-life (t
) of roflumilast ranges from 10 to 20 hours, with a mean value of about 17 hours. After oral intake, roflumilast is extensively metabolized by cytochrome P450 (CYP) 3A4 and CYP1A2 isozymes to its primary active metabolite roflumilast N-oxide, which has a phosphodiesterase selectivity profile and in vivo potency similar to roflumilast. The mean apparent terminal plasma t of roflumilast N-oxide is about 27 hours. The mean AUC of roflumilast N-oxide exceeds that of the parent drug by about 10-fold.22 After drug intake, the mean peak plasma concentration (Cmax) of roflumilast is reached in less than 1 hour; the Cmax of roflumilast N-oxide is reached at about 4 hours and remains constant, with only minor fluctuations, for about 6 to 8 hours.22 Steady state plasma concentrations of roflumilast are achieved after 4 days of once-daily administration, whereas roflumilast N-oxide steady-state concentrations are achieved within 6 days. Roflumilast and roflumilast N-oxide have a high plasma protein binding of 98.9% and 96.6%, respectively (data on file). Based on a comprehensive consideration of the pharmacological and pharmacokinetic properties of roflumilast and its active metabolite (ie, in vitro potencies, in vivo exposure data, and free fractions), it is estimated that the N-oxide metabolite accounts for about 90% of roflumilast's overall pharmacologic effects (ie, total PDE4 inhibitory activity).23 Thus, roflumilast N-oxide is considered as the major contributor to the overall clinical efficacy of roflumilast, allowing for a once-daily dosing regimen.
This study evaluated the single-dose and steady state pharmacokinetics and intraindividual dose proportionality of roflumilast and its pharmacologically active metabolite roflumilast N-oxide for the clinically relevant doses of roflumilast 250 and 500 µg once daily in healthy adult subjects.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The protocol was approved by the Ethics Committee of the Medical Faculty of the University of Tübingen, Tübingen, Germany. The study was conducted in accordance with the Declaration of Helsinki (Somerset West Amendment, 1996) and the International Conference on Harmonization (ICH) Guideline on Good Clinical Practice (Note for Guidance on Good Clinical Practice [CPMP/ICH/135/95]) and performed at the Research Unit of the Department of Clinical Pharmacology, University of Tübingen, Tübingen, Germany.
Study Design
This monocenter study was conducted according to an open, randomized, 2-period, 2-sequence crossover design. Each study period involved a single dose of roflumilast either administered as a single 250-µg or 500-µg tablet in the morning on study day 1, followed by repeated once-daily administrations of the same roflumilast dose from study days 5 to 12. Roflumilast tablets were manufactured by ALTANA Pharma Oranienburg GmbH, Oranienburg, Germany. Each dose was administered in the morning (at about 8:00 AM) with 240 mL tap water after an overnight fast of 10 hours. During in-house study days (ie, days 1 and 12 of each study period), a 2-hour fasting period for liquids and a 4-h fasting period for solid food were required after drug intake. On all other study days, no fasting periods were required after drug intake. Between the 2 study periods, there was a washout period of 10 to 14 days. No other drug intake was allowed throughout the study except a limited amount of paracetamol or registered hormonal contraceptives.
During each study period and 2 preceding days, all subjects had to refrain from ingesting grapefruit juice and beverages that contain alcohol or caffeine. Smokers were asked to keep their smoking habits constant throughout the entire study. The subjects enrolled in the study were asked to avoid strenuous physical exercise during each study period. On study days 1 and 12 of each study period, subjects remained at the clinical study ward and received standardized meals at specific time points after administration of study medication: lunch after 4 hours, snack after 8 hours, and dinner after 12 hours.
Sample Collection
Serial plasma samples were collected for the pharmacokinetic profiles of roflumilast and roflumilast N-oxide. Blood samples (4.5 mL collected in lithium heparinate monovettes) were taken during each study period on day 1 at baseline (ie, predose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 30, 48, 72, and 96 hours (last sample on day 4 after drug administration), as well as on day 12 at baseline (predose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 30, 48, and 72 hours after each drug administration. The blood samples were centrifuged at 4°C for 15 minutes at 3000 rpm within 20 to 30 minutes after sampling. Plasma was transferred into polypropylene plastic tubes and stored at -20°C until analysis.
Bioanalytics
Plasma concentrations of roflumilast and roflumilast N-oxide were measured using a validated highperformance liquid chromatographic tandem mass spectrometric method (HPLC-MS/MS). The method used deuterium-labeled roflumilast and roflumilast N-oxide as internal standards. Roflumilast was monitored in positive ion mode with the transition of m/z 403.1 to m/z 187.0 and roflumilast N-oxide was monitored with the transition of m/z 419.1 to m/z 187.0. The internal standards [2H5] roflumilast and [2H5] roflumilast N-oxide were monitored in positive ion mode with transitions of m/z 408.1 to m/z 190.0 and m/z 424.1 to m/z 190.0, respectively. The assay was linear between 0.1 and 20 µg/L for roflumilast and between 0.1 and 40 µg/L for roflumilast N-oxide. For the quality control samples, the interday precision (between-day coefficient of variation) ranged between 7.63% and 12.65%, and the interday accuracy ranged from 99.17% to 109.55%. In the case of roflumilast N-oxide, the interday precision ranged from 4.84% to 8.01%, and the interday accuracy ranged from 94.78% to 102.53%. The lower limit of quantification (LLOQ) was 0.1 µg/L for both compounds.
Safety and Tolerability
On study days 1 and 12, vital signs, including arterial blood pressure and heart rate, and 12-lead resting ECG recordings were assessed at predose and 1 and 8 hours after drug administration. Clinical laboratory parameters, including blood chemistry, hematology, and urinalysis, were assessed at screening and poststudy examination (including a pregnancy test in women). The pregnancy test was repeated on day -1 of each study period. Illicit drug screening and ethanol blood tests were done at screening and on day -1 and day 11 on admission to the study ward. Adverse events were documented throughout the entire study.
The safety and tolerability variables, such as clinical laboratory and adverse events of all randomized subjects who had received at least 1 dose of the study medication, were included in the safety analysis.
Pharmacokinetics
The pharmacokinetic analysis of roflumilast and roflumilast N-oxide plasma concentrations was performed by noncompartmental evaluation using the KINT PC program (version 2.0; ALTANA Pharma AG, Konstanz, Germany). The observed Cmax with the corresponding time points (tmax) were obtained directly from the measured data. The slope of the visually identified terminal log-linear portion (
) of each individual plasma concentration-time profile was determined by log-linear regression. The apparent terminal plasma t was calculated as ln(2)/. Estimates of the area under the concentration-time curves (AUC0-last) were obtained by use of linear trapezoidal integration over the sampling points. Estimates of total AUC (AUC0-
) were derived by AUC0-last + Clast/, where Clast denotes the last quantifiable plasma concentration. If the extrapolated section of the AUC0- exceeded 30% of the area that was covered by sampling points, AUC0-last was calculated and used instead. For analysis of steady-state exposure, AUC0-24 = AUC
was determined and used for data analysis.
The primary pharmacokinetic variables were AUC and Cmax of roflumilast and roflumilast N-oxide, and these were calculated for all "per-protocol" subjects (ie, for all study subjects for whom evaluable primary pharmacokinetic data were obtained and no major protocol violation occurred).
Statistics
The statistical analysis was performed using the BIOQPC program (version 1.2.2; ALTANA Pharma AG, Konstanz, Germany). AUC and Cmax values were evaluated using a multiplicative model (ie, an analysis of variance [ANOVA]) after logarithmic transformation and values normalized to the 250-µg dose. The resulting point estimates and 90% confidence intervals for the respective test/reference ratios are presented on the original scale. Point estimates for the single or repeated doses of roflumilast 500 µg were used as test and were compared to the reference dose of the same dosage scheme (single or repeated doses of roflumilast 250 µg once daily). Dose proportionality for AUC and Cmax (based on dose-normalized values) of roflumilast and roflumilast N-oxide for the investigated roflumilast doses 250 and 500 µg were concluded if the standard equivalence criteria were met (ie, the respective test/reference ratios of the point estimates and 90% confidence intervals were within 0.80 to 1.25).
The secondary pharmacokinetic variables tmax and t were analyzed for roflumilast and roflumilast N-oxide in an exploratory manner. A multiplicative model was applied for the variable Cmax. The safety variables were analyzed in a descriptive manner.
The power of the (dose-adjusted) equivalence decisions for the primary variables AUC and Cmax of roflumilast and roflumilast N-oxide was based on coefficient of variation (CV%) data obtained on roflumilast and roflumilast N-oxide primary pharmacokinetic parameter estimates (ie, Cmax and AUC values) from previous studies. Specifically, it was assessed with 2 one-sided t tests for ratio of means (nQuery Advisor 3.0, Statistical Solutions Ltd, Cork, Ireland) using the measured point estimates and the coefficients of variation of the reference study, the predefined equivalence limits (ie, 0.8-1.25), the estimated sample size of per-protocol subjects, and the first-order error of 
0.05 for the planned study. The results of the power calculation suggest that for each pharmacokinetic parameter estimate, a power of 
95% can be assumed with a per-protocol subject number of 12. In the present study, data from n = 15 perprotocol subjects were obtained and allowed for a statistical power between 95% and 99% to show dose proportionality for Cmax and AUC.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics of Roflumilast and Roflumilast N-oxide
Steady-state concentrations were achieved for both roflumilast and roflumilast N-oxide at day 12, as indicated by similar trough concentrations before administration of the last dose (morning of day 12, predose) of the repeated-dose treatment course and 24 hours later (morning of day 13), that is, at the end of the last dosing interval. For the time points in the morning of days 12 and 13, the geometric mean trough concentrations were as follows: roflumilast, 250-µg dose: 0.32 and 0.30 µg/L; roflumilast, 500-µg dose: 0.54 and 0.49 µg/L; roflumilast N-oxide, 250-µg dose: 5.73 and 5.62 µg/L; and roflumilast N-oxide, 500-µg dose: 11.69 and 11.63 µg/L.
Mean plasma concentration-time curves for roflumilast and roflumilast N-oxide after administration of single and repeated doses of roflumilast 250 and 500 µg are illustrated in Figure 1a,b and Figure 2a,b, respectively. The course of plasma concentrations of roflumilast after single as well as after repeated doses of roflumilast 250 and 500 µg was almost equidistant over the entire assessment period. Similar profile characteristics were observed for the plasma concentrations of roflumilast N-oxide. This indicated that the absorption and disposition of the roflumilast parent compound as well as its N-oxide metabolite were proportional to the administered dose. Secondary peaks in the plasma concentrationtime curves of the metabolite were observed and occurred at the times when subjects took their meals, which could be explained by enterohepatic recirculation of the metabolite.
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A summary of the geometric mean (median for tmax) pharmacokinetic parameter estimates of roflumilast and roflumilast N-oxide by dose is presented in Tables I and II for single and repeated dosing, respectively. Under both regimens, doubling the roflumilast dose from 250 to 500 µg resulted in almost doubled exposure values, that is, the geometric mean AUC after single dosing was 18.1 µg·h/L with roflumilast 250 µg and increased to 35.0 µg·h/L with roflumilast 500 µg. After repeated dosing, the corresponding AUC values were 17.0 and 33.7 µg·h/L. Similarly, almost doubled geometric mean Cmax values of roflumilast were observed with doubling the roflumilast dose from 250 to 500 µg (single dose: 2.92 and 5.27 µg/L; repeated doses: 3.06 and 6.01 µg/L, respectively). Roflumilast N-oxide presented the same linearly dose-proportional pharmacokinetic exposure characteristics. The time of observed maximum exposure (tmax) of roflumilast and roflumilast N-oxide was not significantly affected by dose or regimen with comparable values across all treatments; median tmax of roflumilast was about 1 hour and showed a narrow range of 0.5 to 2 hours, indicating rapid absorption. The apparent terminal plasma disposition t of roflumilast (range, 13.56-18.01 hours) and roflumilast N-oxide (range, 21.16-23.16 hours) showed only minor variation across the treatments.
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As depicted by the scatter diagrams (Figure 3a,b), comparable distribution patterns and similar arithmetic means of AUC values for roflumilast after single and repeated administration of the 250-µg and 500-µg doses were evident in this subject population. For roflumilast N-oxide, the distribution pattern of individual AUC values and arithmetic means of all treatment groups resembled those of roflumilast. Corresponding presentations for Cmax values of roflumilast and roflumilast N-oxide for all treatment groups are given in Figure 4a,b, respectively. Similar arithmetic mean Cmax values for roflumilast were observed after single and repeated dosing with roflumilast 250 and 500 µg, respectively. Due to the substantially longer t of the N-oxide metabolite versus its parent compound, mean Cmax values for roflumilast N-oxide increased from single-dosing to steady-state conditions by a factor of about 2. This doubling of Cmax was observed with both roflumilast doses (Tables I and II).
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Safety and Tolerability
During the study, 10 subjects reported 20 adverse events after administration of roflumilast 250 µg, and 15 subjects reported 59 adverse events after the administration of roflumilast 500 µg. The intensity of most adverse events was mild or moderate. The most frequent adverse events were headache (5 and 7 subjects with roflumilast 250 and 500 µg, respectively), asthenia (2 and 3 subjects with roflumilast 250 and 500 µg, respectively), and abdominal discomfort (3 subjects with roflumilast 500 µg). All of these symptoms were of transient duration, and only some required medical intervention (mostly for treatment of headache with paracetamol). These symptoms represent known adverse effects of PDE4 inhibitors and are part of the expected adverse event profile of roflumilast. Two subjects discontinued the study because of adverse events, which were of mild to moderate intensity and were assessed as unlikely (erectile dysfunction) and likely related (visual flickering and blurred vision) to treatment by the investigator. Both adverse events subsided upon discontinuation of study medication. Overall, there were no clinically relevant, treatment-emergent changes in blood pressure, heart rate, ECG, or any hematological or biochemical parameters.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Treatment of COPD and asthma requires long-term controller therapy and the option of individual dose adjustment to achieve satisfactory anti-inflammatory control with the lowest effective dose. Therefore, oral roflumilast therapy must provide predictable and reproducible drug concentrations. The present study was designed to address the issue of dose-proportional pharmacokinetics of roflumilast and its active metabolite roflumilast N-oxide under clinically meaningful, repeated-dose conditions and for doses that were shown to be effective and safe.16,19,21,24
In the present study, dose-proportional increases of AUC and Cmax values of roflumilast and roflumilast N-oxide for the investigated doses of roflumilast 250 to 500 µg were demonstrated with no difference between the single- and repeated-dose regimens. The results complement and confirm those obtained in a previous clinical study in healthy adult subjects. In that study, it was already reported that the repeated-dose pharmacokinetics of roflumilast and roflumilast N-oxide are linearly dose-proportional over a dose range of 500 to 1000 µg.25 Due to the close relationship between administered roflumilast doses and the resulting rate as well as extent of exposure to roflumilast and its active N-oxide metabolite, the pharmacokinetics of the drug are largely predictable.
The steady-state dose proportionality in the present clinical study is also consistent with in vitro and in vivo data indicating that neither roflumilast nor roflumilast N-oxide inhibit its major drug-metabolizing enzymes (ie, CYP3A4 and CYP1A2)26 or drug transporters at clinically relevant concentrations (data on file). While CYP3A4 and CYP1A2 isozymes are highly abundant in the hepatic system and CYP3A4 activity exists also in the gut wall, the proposed daily roflumilast dose of 500 µg represents a low amount of drug molecules in the circulation. Thus, a potential saturation of the metabolizing enzymes of roflumilast and roflumilast N-oxide in the absence of any autoinhibiting potential is very unlikely. Although the plasma protein binding of roflumilast and its N-oxide metabolite is high, it was shown to be nonsaturable in the range of clinically relevant concentrations (data on file). The outcome of the present study is in line with these previous findings.
In conclusion, the results of the present study demonstrate predictable and dose-proportional, intraindividual pharmacokinetics of roflumilast and roflumilast N-oxide under steady-state conditions with 2 oral, once-daily dosage forms of roflumilast (ie, roflumilast immediate-release tablets of 250 and 500 µg). The pharmacokinetic properties of both dosage forms provide clinically relevant evidence of predictable intraindividual changes of the total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N-oxide. Based on these results, oral administration of roflumilast in the dose range of 250 to 500 µg would be expected to show a predictable relationship between pharmacokinetic exposure and therapeutic response.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was sponsored by ALTANA Pharma AG, Konstanz, Germany.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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