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DRUG INTERACTIONS |
From Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, Germany (Mr Lahu, Dr Huennemeyer, Mr Herzog, Dr McCracken, Dr von Richter, Dr Zech); University of Tuebingen, Institute for Toxicology, Pharmacy and Chemistry, Tuebingen, Germany (Mr Lahu); and Clinical Research Appliance, Radolfzell, Germany (Dr Hermann). Dr von Richter and Dr Hermann are fellows of the American College of Clinical Pharmacology.
Address for reprints: Gezim Lahu, MSc, Nycomed GmbH, Department of Pharmacometrics and Pharmacokinetics, Byk-Gulden-Str. 2, 78467 Konstanz, Germany; e-mail: gezim.lahu{at}nycomed.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Key Words: Drug-drug interactions • healthy subjects • ketoconazole • Phase 1 study • roflumilast
Orally administered roflumilast 500 µg is absorbed readily and almost completely, with an average absolute bioavailability of 79%.5 The maximum plasma concentration (Cmax) is attained after about 0.5 to 1 hour.5 In healthy adult subjects, roflumilast exposure is dose-proportional over 250 to 1000 µg.6 The mean elimination plasma disposition half-life time (t1/2) of roflumilast is about 17 hours.7 In humans, roflumilast is mainly cleared by biotransformation via cytochrome P450 enzymes CYP3A4 and 1A2 isozymes to its active metabolite, roflumilast N-oxide. Roflumilast N-oxide is subsequently dealkylated by CYP3A4, glucuronidated, and eliminated renally. Roflumilast N-oxide has a phosphodiesterase selectivity profile and in vivo potency similar to roflumilast.8
The total systemic exposure (ie, AUC) of the N-oxide metabolite exceeds that of roflumilast by about 10-fold. Following oral administration of roflumilast to healthy subjects, Cmax of roflumilast N-oxide is reached after 4 to 8 hours and remains constant for about 6 to 8 hours. The apparent terminal plasma t1/2 of roflumilast N-oxide is about 27 hours. The plasma protein binding of both roflumilast and roflumilast N-oxide is high (98.9% and 96.6%, respectively). The N-oxide is estimated to account for about 90% of roflumilast's overall pharmacologic effects (ie, total PDE4 inhibitory activity).9,10
Ketoconazole is an imidazole antifungal drug used for treatment of fungal infections such as oral thrush, candidiasis, and hard to treat fungal skin infections. The maximum recommended daily dose of ketoconazole is 400 mg. This can be administered orally either as a single dose of 400 mg or as 200 mg twice daily. Ketoconazole is a potent competitive inhibitor of CYP3A4, with some inhibitory activity of CYP1A2, CYP1A1, and CYP2C19; the Ki values for these enzymes are 0.0054 µM, 32 µM, 36.6 nM, and 6.9 µM, respectively.11-14 Several other CYP enzymes as well as ABCB1 (P-glycoprotein) are also inhibited by ketoconazole.15 The US Food and Drug Administration (FDA) recommends that researchers investigate ketoconazole when evaluating in vivo drug-drug interaction that involve CYP3A4.16
Because ketoconazole is a potent, competitive, and short-acting CYP3A4 inhibitor (t1/2 of about 2.5 hours)17 of CYP enzymes that are relevant also for the metabolism of roflumilast and its major metabolite, roflumilast N-oxide, we evaluated the interaction between these 2 drugs. Given the pharmacokinetic properties of roflumilast, 2 studies were performed. The focus of these studies was to investigate the effect of CYP3A4 inhibition by ketoconazole (after a single dose of ketoconazole and after a repeated dose of ketoconazole in steady state) on the metabolism of roflumilast. For safety reasons, the single-dose study preceded the repeated-dose study.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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The study protocol of study 1 was reviewed and approved by the Ethics Committee for Medical Research of the University of the Free State, Bloemfontein, South Africa. The protocol and the approval of the ethics committee were submitted to the South African Medicines Control Council. The study protocol of study 2 was reviewed and approved by the institutional review board of MDS Pharma Services (New Orleans, Louisiana, USA).
The studies were conducted in accordance with the Declaration of Helsinki (Somerset West Amendment, 1996) and the International Conference on Harmonisation (ICH) Guideline on Good Clinical Practice (Note for Guidance on Good Clinical Practice [CPMP/ICH/135/95], January 17, 1997) (study 1) and in accordance with Food and Drug Administration Regulations (Title 21 Code of Federal Regulations [21 CFR], Parts 50, 56, and 312) (study 2). The studies were performed at FARMOVS-PAREXEL, Bloemfontein, South Africa (study 1) and at MDS Pharma Services, Inc, New Orleans, Louisiana (study 2). Written informed consent was obtained from each subject prior to study-related procedures.
Study Design
The design of the studies reported here was based on the published data for ketoconazole inhibition of CYP3A4 and on the recommendations of the FDA guidelines. As reported by Olkkola et al,18 inhibition of CYP3A4 by ketoconazole can be achieved after administering 400 mg once daily for 4 days, leading to a 16-fold change in midazolam AUC, following oral administration of 7.5 mg midazolam. Others have reported that 3 doses of oral 200-mg ketoconazole were sufficient to achieve an 11-fold change in midazolam AUC, following oral administration of 6.5 mg midazolam.19 Finally, the current FDA concept paper on drug-drug interaction recommends the highest dose of inhibitor within the shortest possible dosing interval to be used as precipitant and specifically emphasizes that the inhibitor should be present throughout the elimination phase of the probe compound.16
Single-Dose Ketoconazole (Study 1)
This was an open-label, nonrandomized, 1-sequence, 2-period, 2-treatment crossover study in 26 healthy male and female subjects who received oral roflumilast 500 µg once daily from days 1 to 11. On day 11, a single dose of oral ketoconazole 200 mg and roflumilast 500 µg was administered together. Blood samples for pharmacokinetic analysis were taken over a full 24-hour roflumilast dosing interval on study day 10 (reference: roflumilast alone at steady state) and day 11 (test: roflumilast at steady state with single-dose ketoconazole) at predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours after morning administration. The sample collected at 24 hours of day 10 and the predose sample of day 11 were identical.
Repeated-Dose Ketoconazole (Study 2)
This was an open-label, nonrandomized, 1-sequence, 2-period, 2-treatment crossover study in 16 healthy male and female subjects who received a single oral dose of roflumilast 500 µg on days 1 and 11. Ketoconazole 200 mg twice daily was administered orally from days 8 to 20, in the morning and in the evening, every 12 hours. On day 11, roflumilast and the morning dose of ketoconazole were administered together. Blood for pharmacokinetic analysis was taken after the roflumilast dose on day 1 at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours. After the roflumilast dose on day 11, blood was taken at the same time intervals and also at 144, 168, 192, 216, and 240 hours. The 24-, 48-, 72-, 96-, 120-, 144-, 168-, 192-, and 216hour blood samples were taken before administration of ketoconazole on days 12 to 20.
Study Conduct
Roflumilast and ketoconazole tablets were administered with about 240 mL of tap water. On blood sampling days, subjects began fasting about 8 hours prior to the administration of roflumilast and continued fasting for at least 4 hours after drug administration. Subjects were required to abstain from any food or drink (except water) at least 4 hours prior to any safety laboratory evaluations and 8 hours prior to the start of blood sample collection. Non-caffeinated drinks (except grapefruit juice) could be consumed with meals and the evening snack. Lunch was provided about 4 hours after drug administration. Lunch could differ slightly among the subjects; each subject received an identical lunch on blood sampling days. During the 14 days prior to study drug administration, none of the subjects was allowed to take any prescription or nonprescription drugs that were expected to affect the pharmacokinetic parameters measured in these studies. Roflumilast 500-µg tablets were provided by ALTANA Pharma AG (Konstanz, Germany). Ketoconazole 200-mg tablets were purchased from commercial sources. Study 1 was performed in South Africa; Nizoral 200-mg tablets were purchased (Janssen-Cilag, Neuss, Germany, charge no. 02CL475). Study 2 was performed in the United States; ketoconazole 200-mg tablets were purchased (Mylan Pharmaceuticals, Morgantown, WV, charge no. 1L1820).
Blood Sample Processing
At sampling times specified above, venous blood (5-9 mL) was drawn into lithium-heparinized tubes. The blood was mixed by gentle inversion and centrifuged at 1200 g for 15 minutes in a refrigerated centrifuge. Plasma was separated from whole blood within 30 minutes of collection and stored within 1 hour of collection at –20°C until analysis.
Safety and Tolerability Assessment
Safety monitoring included physical examinations, vital signs (heart rate, blood pressure), 12-lead ECG, clinical laboratory tests, and recording adverse events. Blood pressure and pulse rate (both in sitting position) were measured at screening, predose, on days when blood sampling was scheduled, and at the end of the study. Clinical chemistry, hematology, and urine analysis were performed at screening, on the blood sampling day, and at the end of the study. A 12-lead ECG was performed at screening, at frequent intervals during the study, at the end of the study, and 12 hours after the end of the study. Adverse events were monitored throughout the study.
Determination of Roflumilast and Roflumilast N-Oxide in Human Plasma
In both studies, plasma concentrations of roflumilast and roflumilast N-oxide were determined using a validated high-performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS) assay with [D5]roflumilast and [D5]roflumilast N-oxide as internal standards. The assay was validated according to standards recommended by the regulatory authorities.20 The assay was linear between 0.04 and 60 µg/L for roflumilast and roflumilast N-oxide. The lower limit of quantitation (LLOQ) was 0.04 µg/L for both analytes, using a sample volume of 0.5 mL. Sample preparation was performed using liquid/liquid extraction. Chromatography was performed on a Luna (Phenomenex) C18(2), 5-µm, 100-Å, 50 x 2-mm analytical column using a linear gradient with acetonitrile/5 mM aqueous ammonium acetate as eluent. Roflumilast was monitored in the positive ion mode with the mass transition of m/z 403.1 to 187.1; the respective internal standard was analyzed with the mass transition of m/z 408.2 to 190.0. Roflumilast N-oxide was monitored in the positive ion mode with the mass transition of m/z 419.0 to 187.1; the respective internal standard was analyzed with the mass transition of m/z 424.2 to 190.0. No interconversion of roflumilast N-oxide back to parent compound roflumilast, either in plasma or in the MS source, was observed. Ketoconazole did not interfere with the quantification of roflumilast or roflumilast N-oxide; this was determined before the sample analysis.
In study 1, the interday precision (between-day coefficient of variation) for roflumilast ranged between 4.03% and 9.16%, and interday accuracy ranged between 98.5% and 101.3%. For roflumilast N-oxide, the interday precision ranged between 1.72% and 3.67%, and interday accuracy ranged between 101.4% and 106.5%. In study 2, the interday precision (between-day coefficient of variation) for roflumilast ranged between 7.71% and 8.76%, and interday accuracy ranged between 98.0% and 98.8%. For roflumilast N-oxide, the interday precision ranged between 3.13% and 5.89%, and interday accuracy ranged between 99.4% and 105.6%.
Statistical Methods
Sample Size
For study 1, which evaluated the effects of a single dose of ketoconazole on steady-state roflumilast, no formal sample size calculation was performed; the number of subjects was set to 26, which is often used as a sample size for drug-drug interaction studies. For study 2, which evaluated the effect of steady-state ketoconazole on single-dose roflumilast, the considerations of sample size were based on the experience of study 1. Thus, for the second study, the sample size calculation was performed for an assumed ratio of 150% (ratio of roflumilast together with ketoconazole/roflumilast) for both observed Cmax and total exposure (AUC) and an associated 90% confidence interval (CI) of 100% to 200%.
When investigating the effect of a single dose of ketoconazole on steady-state roflumilast, the mean square error (MSE) of ln(Cmax) was 0.031671 (the maximum MSE observed in the study); the MSE of ln(AUC0-
) was smaller than 0.0062091, and the MSE of ln(Cmax) of roflumilast N-oxide also was smaller than the MSE of ln(Cmax) of roflumilast. Assuming variability equivalent to that found in study 1, at least 12 subjects were required for the second study to provide greater than 80% and 90% power to state that the upper limit of 90% CI would be less than 200% for the Cmax and AUC ratio.
Pharmacokinetic Parameters
Pharmacokinetic parameter estimates for roflumilast and roflumilast N-oxide were calculated by non-compartmental analysis using WinNonlin Version 4.0.1 (Pharsight, Mountain View, California, USA). The observed Cmax with the corresponding times of observation (tmax) were obtained directly from the data. The slope of the visually identified terminal log-linear portion (
z) of each individual plasma concentration-time curve was determined by log-linear regression. The apparent terminal plasma disposition t1/2 was calculated as ln(2)/z. Estimates of the area under the plasma concentration-time curve (AUC0-last and AUC0-24) were obtained in study 1 (single-dose ketoconazole) using linear trapezoidal integration up to the last sampling point. Estimates of total AUC (AUC0-) in study 2 (repeated-dose ketoconazole) were derived by AUC0-last + Clast/z, where Clast is the last quantifiable plasma concentration. The apparent oral clearance (CL/F, where F denotes the fraction of the dose absorbed) was calculated using the formula CL = dose(oral)/AUC0- and dose(oral)/AUC0-24. The relationship between the formation clearance (CLf) of roflumilast N-oxide from roflumilast, the metabolic clearance of roflumilast N-oxide (CLm), the exposure to roflumilast (AUC), and the exposure to roflumilast N-oxide (AUCm) was described according to the following equation:
 | (1) |
Total PDE4 Inhibitory Activity (tPDE4i)
After administration of roflumilast, the total PDE4 inhibition in humans is due to the combined effect of both roflumilast and roflumilast N-oxide. The active metabolite roflumilast N-oxide accounts for about 90% of roflumilast's overall pharmacologic effects. To estimate the combined PDE4 inhibition of roflumilast and roflumilast N-oxide in humans after administration of roflumilast, we established the parameter termed the total PDE4 inhibitory activity (tPDE4i), which is based on the following equation9:
 | (2) |
following a single dose or AUC0-
following multiple doses at steady state), furof and furofNO are the unbound fraction of roflumilast (0.011) and roflumilast N-oxide (0.0034), IC50,rof and IC50,rofNO are the roflumilast and roflumilast N-oxide concentration (µg/L) resulting in 50% PDE4 inhibition in vitro (0.7 nM [0.3 µg/L] for roflumilast8 and 2.0 nM [0.8 µg/L] for roflumilast N-oxide), and is the dosing interval (24 hours).
Statistical Analysis
Pharmacokinetic parameters, including log-transformed Cmax, AUC, and oral plasma clearance (CL/F) values, were analyzed with an analysis of variance (ANOVA) model consisting of subjects as random effects and treatments as fixed effects. Model-based 90% CIs for test (roflumilast with ketoconazole) as a percentage of reference (roflumilast alone) were generated using the linear mixed-effect module of WinNonlin Version 4.0.1. This procedure was equivalent to the two 1-sided test.21 Lack of an effect of ketoconazole on roflumilast was concluded if the 90% CIs for Cmax, AUC, and tPDE4i (based on log-transformed data) were within the standard equivalence acceptance range of 80% to 125%.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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and Cmax of roflumilast by about 99% and 23%, respectively (Table III). In parallel, a decrease in the apparent clearance of roflumilast from 11.3 µg·h/L (single-dose roflumilast, alone) to 5.7 µg·h/L (single-dose roflumilast with steady-state ketoconazole) was observed.
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In contrast to the alterations seen for the parent drug roflumilast, the AUC of roflumilast N-oxide remained unchanged; the Cmax of roflumilast N-oxide decreased by about 38%. Notably, the tmax of roflumilast N-oxide was 9.6 hours (roflumilast alone) as compared with 21.5 hours (roflumilast with ketoconazole).
The effect of steady-state ketoconazole on both roflumilast AUC0-last and AUC0- was more pronounced than on the respective AUCs of roflumilast N-oxide. This was reflected by a decrease in the ratio AUCroflumilast N-oxide/AUCroflumilast from 13.4 (roflumilast alone) to 6.9 (roflumilast with ketoconazole). Overall, ketoconazole did not affect the tPDE4i activity of roflumilast (Figure 3).
Safety Evaluation
Single-Dose Ketoconazole (Study 1)
During study 1, a total of 57 adverse events were reported by 21 of the 25 subjects. Of these, 20 subjects reported 51 adverse events during roflumilast administration, and 3 subjects reported 6 adverse events during coadministration of roflumilast with ketoconazole. The intensity of the adverse events was mostly mild (n = 42); some were moderate (n = 14) or severe (n = 1). Headache was the most frequent adverse event when roflumilast was given alone or during coadministration of roflumilast with ketoconazole. No clinically relevant changes were seen for hematology, clinical chemistry, or urine analysis parameters. Change from baseline for vital signs and ECG parameters was comparable after administration of roflumilast alone and roflumilast together with ketoconazole. One adverse event (moderate tracheitis) was classified as serious because it required hospitalization; the subject recovered within 10 days without sequel. This subject dropped out of the study due to this adverse event.
Repeated-Dose Ketoconazole (Study 2)
During the study, 21 adverse events were reported by 11 of the 16 subjects. Two subjects reported 4 adverse events after roflumilast was given alone, 7 subjects reported 8 adverse events after concomitant intake of roflumilast and ketoconazole, and 7 subjects reported 9 adverse events during administration of ketoconazole alone. Adverse events were mostly mild or moderate in intensity; they were assessed by the investigator as not related (n = 4), unlikely related (n = 5), possibly related (n = 6), probably related (n = 2), and definitely related (n = 1) to the study medication. Headache and diarrhea were the most common adverse events during the study. Laboratory values did not show any clinically relevant changes between the screening and post-study examination. One subject was withdrawn due to an adverse event of abnormal liver function tests on study day 14. This adverse event was assessed as related to the administration of study drug (ketoconazole). On study day 14, alanine aminotransferase (ALT) was 190 (reference range, 2-60 U/L), exceeding the protocol-specified withdrawal criterion of ALT >2 times the upper limit of normal (ULN), and the subject was withdrawn from the study. The ALT then ranged from 196 to 273 between days 16 and 21 before starting a decline to a normal value of 51 on day 35. This subject's aspartate aminotransferase (AST) level also was elevated beginning on study day 14 and increased to about 1.5 to 2 times the ULN before returning to within normal limits by study day 28.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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The study design for study 2 addresses the pharmacokinetic properties of roflumilast, roflumilast N-oxide, and ketoconazole (tmax and t1/2) and allows evaluation of the extent of drug-drug interaction of roflumilast and ketoconazole. The tmax of roflumilast and roflumilast N-oxide occurs at different times, and a significant disparity in tmax is anticipated between roflumilast, roflumilast N-oxide, and ketoconazole. Dosing of subjects in study 2 with ketoconazole was 200 mg twice a day (maximum recommended dose 400 mg a day). The dosing schedule was chosen such that the tmax for all compounds coincided with the competitive and reversible inhibition of CYP3A4 by ketoconazole. Furthermore, the typical population values for the t1/2 of roflumilast (17 hours) and roflumilast N-oxide (27 hours) are substantially longer than that of ketoconazole (2.5 hours). The chosen study design (study 2) takes into account the shortest dosing interval of ketoconazole and the presence of ketoconazole throughout the elimination phase of roflumilast. Both of these aspects are aligned with the recommendations from the FDA guideline on drug-drug interaction when the probe has a long terminal elimination t1/2 and a substantially different tmax from the inhibitor.16
The results from these studies indicate that the effects of single-dose ketoconazole on steady-state roflumilast were less pronounced than the effects of steady-state ketoconazole. These findings are in line with the competitive inhibition of CYP3A4 by ketoconazole and its high clearance rate, both of which lead to temporary inhibition of CYP3A4. Thus, after a single dose of ketoconazole, the AUC of steady-state roflumilast increased by 34%, whereas the Cmax was unchanged. When roflumilast was administered in steady-state ketoconazole, the AUC increase was about 2-fold, and Cmax increased by 23%, reflecting the sustained inhibition of CYP3A4 by steady-state ketoconazole.
For the active metabolite roflumilast N-oxide, the Cmax decreased by about 12% after a single dose of ketoconazole (study 1) and by 38% when roflumilast was administered to steady-state ketoconazole (study 2). These results are consistent with a delayed formation of roflumilast N-oxide, reaching its peak at 21 hours after roflumilast administration and temporary inhibition of CYP3A4 by ketoconazole. The results of both studies are consistent with a limited effect of ketoconazole on CYP3A4 during the metabolism of roflumilast to roflumilast N-oxide, emphasizing the important role of CYP3A4 in the formation of the active N-oxide metabolite. The exposure of roflumilast and roflumilast N-oxide, seen when roflumilast was coadministered at steady-state ketoconazole, most accurately reflects the clinical setting due to the repeated-dosing regimen.
The metabolism of roflumilast to roflumilast N-oxide is affected by the formation clearance (CLf) of roflumilast N-oxide from roflumilast and by the metabolic clearance of roflumilast N-oxide (CLm), as described in equation (1). Although CLm was not directly estimated in this study, the data indicate that the CLm of roflumilast N-oxide may have decreased when roflumilast was coadministered with steady-state ketoconazole. After a single dose of ketoconazole, roflumilast N-oxide exposure was reduced by 12%, reflecting the effect of CYP3A4 inhibition on the CLf of the metabolite. This effect was not observed upon coadministration with steady-state ketoconazole. A possible explanation for this could be a counter-balancing effect on CLf by the first dose of ketoconazole and on CLm by the second dose of ketoconazole, administered 12 hours later, showing no apparent effect on roflumilast N-oxide exposure. This finding is also supported by in vitro studies, which showed that dealkylation of roflumilast N-oxide is catalyzed via CYP3A4 and by extrahepatic CYP1A1 and CYP2C19 (data not shown).
Similarly, a decrease in CLf of roflumilast N-oxide caused by ketoconazole is consistent with the in vitro metabolism, confirming that the formation of this metabolite is mediated partly by CYP3A4 and CYP1A2. A decrease in CLf and CLm is consistent with in vitro data, considering that CYP3A4 not only mediates the clearance of roflumilast but, to a different extent, also affects the formation and elimination of roflumilast N-oxide.
Based on the results of the presented 2 studies, it can be concluded that moderate inhibition of roflumilast metabolism takes place after the coadministration of single and repeated doses of ketoconazole. Coadministration of roflumilast with the maximum recommended dose of ketoconazole showed a doubling of roflumilast AUC. In contrast, no change in AUC was observed for the active metabolite roflumilast N-oxide. These results indicate that concomitant administration of roflumilast with potent CYP3A4 inhibitors would not have any effect on roflumilast's major active metabolite because CYP3A4 is involved to a different extent in the formation and clearance of the metabolite.
In vivo, the total PDE4 inhibition in humans is considered to be due to the combined effect of both roflumilast and roflumilast N-oxide, whereby roflumilast N-oxide accounts for about 90% of roflumilast's overall pharmacologic effects (equation (2)). This concept has been used to assess roflumilast drug-drug interaction studies and studies in special populations.9 Administration of roflumilast alone or together with ketoconazole had no effect on tPDE4i because concomitant ketoconazole did not alter the exposure to roflumilast N-oxide. Considering that disposition of roflumilast and roflumilast N-oxide is mediated not just by CYP3A4 but also by CYP1A2, CYP1A1, and CYP2C19 suggests that their specific inhibitors cannot significantly alter the tPDE4i due to the presence of alternative pathways. This, however, was not the case for multiple pathway inhibitors such as fluvoxamine (CYP1A2, CYP2C19), which showed a greater effect due to its inhibitory potential on all CYPs involved in the metabolism of roflumilast.22
In respiratory diseases such as COPD and asthma, ketoconazole is used as a systemic treatment to treat oral thrush and candidiasis, which are some of the undesirable effects of inhaled corticosteroids. Our results show that ketoconazole may be coadministered with roflumilast in these patients without affecting the tPDE4i activity. During both studies and for both drugs, no new untoward safety signals were identified. Adverse events observed during roflumilast administration were consistent with the known safety and tolerability profile of roflumilast. The overall number and nature of observed adverse events suggest that coadministration of roflumilast and of the highest recommended daily dose of ketoconazole does not substantially affect the known safety and tolerability profile of either drug.
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CONCLUSIONS |
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ACKNOWLEDGEMENTS |
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Financial disclosure: This study was sponsored by Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, Germany.
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REFERENCES |
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