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BRIEF REPORT/PHARMACOKINETICS |
From Exploratory Medicine (Dr Nassr, Dr von Richter, Dr Hermann), Pharmacometrics and Pharmacokinetics (Mr Lahu, Dr Hünnemeyer, Dr Knoerzer), and Preclinical Research (Dr Zech), ALTANA Pharma AG, Konstanz, Germany, and Chemical Research, ALTANA Pharma Pvt. Ltd, Mumbai, India (Dr Reutter).
Address for reprints: Dr Robert Hermann, Department of Exploratory Medicine, ALTANA Pharma AG, Byk-Gulden-Str. 2, 78467 Konstanz, Germany; e-mail: robert.hermann{at}altanapharma.com.
Key Words: roflumilast • PDE4 inhibitor • Mg/Al-containing antacid • drug-drug interaction
Roflumilast is a targeted, oral, once-daily phosphodiesterase 4 inhibitor (PDE) currently under clinical investigation as an anti-inflammatory treatment for chronic obstructive pulmonary disease (COPD) and bronchial asthma.1,2 In clinical studies, roflumilast 500 µg once daily has been shown to be safe and clinically effective in the treatment of COPD and asthma.3,4
Oral roflumilast is rapidly and almost completely absorbed. The maximum plasma concentration (Cmax) is attained after about 0.5 to 1 hour; the mean absolute bioavailability of a single roflumilast 500-µg tablet is 79%.5 In healthy adult subjects, roflumilast exposure is dose proportional over 250 to 1000 µg, and the apparent terminal plasma disposition half-life time (t
) is about 17 hours.6 In humans, the major metabolic step of roflumilast to its active N-oxide metabolite is mediated by cytochrome P450 (CYP) 3A4 and CYP1A2. Roflumilast N-oxide has a phosphodiesterase selectivity profile and in vivo potency similar to roflumilast.7
The total systemic exposure (ie, AUC) of the N-oxide metabolite exceeds that of roflumilast by about 10-fold. The maximum plasma concentration of roflumilast N-oxide is reached about 4 to 8 hours after oral roflumilast intake and remains constant for about 6 to 8 hours. The apparent terminal plasma t 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). In summary, it is estimated that the N-oxide accounts for about 90% of roflumilast's overall pharmacologic effects (ie, total PDE4 inhibitory activity).8
Balanced mixtures of magnesium hydroxide and aluminium hydroxide are widely used as nonprescription antacids for the symptomatic treatment of hyperacidity-associated gastric symptoms and complications.9 Antacids are known for their potential to interfere with the absorption of many drugs, including chloroquine, itraconazole, and fluoroquinolone antibiotics.10-17
Chronic obstructive pulmonary disease occurs more often in elderly patients, who generally may have associated comorbidities such as gastric acid-related disease.18 Only recently, it was recognized that patients with COPD have a higher prevalence of gastroesophageal reflux disease (GERD) than subjects with-out COPD and that the frequency of coexisting GERD symptoms appears to be related to COPD severity.18-20 This suggests that in the daily clinical management of COPD, concomitant treatments for GERD symptoms have to be taken into account.
The objectives of this study were to evaluate the effect of an antacid suspension on the disposition of roflumilast and the active metabolite roflumilast N-oxide and to assess the safety and tolerability of roflumilast coadministration with the antacid.
METHODS
Subjects
Thirty healthy adult subjects were enrolled into the study. Eligible subjects were of any ethnic origin, both genders, aged 18 to 55 years (inclusive), with a body mass index (BMI) between 18 and 30 kg/m2 and a total body weight greater than 50 kg. Female subjects of childbearing potential were required to use acceptable methods of nonhormonal contraception for at least 14 days before the first dose of study medication and continuously until completion of follow-up procedures.
Subjects with any of the following characteristics were not eligible: any condition possibly affecting drug absorption (eg, gastrectomy); known history of adverse reactions to the study medication; study participation with investigational or marketed drugs during the 30-day period before study start; blood donation of approximately 500 mL within 56 days before study start; use of any medication known to induce or inhibit CYP3A4 or CYP1A2, use of St John's wort, and use of any tobacco-containing products during the 14-day period before study start and until end; consumption of grapefruit juice or food products/beverages containing grapefruit during the 7-day period before study start and until end; consumption of caffeine-containing products 48 hours before study start and until end; history of regular alcohol consumption exceeding 7 drinks/week (women) or 14 drinks/week (men) (1 drink = 360 mL of beer or 45 mL of hard liquor) within 6 months of screening; and positive urine drug screen.
Ethics
The study protocol was reviewed and approved by the Independent Investigational Review Board, Inc (Fort Lauderdale, Fla). 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. The study was performed at the clinical unit of Comprehensive NeuroScience, Inc (Fort Lauderdale, Fla). Written informed consent was obtained from each subject before any study-related procedure.
Study Design and Conduct
This was an open-label, randomized, 6-sequence, 3-period, 3-treatment, 3-way crossover study. Subjects were confined to the research clinic from the evening before study days 1, 15, and 29 until 36 hours after having received the study treatments. Subjects were randomly assigned to receive 1 of 6 possible treatment sequences according to a Latin square design. Subjects received the following 3 treatments at separate times: (1) single roflumilast 500-µg tablet (reference; roflumilastalone), (2) single roflumilast 500-µg tablet with coadministration of 30 mL antacid liquid (test 1; roflumilast + antacid), and (3) single roflumilast 500-µg tablet followed 2 hours later by 30 mL antacid liquid administration (test 2; roflumilast + antacid2 h). Washout intervals between treatments were at least 14 days. Each roflumilast dose was administered at about 8:00 AM together with 240 mL of water. On days 1, 15, and 29, subjects began fasting 8 hours before dosing and continued fasting for 4 hours after dosing. For the roflumilast + antacid treatment, antacid was taken first, and roflumilast was immediately followed; for the roflumilast + antacid2 h treatment, antacid was taken without water. Roflumilast 500-µg tablets were provided by ALTANA Pharma (Konstanz, Germany). Antacid suspension (Maalox Max Fast Relief, Novartis Consumer Health) was obtained from a commercial lot.
Subjects were required to abstain from prescription or nonprescription drugs, vitamins, and dietary supplements within 14 days before the first dose of study medication throughout study conduct. Herbal supplements were to be discontinued at least 28 days before the first dose of study medication. Intermittent use of acetaminophen at doses of less than 1 g per day was the only allowed concomitant medication in cases of the subject's discomfort. Female subjects on oral, transdermal injected, or implanted hormonal contraceptives or hormone replacement therapies were required to be on a stable dose for 90 days before day 1. All concomitant medications taken during the study were recorded with indication, daily dose, and administration start and end dates. Consumption of alcoholic beverages was prohibited from 48 hours before day 1 until study end.
Safety Evaluations
The study was performed under medical supervision and all subjects were monitored for safety, including physical examinations, vital signs (heart rate, blood pressure), 12-lead electrocardiograms (ECGs), adverse events, and clinical laboratory parameters. Sitting blood pressure and heart rate measurements were performed during screening (days -14 to -1), predose, on days 1, 15, and 29, and at study end. A single 12-lead ECG and clinical laboratory evaluations were performed at screening and at study end. All vital sign assessments and ECG recordings were obtained after subjects had rested for at least 10 minutes.
Sample Collection
On days 1, 15, and 29, venous blood (5 mL collected in lithium-heparinated monovettes) was collected: 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 administrations. Plasma was separated from whole blood within 30 minutes of collection. After refrigerated centrifugation at 1000 to 1200 g for 15 minutes, plasma was transferred into polypropylene plastic tubes, frozen within 60 minutes, and stored at -20°C until analysis.
Determination of Roflumilast and Roflumilast N-Oxide in Plasma
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 [2H5]roflumilast and [2H5]roflumilast N-oxide as internal standards. The assay was validated according to good laboratory practice standards. Roflumilast was monitored in the positive ion mode with the mass transition of m/z 403.1 to m/z 187.1; the respective internal standard was analyzed with the mass transition m/z 408.2 to m/z 190.0. Roflumilast N-oxide was monitored in the positive ion mode with the mass transition of m/z 419.0 to m/z 187.1; the respective internal standard was analyzed with the mass transition m/z 424.2 to m/z 190.0.
For roflumilast, the interday precision (between-day coefficient of variation) ranged between 5.45% and 10.01%. Interday accuracy ranged between 95.0% and 100.4%. For roflumilast N-oxide, the interday precision ranged between 3.96% and 7.96%, and interday accuracy ranged between 94.8% and 98.8%. The lower limit of quantitation was 0.04 µg/L for both compounds.
Calculation of Pharmacokinetic Parameters
Pharmacokinetic parameter estimates for plasma roflumilast and roflumilast N-oxide were calculated by noncompartmental analysis with WinNonlin Version 4.0.1 (PharSight, Mountain View, Calif) using actual sample collection times. The observed Cmax values with the corresponding observation times (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 t was calculated as ln(2)/z. Estimates of AUClast were obtained using linear trapezoidal integration up to the last sampling point. Estimates of total AUC (AUC
) were derived by AUClast + Clast/z, where Clast denotes the last quantifiable plasma concentration.
Sample Size Considerations
Based on the variabilities observed for roflumilast Cmax and AUC values in previous studies and assuming similar variabilities in this study, a total number of N = 30 subjects was estimated to provide a probability of declaring "no effect" of at least 0.85. This calculation was based on the assumption that the antacid would not alter the primary pharmacokinetic parameter estimates of roflumilast by more than ±5%.
Data Analysis
Pharmacokinetic parameter estimates were analyzed with an analysis of variance (ANOVA) model consisting of subject, period, sequence, and treatment, whereby the subject-nested sequence effect was considered random. Values of Cmax and AUC were log-transformed before analysis. Model-based point estimates and 90% confidence intervals (CI) for the ratios of test (test 1: roflumilast + antacid and test 2: roflumilast + antacid2 h) to reference (roflumilastalone) were calculated. Lack of an effect of antacid on roflumilast and roflumilast N-oxide pharmacokinetics was concluded if the 90% CI for both Cmax and AUC were within the standard bioequivalence acceptance range of 0.80 to 1.25.
For tmax, a nonparametric analysis was used for the untransformed data of population medians for roflumilast alone, roflumilast + antacid, and roflumilast + antacid2 h—that is, applying an additive model using the program BIOQPC Version 1.2.2 (ALTANA Pharma AG, Konstanz, Germany).
RESULTS
Subjects
Of the 30 enrolled subjects, the majority was of Hispanic origin (n = 28; 93.3%). Sixteen subjects were women (53.3%). The subjects' ages ranged between 25 to 55 years (median: 42.2 years), and weight and height ranged from 54 to 91 kg (median: 72.0 kg) and 150 to 182 cm (mean: 166.3 cm), respectively; the BMI was between 20 and 30 kg/m2 (median: 26.0 kg/m2). Two of the 30 enrolled subjects discontinued the study because of adverse events, and 1 subject withdrew consent for other reasons. Thus, 27 subjects completed the study according to protocol.
Pharmacokinetics of Roflumilast and Roflumilast N-Oxide in Plasma
After administration of roflumilastalone, roflumilast + antacid, and roflumilast + antacid2 h, the mean (± SD) roflumilast and roflumilast N-oxide plasma concentration-time courses showed no significant differences between the study treatments as demonstrated by superimposed profiles (Fig. 1A,B).
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The pharmacokinetic parameter estimates for roflumilast and roflumilast N-oxide were well comparable between the study treatments and showed no relevant differences except for a slight (11%) decrease in the observed roflumilast Cmax after coadministration of roflumilast + antacid (Table I). Point estimates and 90% CIs of the least squares mean ratios for Cmax, AUClast, and AUC values of roflumilast and roflumilast N-oxide were all within the standard equivalence range of 0.80 to 1.25, confirming that the rate and extent of roflumilast and roflumilast N-oxide exposure were unaffected by concomitant or subsequent antacid administration (Table I).
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The mean apparent terminal plasma t was between 28 and 30 hours for roflumilast and about 32 to 35 hours for roflumilast N-oxide without showing any significant treatment differences. Similarly, median roflumilast and roflumilast N-oxide tmax values did not differ significantly between treatments (Table I).
Safety and Tolerability
During the study, 9 subjects reported a total of 36 adverse events, which were either mild or moderate in intensity. Following roflumilastalone, 10 adverse events were reported, whereas after roflumilast + antacid and roflumilast + antacid2 h, 12 and 14 adverse events occurred, respectively. In all 3 treatment groups, the most frequently reported adverse events were headache (18 subjects), dizziness (4 subjects), and nausea (3 subjects). All adverse events resolved completely. Two subjects discontinued the study because of adverse events (multiple episodes of chest pain, urinary tract infection). These adverse events were of moderate intensity, and the investigator assessed these as causally unlikely related to study medication. No clinically relevant changes in physical examination, ECG, clinical laboratory, or vital sign measurements were observed.
DISCUSSION
From a mechanistic perspective, drug absorption interactions caused by antacids may result either from their effects on the intraluminal gastric pH, gastric emptying rate, or intraluminal binding or chelation of coadministered drugs. Apart from gastrointestinal absorption, antacids may also alter the renal elimination of drugs due to changes in urinary pH.21-26 Because these mechanisms may contribute to potential interactions with antacids, it is difficult to predict the probability of a potential in vivo interaction for a new chemical entity in humans, merely on physicochemical considerations and/or preclinical data. Thus, interactions with antacids and other classes of antisecretory compounds need to be addressed in clinical studies.27
Several physicochemical properties may influence the overall absorption characteristics and respective pH dependence of a drug. Of particular importance is the degree of ionization and solubility in hydrophilic and lipophilic body fluids and cellular environments. According to the biopharmaceutical classification system (BCS),28,29 roflumilast can be characterized as a BCS class 2 drug with high membrane permeability (roflumilast Fabs in humans = 84%)5 and low water solubility (0.6 to 1 mg/L at 37°C). However, the latter characteristic probably has little in vivo relevance for the overall fraction absorbed (Fabs) of roflumilast because of the small maximum therapeutic doses of 500 µg daily and the fact that water solubility may underestimate the "biorelevant" in vivo solubility of lipophilic compounds in the gastrointestinal environment, especially in the presence of bile acids. On the other hand, lipophilicity of roflumilast is high with a partition coefficient (logP octanol/buffer) at pH 7.4 of 3.99. Because roflumilast is a weak acid with a pKa value of 8.8, it is almost completely nonionized over the physiological, gastrointestinal pH range of 1 to 7. Therefore, no effects on permeability and solubility and, consequently, on the fraction absorbed were expected. Furthermore, according to its physicochemical characteristics, the absorption of roflumilast should be almost complete, most probably dominated by passive diffusion, and robust against pH changes in gastric or intestinal environments. These physicochemical characteristics of roflumilast are consistent with the results of the present study, which confirmed (1) the absence of pharmacokinetic alterations of roflumilast and (2) the unaltered formation and disposition of the active N-oxide metabolite by coadministration of a magnesium hydroxide/aluminium hydroxide-containing antacid. The latter finding is of particular importance because roflumilast N-oxide is estimated to account for about 90% of the overall pharmacological effect of roflumilast.5,8
The results of this study are consistent with a previously reported roflumilast-food interaction study, which showed that a high-fat/high-calorie breakfast does not affect the total exposure to roflumilast and also does not alter the formation rate (Cmax, tmax) as well as the total exposure to roflumilast N-oxide.30 High-fat meals exert effects that are in many aspects similar to antacid-related effects, such as changes in drug solubility and gastrointestinal pH, or delay of gastric emptying. These 2 studies on roflumilast allow us to conclude that the disposition of roflumilast and its active N-oxide metabolite is robust and unlikely to be significantly affected by physiological changes in the gastrointestinal environment.
Regarding safety and tolerability of coadministered roflumilast and antacid, the short, single-dose exposure to both drugs in this open-label study does not allow for a reliable and robust conclusion. However, the number and nature of observed adverse events and the absence of treatment-related changes in vital signs, ECG parameters, and clinical laboratory abnormalities suggest that coadministration of roflumilast and antacid may not affect the known safety and tolerability profile of either drug. Besides, the most frequently observed adverse events of headache, dizziness, and nausea are known to be frequently reported by healthy subjects in clinical pharmacology settings because of the strenuous study conditions and dietary restrictions, including caffeine cessation.31,32 Furthermore, these adverse events are also part of the known side effect profiles of roflumilast and the specific antacid investigated.10
In conclusion, the present study demonstrates that coadministration or subsequent administration of a magnesium hydroxide/aluminium hydroxide-containing antacid has no effect on the pharmacokinetics of roflumilast and no effect on the formation and disposition of the primary active metabolite roflumilast N-oxide. Furthermore, coadministration of roflumilast and antacid is expected to have no adverse effects on the safety and tolerability profile of either drug.
ACKNOWLEDGEMENTS
The authors thank Dr Kathy B. Thomas and Dr Angela Schilling (ALTANA Pharma AG, Department of Medical Writing, Konstanz, Germany) for their helpful suggestions during the preparation of this article.
Financial disclosure: This study was funded by ALTANA Pharma AG. All authors of this article are employees of ALTANA Pharma AG. The study described in the article was designed, conducted, analyzed, and reported by the authors within the scope of their employment.
REFERENCES
1. Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet. 2005;365: 167-175.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Reid P. Roflumilast Altana Pharma. Curr Opin Investig Drugs. 2002;3: 1165-1170.[Medline] [Order article via Infotrieve]
3. Bousquet J, Aubier M, Sastre J, et al. Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy. 2006;61: 72-78.[Web of Science][Medline] [Order article via Infotrieve]
4. Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366: 563-571.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. David M, Zech K, Seiberling M, Weimar C, Bethke TD. Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high absolute bioavailability [abstract]. J Allergy Clin Immunol. 2004; 113: S220-S221.
6. Hünnemeyer A, Hauns B, David M, et al. Pharmacokinetics and safety of roflumilast, a once-daily, oral, selective PDE4 inhibitor, and its active metabolite roflumilast N-oxide in healthy subjects [abstract]. J Allergy Clin Immunol. 2004;113: S222.
7. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001;297: 267-279.
8. Hermann R, Lahu G, Hauns B, Bethke T, Zech K. Total PDE4 inhibitory activity: a concept for evaluating pharmacokinetic alterations of roflumilast and roflumilast N-oxide in special populations and drug-drug interactions [abstract]. Eur Respir J. 2006; 28: 436s.
9. Woodson GC. An interesting case of osteomalacia due to antacid use associated with stainable bone aluminum in a patient with normal renal function. Bone. 1998;22: 695-698.[Medline] [Order article via Infotrieve]
10. Maalox Suspension SPC. electronic Medicines Compendium (eMC). Available at: http://emc/medicines.org.uk. Accessed February 5, 2006.
11. Grasela TH Jr, Schentag JJ, Sedman AJ, et al. Inhibition of enoxacin absorption by antacids or ranitidine. Antimicrob Agents Chemother. 1989;33: 615-617.
12. Grunder G, Zysset-Aschmann Y, Vollenweider F, Maier T, Krahenbuhl S, Drewe J. Lack of pharmacokinetic interaction between linezolid and antacid in healthy volunteers. Antimicrob Agents Chemother. 2006;50: 68-72.
13. Healy DP, Sahai JV, Sterling LP, Racht EM. Influence of an antacid containing aluminum and magnesium on the pharmacokinetics of cefixime. Antimicrob Agents Chemother. 1989;33: 1994-1997.
14. Lazzaroni M, Imbimbo BP, Bargiggia S, et al. Effects of magnesium-aluminum hydroxide antacid on absorption of rufloxacin. Antimicrob Agents Chemother. 1993;37: 2212-2216.
15. Lohitnavy M, Lohitnavy O, Thangkeattiyanon O, Srichai W. Reduced oral itraconazole bioavailability by antacid suspension. J Clin Pharm Ther. 2005;30: 201-206.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Shyu WC, Wilber RB, Pittman KA, Barbhaiya RH. Effect of antacid on the bioavailability of cefprozil. Antimicrob Agents Chemother. 1992;36: 962-965.
17. Stass H, Bottcher MF, Ochmann K. Evaluation of the influence of antacids and H2 antagonists on the absorption of moxifloxacin after oral administration of a 400mg dose to healthy volunteers. Clin Pharmacokinet. 2001;40(suppl 1): 39-48.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Mokhlesi B, Morris AL, Huang CF, Curcio AJ, Barrett TA, Kamp DW. Increased prevalence of gastroesophageal reflux symptoms in patients with COPD. Chest. 2001;119: 1043-1048.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Andreu M, Delgado S, Seoane A, et al. Gastroesophageal reflux (GER) symptoms in patients with chronic obstructive pulmonary disease (COPD). Gut. 2003;52: A124.
20. Phulpoto MA, Qayyum S, Rizvi N, Khuhawar SM. Proportion of gastroesophageal reflux symptoms in patients with chronic obstructive pulmonary disease. J Pak Med Assoc. 2005;55: 276-279.[Medline] [Order article via Infotrieve]
21. Gugler R, Allgayer H. Effects of antacids on the clinical pharmacokinetics of drugs: an update. Clin Pharmacokinet. 1990; 18: 210-219.[Web of Science][Medline] [Order article via Infotrieve]
22. Hurwitz A. Antacid therapy and drug kinetics. Clin Pharmacokinet. 1977;2: 269-280.[Web of Science][Medline] [Order article via Infotrieve]
23. Lomaestro BM, Bailie GR. Absorption interactions with fluoroquinolones. 1995 update. Drug Saf. 1995;12: 314-333.[Web of Science][Medline] [Order article via Infotrieve]
24. Maton PN, Burton ME. Antacids revisited: a review of their clinical pharmacology and recommended therapeutic use. Drugs. 1999;57: 855-870.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
25. Reynolds JC. The clinical importance of drug interactions with antiulcer therapy. J Clin Gastroenterol. 1990;12(suppl 2): S54-S63.[Web of Science][Medline] [Order article via Infotrieve]
26. Welling PG. Interactions affecting drug absorption. Clin Pharmacokinet. 1984;9: 404-434.[Web of Science][Medline] [Order article via Infotrieve]
27. Scott G, Vinluan RC, Milosavljev S, Langholff W, Shenouda M, Rordorf C. Lack of effect of omeprazole or of an aluminium hydroxide/magnesium hydroxide antacid on the pharmacokinetics of lumiracoxib. Clin Pharmacokinet. 2004;43: 341-348.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
28. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12: 413-420.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
29. Wu CY, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22: 11-23.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
30. Hauns B, Hermann R, Hünnemeyer A, et al. Investigation of a potential food effect on the pharmacokinetics of roflumilast, a once daily, oral phosphodiesterase 4 inhibitor in healthy subjects. J Clin Pharmacol. 2006;46: 1146-1153.
31. Hermann R, Heger-Mahn D, Mahler M, et al. Adverse events and discomfort in studies on healthy subjects: the volunteer's perspective. A survey conducted by the German Association for Applied Human Pharmacology. Eur J Clin Pharmacol. 1997;53: 207-214.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
32. Silverman K, Evans SM, Strain EC, Griffiths RR. Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med. 1992;327: 1109-1114.[Abstract]
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