Volume 43, No. 3/2005(March)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacodynamics
Interpretation of absorption rate data for inhaled fluticasone propionate obtained in compartmental pharmacokinetic modeling
S. Krishnaswami, G. Hochhaus, H. Möllmann, J. Barth and H. Derendorf
Abstract
S. Krishnaswami1,2, G. Hochhaus1, H. Möllmann3, J. Barth4 and H. Derendorf1
1Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 2Pfizer Global R&D, Ann Arbor, MI, USA,
3University of Bochum and 4Clinic Bergmannstrost, Halle, Germany
Objective: Reports characterizing the pharmacokinetics of inhaled fluticasone propionate (FP) using compartmental approaches have suggested that the absorption of FP into the systemic circulation is rapid with a half-life of approximately 10 min. We believe that this is a classical case of misassignment of the pharmacokinetic parameter estimates, a problem often encountered while modeling pharmacokinetic data. The objective of this study was to illustrate and analyze this problem using actual blood level data of FP obtained in 14 healthy subjects. Materials and methods: Serum concentration-time data of FP were obtained from a double-blind, randomized study involving single and multiple twice-daily inhalations of 500 mg via a dry powder device, Diskus®. The profiles were fitted using one- and two-compartment pharmacokinetic models with first order absorption. Various permutations of the resulting exponential rate constants were analyzed to determine the combination that was most consistent with the underlying physical process. Results: The two-compartment body model with first order absorption gave excellent fits for the observed FP concentrations after both single and multiple dosing. Even though peak levels were reached relatively early (30 – 90 min) after inhalation, the combination that most appropriately described the underlying process was a > Ka > b, i.e. slow absorption, rapid distribution and slower elimination kinetics. The absorption, distribution and elimination half-lives resulted to be 3.8 h, 9.9 min and 13.6 h, respectively, consistent with the high lipophilicity and sustained dissolution characteristics observed in vitro. Conclusions: Analysis of FP pharmacokinetics after inhalation represents a classical case of potential misassignment of the exponential rate constants, which if ignored, could lead to erroneous interpretations regarding the underlying process. The study also elucidates the pitfall of using tmax to calculate absorption rate.Correspondence to:
H. Derendorf, Ph.D
P.O.Box 100494
Dept. of Pharmaceutics,
College of Pharmacy
University of Florida
Gainesville, FL 32610-0494, USA
Email: hartmut@cop.ufl.edu
Drug Interactions
Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment
J. Shi, S. Chapel, G. Montay, P. Hardy, J.S. Barrett, D. Sica, S.K. Swan, R. Noveck, B. Leroy and V.O. Bhargava
Abstract
J. Shi, S. Chapel, G. Montay, P. Hardy, J.S. Barrett, D. Sica, S.K. Swan, R. Noveck, B. Leroy and V.O. Bhargava
1Aventis, Bridgewater, NJ, USA, 2Aventis, Vitry-sur-Seine, France,
3Medical College of Virginia, Richmond, VA, 4DaVita Clinical Research
and Hennepin County Medical Center, Minneapolis, MN, and
5Clinical Research Center, New Orleans, LA, USA
Objective: The objective of this study was to determine the effect of multiple impairments in drug elimination on the pharmacokinetics and pharmacodynamics (effect on QTc interval), using clarithromycin as a comparator. Methods: Thirty-two subjects aged ³ 60 years with renal impairment who were otherwise medically stable were recruited into this parallel-group study. Following stratification according to creatinine clearance (CLCR), subjects were randomized to a five-day treatment with ketoconazole (400 mg once daily) alone, or a five-day treatment with ketoconazole (400 mg once daily) and telithromycin (800 mg once daily) given concomitantly or a five-day treatment with ketoconazole (400 mg once daily) and clarithromycin (500 mg twice daily) given concomitantly. Steady-state pharmacokinetics and safety, including serial electrocardiograms, were assessed. Results: In subjects with CLCR 30 – 80 ml/min, the mean maximal telithromycin concentration at steady state (Cmax,ss) was 3.6 mg/l and the steady state area under the plasma concentration-time curve from time zero to 24 hours (AUC(0 – 24 h)ss) was 33.4 mg ´ h/l. The mean Cmax,ss and AUC(0–12 h)ss for clarithromycin were 6.2 mg/l and 56.1 mg ´ h/l, respectively. The increases in telithromycin Cmax,ss and AUC(0 – 24 h)ss compared to corresponding data for healthy young subjects were 1.6- and 2.7-fold, respectively, whereas corresponding increases for clarithromycin were 2.2- and 3.3-fold, respectively. In the telithromycin plus ketoconazole group DQTc values were equal or < 60 ms. All QTc values were equal or < 450 ms in males and equal or < 470 ms in females. Conclusions: The increase in telithromycin plasma concentrations during ketoconazole-mediated inhibition of CYP3A4 in subjects aged 60 years or older with renal impairment was similar to that for clarithromycin under the same conditions. Telithromycin was well tolerated and produced no clinically significant prolongations in the QTc interval.Correspondence to:
J. Shi
Aventis
Global Biopharmaceutics and Clinical Pharmacokinetics
Drug Metabolism and Pharmacokinetics
1041 Route 202 – 206
Bridgewater, NJ 08807-0800, USA
Email: junshi88@yahoo.com
Pharmacokinetics
Pharmacokinetics of scopolamine in serum and subcutaneous adipose tissue in healthy volunteers
P.M. Stetina, B. Madai, V. Kulemann, W. Kirch and C. Joukhadar
Abstract
P.M. Stetina1, B. Madai2, V. Kulemann1, W. Kirch2 and C. Joukhadar1,3
1Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Austria, 2Institute of Clinical Pharmacology, Faculty of Medicine, Technical University Dresden, Germany and 3Institute of Pharmacology, Medical University of Vienna, Austria
Objective: The objective was to develop a microdialysis set-up to measure the concentration-time course of scopolamine in the interstitium of subcutaneous adipose tissue. Materials and methods: Six healthy male volunteers were eligible for data analysis. Subjects received 0.5 mg scopolamine as a 15-minute intravenous infusion. Microdialysis samples from interstitial space fluid of subcutaneous adipose tissue and blood samples were taken at predefined intervals over a period of 360 minutes. Scopolamine concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Results: High inter-individual variability was observed in all pharmacokinetic parameters. The mean peak serum concentration (Cmax) of 6.5 ± 3.9 ng/ml (data in mean ± SD) was attained after 15 ± 3 minutes (tmax), whereas in dialysate, a mean peak concentration of 2.7 ± 1.7 ng/ml was measured after 27 ± 8 minutes. The ratio of the area under the concentration versus time curve from 0 – 360 min for interstitium (AUCinterstitium 0 – 360 min) to the AUC for serum (AUCserum 0 – 360 min) was 0.96 ± 0.7. The elimination half-life of scopolamine was 121 ± 85 minutes in serum and 166 ± 117 minutes in dialysate. Values for total clearance and volume of distribution in serum were 99.1 ± 35.0 l/h and 188 ± 76 l, respectively. Conclusions: In the present study, we were able to define a microdialysis set-up, which allows for the measurement of scopolamine concentrations in target tissues. In addition, we demonstrated that the concentrations of scopolamine in subcutaneous adipose tissue resemble closely the concentration-time course in serum of healthy volunteers.Correspondence to:
Ch. Joukhadar, MD
Department of Clinical Pharmacology
Division of Clinical Pharmacokinetics
Medical University of Vienna
Währinger Gürtel 18 – 20
1090 Vienna, Austria
Email: christian.joukhadar@meduniwien.ac.at
Pharmacokinetics
Pharmacokinetics of ibuprofen sodium dihydrate and gastrointestinal tolerability of short-term treatment with a novel, rapidly absorbed formulation
F. Sörgel, U. Fuhr, M. Minic, M. Siegmund, J. Maares, A. Jetter, M. Kinzig- Schippers, D. Tomalik-Scharte, J. Szymanski, T. Goeser, U. Toex, B. Scheidel and W. Lehmacher
Abstract
F. Sörgel1, U. Fuhr2, M. Minic3, M. Siegmund4, J. Maares4, A. Jetter2, M. Kinzig- Schippers2, D. Tomalik-Scharte2, J. Szymanski2, T. Goeser5, U. Toex5, B. Scheidel1 and W. Lehmacher6
1Institute for Biomedical and Pharmaceutical Research, Nuremberg-Heroldsberg, 2University of Cologne, Department of Pharmacology, Clinical Pharmacology, Cologne, Germany, 3F. Hoffmann-La Roche Ltd., Basel, 4Roche Consumer Health Ltd., Kaiseraugst, Switzerland, 5University of Cologne, Department of Gastroenterology and 6University of Cologne, Department of Medical Statistics, Cologne, Germany
Objective: This paper describes four studies investigating the dissolution, plasma pharmacokinetics and safety of a novel, fast-acting ibuprofen formulation, ibuprofen sodium dihydrate. Material and Method: Four separate studies investigated: the in vitro dissolution rates of ibuprofen sodium dihydrate (at pH 1.2, 3.5 and 7.2); the bioavailability of ibuprofen sodium dihydrate (in two pharmacokinetic studies; combined n = 38) compared with conventional ibuprofen, ibuprofen lysinate, ibuprofen arginate and ibuprofen liquagels (all 2 × 200 mg ibuprofen); and the gastroduodenal tolerance of ibuprofen sodium dihydrate and ibuprofen arginate (both 2 × 200 mg ibuprofen t.i.d.) in an endoscopy safety study, where endoscopy was performed at baseline and at the end of each treatment period using a five-point scale to assess the integrity of the gastric and duodenal mucosa. Results: Ibuprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 than conventional ibuprofen, ibuprofen lysinate and ibuprofen liquagels. Ibuprofen sodium dihydrate had similar Cmax to ibuprofen lysinate and ibuprofen liquagels and significantly higher Cmax than conventional ibuprofen (p = 0.002). The mean plasma concentration for ibuprofen sodium dihydrate was significantly higher than for conventional ibuprofen (p = 0.028) 10 minutes post-dose and the tmax for ibuprofen sodium dihydrate was reached significantly earlier than for conventional ibuprofen (p = 0.018). All three formulations were bioequivalent according to the acceptable boundaries (90% confidence intervals). No statistically significant difference was observed between the ibuprofen formulations in terms of adverse events and specifically with respect to hemorrhagic scores; 41 (46.0%) adverse events (AEs) occurred after administration of ibuprofen sodium dihydrate, and 46 (52.9%) after ibuprofen arginate. One occurrence of an invasive ulcer was observed after administration of ibuprofen arginate. Conclusions: The new formulation of ibuprofen sodium dihydrate dissolves quickly in vitro, has the same extent of absorption as other fast-acting ibuprofen formulations, and is absorbed into plasma more rapidly than conventional ibuprofen. In addition, the present studies suggest that the tolerability and safety profile of ibuprofen sodium dihydrate is comparable to existing ibuprofen formulations.Correspondence to:
Prof. Dr. F. Sörgel; Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Straße 19,
90562 Nürnberg-Heroldsberg, Germany
Email: ibmp@osn.de
Population Kinetics
Frequency distribution of dextromethorphan O-demethylation in a Greek population
V.K. Kimiskidis, I. Niopas, P.D. Firinidis, F.I. Kanaze, C. Gabrieli, D. Kazis, S. Papagiannopoulos and A. Kazis
Abstract
V.K. Kimiskidis, I. Niopas, P.D. Firinidis, F.I. Kanaze, C. Gabrieli, D. Kazis, S. Papagiannopoulos and A. Kazis
1Department of Neurology, George Papanicolaou Hospital, Aristotle University, and 2Department of Pharmacy, Aristotle University, Thessaloniki, Greece
Objective: To determine the CYP2D6 phenotype in a Greek population by using dextromethorphan (DM) as a probe drug. Methods: DM (30 mg) was given orally to 102 unrelated Greek subjects and 8-hour urine samples were collected. Concentrations of DM and its metabolite dextrorphan (DX) were determined using a validated HPLC assay. Metabolic molar ratio (MR) of DM to free DX in log form was used as an in vivo index of metabolic status. Results: The frequency distribution histogram of MR was bimodal. An antimode of 0.25 for the mean log MR was determined using probit analysis. Seven of 102 subjects (6.9%) were poor metabolizers (PMs). Conclusion: The PM frequency of CYP2D6 in Greek subjects was similar to other Caucasian populations.Correspondence to:
Dr. I. Niopas
Department of Pharmacy
School of Health Sciences
Aristotle University
54124 Thessaloniki, Greece
Email: niopas@pharm.auth.gr
Bioavailability Section
Assessment of the bioequivalence of two nelfinavir tablet formulations under fed and fasted conditions in healthy subjects
B. Kaeser, J.-E. Charoin, M. Gerber, P. Oxley, H. Birnboeck, N. Saiedabadi and L. Banken
Abstract
B. Kaeser, J.-E. Charoin, M. Gerber, P. Oxley, H. Birnboeck, N. Saiedabadi and L. Banken
1Department of Clinical Pharmacology, F. Hoffmann-La Roche, Ltd., Basel, Switzerland, 2Institut de Pharmacologie Clinique Roche, Strasbourg, France, 3Department of Clinical Pharmacology Operations, F. Hoffmann-La Roche Ltd., Welwyn Garden City, UK, 4Department of Non-Clinical Drug Safety, F. Hoffmann-La Roche Ltd., Basel, Switzerland, 5Department for Biometrics, F. Hoffmann-La Roche Ltd., Welwyn Garden City, UK, and 6Department for Biometrics, F. Hoffmann-La Roche Ltd., Basel, Switzerland
Objectives: This study was designed to assess the bioequivalence between the commercial 250 mg nelfinavir tablet and the new 625 mg nelfinavir tablet (Roche) which was developed to reduce the daily pill burden for patients from 10 to 4 tablets in a nelfinavir 1250 mg twice daily regimen. Methods: A total of 52 healthy male subjects were enrolled in this randomized four-period crossover study to receive single oral doses of 1250 mg nelfinavir administered as five commercial 250 mg tablets (reference formulation) and as two new 625 mg tablets (test formulation). Each of the two formulations were taken after an overnight fast and immediately after intake of a standard breakfast (820 kcal) on separate occasions. Blood samples were collected pre-dose and at appropriate intervals after drug administration. Plasma concentrations of nelfinavir and its main metabolite M8 were assayed by a validated LC-MS/ MS assay and the pharmacokinetics of nelfinavir and M8 were derived using standard non-compartmental analysis. Results: The primary parameters for bioequivalence testing were the logarithmically transformed AUC0-inf and Cmax of nelfinavir taken from 50 subjects who completed all four treatments. Bioequivalence was accepted if the 90% confidence interval (CI) was contained entirely in the equivalence region (80%, 125%). In the fed state, this criterion was met for AUC (effect ratio = 95%; CI = 87%, 103%) and Cmax (effect ratio = 101%; CI = 94%, 109%) and bioequivalence of the two treatments could be concluded. In the fasted state, AUC clearly failed to meet the bioequivalence criteria (effect ratio = 73%; CI = 59%, 90%) and Cmax was borderline outside the lower acceptance region (effect ratio = 97%; CI = 79.6%, 118%). Therefore, bioequivalence could not be concluded under fasted condition. Food increased the systemic exposure to nelfinavir (as reflected by comparison of the logarithmically transformed AUC0-inf values under fed and fasted conditions) by six- and eight-fold after dosing with the 250 mg and the 625 mg tablet, respectively. Conclusions: Bioequivalence of the new 625 mg nelfinavir tablet relative to the commercial 250 mg tablet, at a dose of 1250 mg, was confirmed in the fed state but not under fasted conditions. As nelfinavir is recommended to be taken with food, the new tablet is well-suited to decrease the daily pill burden for patients on a nelfinavir twice daily regimen and to enhance patient’s compliance and adherence.Correspondence to:
Dr. B. Kaeser
Clinical Pharmacology
F. Hoffmann-La Roche Ltd.
4070 Basel, Switzerland
Email: Benoite.Kaeser@roche.com
