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Abstract

J.V.S. Gobburu and V.J. Sekar

Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, MD, USA
Typical drug development includes few studies to find the right dose/dosing regimen and several other bridging studies evaluating various prognostic factors (e.g.: co-administration of other drugs, organ failure). The drug sponsors and the regulators use this information to formulate labeling instructions for safe and effective use of the drug. In the current article, modeling and simulation are proposed as tools to integrate the knowledge from the effectiveness/safety studies and the bridging studies. Simulations allow exploring the impact of various prognostic factors on the effectiveness and safety. The concept is exemplified using the new drug application of an anti-migraine drug. The exercise aids in integrating all the knowledge across the drug development to suggest rationale dosing strategies; effectively communicating the impact of the prognostic factors to the clinicians/regulators; and protect against any intellectual losses due to development team changes.Correspondence to:
J.V.S. Gobburu, PhD; 1451 Rockville Pike, Room 5088, HFD-860 Rockville, MD 20852, USA
Email: gobburuj@cder.fda.gov

Abstract

P. Ahtoy¹, P. Chrétien¹, T. Dupain¹, C. Rauch², A. Rouchouse³ and A. Delfolie⁴

¹CéMax:³, Rouen, ²Clinical Metabolism and Pharmacokinetics Department, Sanofi-Synthelabo Recherche, Montpellier, ³Bioanalysis Group, Sanofi-Synthelabo Recherche, and ⁴Biostatistics Group, Sanofi-Synthelabo Recherche, Chilly Mazarin, France
Objective: A new patented prolonged release formulation of the a1-adrenoceptor antagonist alfuzosin has been developed for once-daily (OD) administration in benign prostatic hyperplasia (BPH). This study was designed to compare 2 dose regimens: 10 mg OD alfuzosin and 2.5 mg TID alfuzosin at steady state. Methods: In an open, randomized crossover study with a 9-day washout between treatments, 18 healthy male subjects (50 – 65 years) received OD or TID alfuzosin tablets orally over 5 days. Both formulations were administered according to the schedule recommended for therapeutic use: OD was administered 5 min after the evening meal, TID was administered in the evening, then in the morning and at noon (30 min before meals). On the fifth day, plasma concentrations were quantitated by HPLC with spectrofluorometric detection. Results: The following pharmacokinetic parameters refer to the geometric mean values for both formulations. Mean Cmax value of 10 mg OD alfuzosin was 15.8 ng/ml at a median tmax of 9.0 h; Cmax was higher and reached earlier from 2.5 mg alfuzosin TID: 19.3 ng/ml, 19.7 ng/ml and 20.3 at 1.0 hour after each dosing, respectively. Mean AUC(0-24) values after OD and TID were 228. 3 and 226.0 ng × h/ml, respectively. Based on AUC(0-24) values corrected by the administered daily dose, the relative bioavailability of alfuzosin OD was 75.7% with a 90% confidence interval of 68.0 – 84.3%. Non-corrected AUC(0-24) values were bioequivalent with a ratio estimate of 101.0% and a 90% confidence interval of 90.7 – 112.5%. The higher daily dose compensated for the loss of bioavailability observed with the OD formulation. Mean t1/2z value was longer for the OD (8.9 h) than the TID formulation (6.9 h). Variability between individuals was similar for the 2 formulations. Both dose regimens were well tolerated. Conclusions: Alfuzosin 10 mg once-daily provides a suitable pharmacokinetic profile for a once-daily administration; equivalent bioavailability between the 2 dosage regimens and a good safety profile justify the use of alfuzosin 10 mg in patients with BPH.Correspondence to:
Dr. P. Chrétien, CéMax:3, rue Dufay, F-76100 Rouen, France

Abstract

G. Fröhlich¹, M. Bulitta² and W. Strösser³

¹Urologist, Toscolano Maderno, Italy, ²Biometrician, CRMB GmbH, Rheinbach, ³Medical Consultant, Bergisch Gladbach, Germany
Objectives: Primary objective of this meta-analysis was to produce a systematic and quantitative review of two independent clinical trials of 20 mg trospium chloride (TCl) twice daily (b.i.d.) in patients with detrusor overactivity [Alloussi et al. 1998, Cardozo et al. 2000]. Patients and methods: In two placebo-controlled, double-blind, multi-center studies, the effect of TCl on detrusor function was evaluated using urodynamic measurements. All 517 patients were randomized to receive TCl or placebo for 3 weeks. Urodynamic variables were measured at the beginning and at the end of the treatment. Safety was evaluated on the basis of adverse events (AEs), vital signs and laboratory tests. Results: TCl produced significant improvements in ‘maximum cystometric bladder capacity’ (median treatment effect = 52 ml, 95% confidence interval 32 – 71 ml, p < 0.0001) and ‘urinary volume at first unstable contraction’ (median treatment effect = 48 ml, 95% confidence interval 28 to 68 ml, p = 0.0001). The patients’ assessment of efficacy also showed significantly greater clinical improvement in the TCl group than in the placebo group (p < 0.0001). The patients recorded a ‘cure’ or a ‘marked improvement’ more often in the TCl group than in the placebo group (47.9% and 19.7%, respectively). TCl was well tolerated, with similar frequencies of AEs reported in both groups (TCl: 35.7%, placebo group: 38.9%). Conclusions: Trospium chloride (20 mg twice daily) is an effective and safe medication for the treatment of detrusor overactivity.Correspondence to:
PD Dr. G. Fröhlich; Via Cervano 23, I-25088 Toscolano Maderno (BS), Italy
Email: gfroehl@tin.it

Abstract

A. Iudice, E. Bonanni, M. Maestri, B. Nucciarone, S. Brotini, L. Manca, G. Iudice and L. Murri

Department of Neurosciences, Section of Neurology, University of Pisa, Italy
Objective: To assess the residual effects of lormetazepam on daytime vigilance, psychomotor performance and simulated driving in adult healthy volunteers. Material: Twelve subjects (7 women, 5 men), aged 27 – 38 years (mean 31). Method: Subjects received lormetazepam 1 mg tablet and placebo for 3 days at nighttime in a randomized, double-blind, crossover design, with a 1-week interval between medications. On the morning following the last drug administration, the subjects completed a 15-min battery of neuropsychological tests aimed at assessing memory and attention, performed simple and choice visual reaction times, and self-rated their own level of sleepiness using the Epworth sleepiness scale. Afterwards, an interactive, computer-based driving simulator (STISIM) was used to assess the effect of the study drugs on driving ability, followed by the multiple sleep latency test (MSLT). Results: The findings showed that participants had similar performance when treated with lormetazepam and placebo. Indeed, as compared with baseline, neuropsychological tests, visual reaction times, sleep latency using the MSLT and driving ability showed no deterioration following either placebo or active medication. Conclusions: The data suggest that 3-day use of lormetazepam 1 mg/day neither influences daytime vigilance nor impairs psychomotor task performance and simulated driving. Results confirm previous evidence that the intermediate-acting hypnotic benzodiazepine lormetazepam is devoid of residual effects in respect to psychomotor ability. However, caution should be exercised in the interpretation of the results due to the limited sensitivity of the study.Correspondence to:
Dr. A. Iudice; Department of Neurosciences, Section of Neurology, University of Pisa, via Roma 67, I-56126 Pisa, Italy
Email: a.iudice@med.unipi.it

Abstract

J. Dingemanse and P.L.M. van Giersbergen

Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland
Background: One of the potential indications of bosentan, a dual endothelin receptor antagonist, is chronic heart failure. Patients with chronic heart failure frequently also suffer from impaired renal function. Objective: To explore the influence of severe renal dysfunction on the pharmacokinetics and metabolism of bosentan in a monocenter, open label, parallel group study. Methods: Eight renal patients with creatinine clearance 17 – 27 ml/min and 8 healthy subjects (creatinine clearance 99 – 135 ml/min) received a single oral dose of 125 mg bosentan and plasma samples drawn for up to 36 hours after administration were analyzed for bosentan and 3 metabolites. Results: The pharmacokinetic parameters of bosentan did not differ significantly between the study groups: geometric means (95% confidence interval) for Cmax were 1.8 (1.2 – 2.8) and 1.1 mg/ml (0.74 – 1.7), and for AUC0–¥ 7.2 (5.1 – 10.4) and 6.4 (3.4 – 11.2) mg´h/ml in healthy subjects and renal patients, respectively. Levels of the 3 CYP2C9- and CYP3A4-derived metabolites increased approximately 2-fold in renal patients, both in absolute terms and in relation to the parent compound. In renal patients, the exposure to Ro 48-5033, the only pharmacologically active metabolite, was 13% of that to bosentan. Conclusion: Severe renal dysfunction did not affect the pharmacokinetics of bosentan to a clinically relevant extent and, therefore, no dose adjustments are deemed necessary in patients with any grade of renal insufficiency.Correspondence to:
J. Dingemanse, PhD, Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Gewerbestrasse 18, CH-4123 Allschwil, Switzerland
Email: jasper.dingemanse@actelion.com

Abstract

D. Schröder-Bernhardi and G. Dietlein

IMS HEALTH, Frankfurt am Main, Germany
Objective: This investigation addresses the question whether physicians in hospitals influence the prescribing behavior of general practitioners regarding patients who are discharged following hospitalization. Case studies for patients on lipid-lowering therapy were used as an example. Methods: All analyses described were carried out with mediplus®, a longitudinal patient database with anonymous access to a representative and valid panel of physicians and patients in Germany. A total of more than 1,000 medical practices with over 6 million patients and over 100 million prescriptions can be analyzed using a cross- and/or longitudinal section of the database. The longest time period per patient exceeds 12 years commencing in 1989 and there are monthly updates. This allows not only cross-tabulation analysis but also time-dependent longitudinal analysis. Results: The results of the study demonstrated that hospitals significantly influence the prescribing behavior of general practitioners. The sum of lipids lowering drugs prescribed in hospitals after admission increased by approximately 45% compared to the initial situation in practices. Physicians in hospitals play a significant role in causing a shift in treatment patterns of practice-based physicians with a reduction in use traditional fibrates in favor of cholesterin synthesizing enzyme inhibitors. Conclusion: The results of this investigation showed a significant increase in lipid-lowering therapy with a shift from fibrates to the more innovative CSE-inhibitors in the treatment pattern of patients following hospitalization. This study also demonstrates that the patient database used provides a useful insight into the extent of hospital physician influence on prescribing behavior of general practitioners and that this behavior can be quantified.Correspondence to:
Dr. G. Dietlein; IMS HEALTH, Hahnstraße 30 – 32, D–60528 Frankfurt/ Main, Germany
Email: gdietlein@de.imshealth.com

Abstract

M.A. Artaza¹, J.L. Puerta², P. Ortiz² and J.-R. Laporte¹

¹Servei de Farmacologia Clínica, HU Vall d’Hebron, Fundació Institut Català de Farmacologia, Universitat Autònoma de Barcelona, Barcelona, and ²Grupo Boehringer Ingelheim España S.A., Madrid, Spain
Objective: The aim of this study was to investigate the extent and the rate of absorption of metamizole, appearing in blood as methylaminoantipyrine (MAA), from a new oral solution and a parenteral solution administered by the oral route relative to capsules. Methods: An open, randomized, 3 single-dose (2 g metamizole), crossover study with intervals of 7 days between periods was performed in 19 male and female healthy volunteers (age 22 – 45 years, body weight 49 – 88 kg, body height 156 – 189 cm). Metamizole metabolites were measured with an HPLC technique. The test formulations were considered bioequivalent with the reference formulation if the 90% confidence limits of the AUC0®¥ and Cmax ratios and the tmax differences were within the range of 80 – 125%. Results: The 90% confidence limits of the comparisons between capsules (reference) and oral solution, capsules (reference) and ampoules, and ampoules (reference) and oral solution were 98.5 – 117.8, 99.5 – 132.6 and 81.3 – 105.8 for AUC0®¥, 98.7 – 119, 101.7 to 129.2, and 82.1 – 104.8 for Cmax, and 84.4 to 115.6, 100 – 105.6 and 70.3 – 100 for tmax, respectively. Conclusion: The oral solution was bioequivalent to capsules with regard both to the extent and the rate of MAA absorption. Metamizole as oral solution was bioequivalent to reference ampoules in the extent of MAA absorption, but absorption rate was faster. Ampoules showed a higher MAA bioavailability than capsules.Correspondence to:
Dr. J.-R. Laporte; Servei de Farmacologia Clínica, HU Vall d’Hebron, Fundació Institut Català de Farmacologia, P Vall d’Hebron, 119-129, E-08035 Barcelona, Spain
Email: jrl@icf.uab.es

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Volume 40, No. 7/2002(July)