Volume 43, No. 10/2005(October)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Drug Profile
Physiochemical properties, safety and pharmacokinetics of bimosiamose disodium after intravenous administration
Abstract
M. Meyer, B. Jilma, R. Zahlten and G. Wolff
1Revotar Biopharmaceuticals AG, Hennigsdorf, Germany, and 2Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Objective: Bimosiamose is a novel synthetic panselectin antagonist being developed for the treatment of acute and chronic inflammatory disorders. Therefore, we have studied the pharmacokinetics and tolerability and determined the pharmacokinetically relevant physicochemical characteristics of bimosiamose. Method: A randomized, double-blind, placebo-controlled dose-escalation trial in healthy male subjects has been carried out. The subjects received intravenous infusions of 0.5 ? 30 mg/kg bimosiamose disodium. Results and conclusions: The maximum plasma concentration (Cmax) was 675 Correspondence to:
Dr. M. Meyer
Revotar Biopharmaceuticals AG
Neuendorfstra
Email: m.meyer@revotar-ag.de
Drug Utilization
What do primary care patients think about generic drugs?
Abstract
W. Himmel, A. Simmenroth-Nayda, W. Niebling, T. Ledig, R.-D. Jansen, M.M. Kochen, C.H. Gleiter and E. Hummers-Pradier
1Department of General Practice, University of G
Objective: To examine the attitude of patients towards generic drugs and prescriptions containing generic drugs as an alternative to brand-name products, with a special focus on information on patients attitude to generic drugs provided by their general practitioners (GPs). Methods: A total of 804 patients in 31 general practices were surveyed using a self-questionnaire. The influence of age, sex, education, disease, knowledge of generic drugs, experience with generic substitution and information provided by the GP on patient attitudes towards generic drugs and substitutions were examined. Results: Nearly two thirds of the patients (509/804) stated that they knew of the difference between brand-name drugs and generics; of these, one third were not satisfied with the information given by their GPs and 37% of patients expressed general skepticism towards generic drugs because of their lower price. This attitude was more frequent among those who felt that generic prescribing was ?invented? to solve the financial crisis in the German health insurance system at their expense (odds ratio (OR): 6.2; 95% confidence interval: 4.0 ? 9.8) and those who had not been confronted personally with a generic substitution (OR: 1.8; 1.3 ? 3.0). Patients who had been skeptical when first confronted with a generic substitution were more frequently among those who considered inexpensive drugs to be inferior (OR: 4.5; 2.0 ? 10.4) and they were frequently not satisfied with the information on substitution provided by their GP (OR: 2.7; 1.2 ? 5.9). Conclusion: GPs are in an ideal position to inform their patients adequately about the equivalence of brand-name and generic drugs. However, the patient view that inexpensive drugs must be inferior may be difficult to rectify in the short term.Correspondence to:
PD Dr. W. Himmel
Department of General Practice
University of G
Email: whimmel@gwdg.de
Case Report
Acute renal failure associated with an accidental overdose of colchicine
Abstract
J. Borr
1Pharmacy Service, and 2Nephrology Section, Hospital General Universitario de Elche, Spain
Case summary: A 47-year-old man with a history of polyarticular gout was admitted to the nephrology service because of severe renal insufficiency (creatinine 6.25 mg/dl). Three days before admission he had a pain crisis in his knees and ankles and self-administered 20 Correspondence to:
Dr. J. Borr
Email: jborrasb@sefh.es
Bioavailability Section
The bioequivalence of highly variable drugs and drug products
Abstract
K.K. Midha, M.J. Rawson and J.W. Hubbard
1PharmaLytics Inc., Drug Metabolism, Drug Disposition Institute, 2College of Pharmacy and Nutrition, and 3College of Medicine, University of Saskatchewan, Saskatoon SK, Canada
'Highly variable drugs' have been defined as those drugs for which the within-subject variability (WSV) equals or exceeds 30% of the maximum concentration (Cmax) and/or the area under the concentration versus time curve (AUC). Despite the fact that highly variable drugs are generally safe with flat dose response curves, the bioequivalence of their formulations is a problem because the high variability means that large numbers of subjects are required to give adequate statistical power. Highly variable drug products are poor quality formulations where high within-formulation variability (e.g. tablet to tablet variability) poses a problem rather than high innate WSV of the drug itself. A further problem caused by high variability is that a subset of the population may respond differently to the two formulations producing a significant subject x formulation interaction. Practical examples are shown using replicate designs. The methods proposed to deal with the problems posed by highly variable drugs include: (i) Drug regulatory jurisdictions states that the 90% confidence interval (90% CI) around the test to reference geometric mean ratio (GMR) is required to fit with bioequivalence acceptance limits of 0.8 ? 1.25 for both Cmax and AUC. The WSV for single point estimation of Cmax is often greater than that for AUC. One strategy therefore is not to require a 90% CI for Cmax of drugs that do not exhibit a toxicity associated with Cmax and merely require the GMR to fall within the acceptance limits. (ii) To arbitrarily broaden the bioequivalence acceptance limits. For example, to permit a sponsor to justify the use of wider limits e.g the 90% CI around the GMR of Cmax values might be required to fit within acceptance limits of 0.75 ? 1.33 or even 0.70 ? 1.42. (iii) A more systematic approach would be to broaden the acceptance limits by scaling to either the residual variance from a 2-period design or to the WSV of the reference product in a replicate design. Subsequent evaluations of scaling procedures have demonstrated that smaller numbers of subjects are required for bioequivalence studies on formulations of highly variable drugs. A disadvantage of scaling is that the method is less sensitive to differences between the means compared with unscaled treatment, such that the GMR may prove to be unacceptably low or high. This possibility has let to a suggestion that the GMR must fall within acceptance limits of 0.8 ? 1.25 in scaled treatments. (iv) A similar method is to scale the metric rather than the acceptance limits. This method was proposed by the United States' Food and Drug Administration in the context of Individual bioequivalence, but may also be applied (v) to average bioequivalence. (vi) To carry out bioequivalence studies at steady state whenever a multiple dose regimen is ethically acceptable for healthy volunteers. This solution is based on the observation that high variability in a single dose study tends to be dampened at steady state, thus increasing statistical power. Drug regulators have not favored this approach on the grounds that bioequivalence testing should be based on the most discriminating test possible. (vii) Finally the use of metabolite data has been proposed since in many (but by no means all) cases, metabolite is less highly variable than that of the parent drug. This subject remains controversial except when the administered substance is a prodrug which converted by metabolism into the active drug.Correspondence to:
J.W. Hubbart
PharmaLytics Inc.
Drug Metabolism
Drug Disposition Institute
University of Saskatchewan
Saskatoon, SK, S7N 3R2Canada
Email: hubbard@pharmalystics.ca
Bioavailability Section
Comparative bioavailability study of cefixime (equivalent to 100 mg/5 ml) suspension (Winex vs Suprax) in healthy male volunteers
Abstract
Y.A. Asiri, M.S. Al-Said, K.I. Al-Khamis, E.M. Niazy, Y.M. El-Sayed, K.A. Al-Rashood, M.J. Al-Yamani, I.A. Alsarra and S.A. Al-Balla
1College of Pharmacy, and 2Department of Medicine, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
This investigation was carried out to evaluate the bioavailability of a new suspension formulation of cefixime (100 mg/5 ml), Winex, relative to the reference product, Suprax (100 mg/5 ml) suspension. The bioavailability study was carried out in 24 healthy male volunteers who received a single oral dose (200 mg) of the test (A) and the reference (B) products on 2 treatment days after an overnight fast of at least 10 hours. The treatment periods were separated by a one-week washout period. A randomized, balanced two-way crossover design was used. After dosing, serial blood samples were collected over a period of 16 hours. Plasma concentrations of cefixime were analyzed using a sensitive high-performance liquid chromatographic assay. The pharmacokinetic parameters for cefixime were determined using standard non-compartmental method. The parameters AUC0-t, AUC0-Correspondence to:
Y.A. Asiri, PhD
Department of Clinical Pharmacy
College of Pharmacy
King Saud University
P. O. Box 2457
Riyadh 11451, Saudi Arabia
Email: yasiri07@ksu.edu.sa
Book Review
Good practice of clinical drug trials
Book Review
Erratum
