Volume 47, No. 6/2009(June)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Biosimilars / Follow-on proteins – a case for Clinical Pharmacology
F. Sörgel
Pharmacotherapy Guidlines for the Aged
Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors – Part D Basic conditions supporting drug treatment. Part E Guidelines group, disclaimer, internet addresses
F.W. Bergert, D. Conrad, K. Ehrenthal, J. Feßler, J. Gross, K. Gundermann, B. Kluthe, W. Lang Heinrich, A. Liesenfeld, P.G. Loew, E. Luther, R. Pchalek, J. Seffrin, A. Sterzing, H.-J. Wolfring and U. Zimmermann
Abstract
F.W. Bergert, D. Conrad, K. Ehrenthal, J. Feßler, J. Gross, K. Gundermann, B. Kluthe, W. Lang Heinrich, A. Liesenfeld, P.G. Loew, E. Luther, R. Pchalek, J. Seffrin, A. Sterzing, H.-J. Wolfring and U. Zimmermann
The family doctor plays a special role in the health system. S/he looks mainly after chronically ill, elderly and multimorbid patients and strives to control the course of disease of these patients with the aid of their own multiple mostly pharmaco-therapies as well as those of other specialists. Evidence-based recommendations that support G.P’s in the therapy of their patients are lacking. Therefore, the Hesse Guidelines Group has put together these guidelines to support family doctor’s in the drug therapy of the aged. General rules for the management of age-associated diseases by family doctors are: Before prescribing medication for the elderly patient the family doctor is required to carry out a thorough check of the patient’s pharmacotherapy including self-medication and drugs prescribed by other doctors. Key questions for family doctors are: Is the therapy causal or symptomatic? Can therapy goals be arranged according to priority in order to avoid unnecessary medication? Which interactions and side effects must be expected? Does the patient understand and accept the prescription? Interface hospital: As a rule, the family doctor is in charge of managing the therapy and takes sole responsibility for the prescriptions after a patient has been discharged from hospital – (including economic and legal aspects). The framework for choosing medication in an out-patient environment differs from that in a hospital. Following-up the progress of therapy: The patient history (questions on previous incompatibilities, additional OTC-drugs taken, drugs prescribed by other doctors), progress checks and close observation of the effects determine the therapeutic approach because at any given time not all possible negative influences on the efficacy of the medication can be known. Elderly patients should always begin drug therapy with a low dose in order to reach the required maintenance dose (and steady-state) and which, as a rule, will be low without over-shooting.
Drug Utilization
Antihypertensive and analgesic/nonsteroidal antiinflammatory drug use by the elderly living in residential homes in Istanbul
C.A. Kaya, E. Kirimli, C. Kalaca and P.C. Unalan
Abstract
C.A. Kaya, E. Kirimli, C. Kalaca and P.C. Unalan
Department of Family Medicine, Marmara University School of Medicine, Istanbul, Turkey
Objective: To assess the usage, knowledge and attitudes of elderly individuals living in residential homes in the Anatolian region of Istanbul, with particular reference to analgesic/nonsteroidal antiinflammatory drugs (NSAIDs) and antihypertensives. Methods: This cross-sectional study was carried out with 247 representative individuals who were >= 65 years old, and were living in residential homes in Istanbul. They scored >= 24 in a Mini Mental Status Examination and were not suffering from speech, understanding or expression disorders, nor was any serious disease included in the study. Each medication that participants held, was recorded at sight. After asking about the dose, frequency, duration, purpose and side effects related with antihypertensives and analgesic/NSAIDs, the individual’s weight, height and blood pressure were measured and activities of daily living and falling status were evaluated. Results: 47% of the participants were male and the mean age was 76 ± 7.2 years. 47% of the participants were using antihypertensives and 45% of them were using analgesic/NSAIDs. 30% of subjects who declared that they had hypertension were not on therapy. There was a statistically significant relationship between NSAID usage and having hypertension (p = 0.013, OR 2.064, 95% CI 1.16 – 3.65). 78 of the antihypertensive and 88% of the analgesic/NSAIDs users explained the purpose of the drug usage properly. However, only 9 and 18% were aware of the effects, respectively. Conclusions: Although these results suggest that regarding the antihypertensive and analgesic/NSAIDs administration, individuals were treated with proper drugs and doses, but a considerable number of old people are not sufficiently aware about their diseases and drugs.Correspondence to:
Dr. A.C. Kaya
Marmara University School of Medicine
Department of Family Medicine
Altunizade, 34662, Uskudar
Istanbul, Turkey
Email: cigdemapaydin@yahoo.com
Pharmacokinetics
Influence of food on the pharmacokinetic profile of fesoterodine
B. Malhotra, R. Sachse and N. Wood
Abstract
B. Malhotra1, R. Sachse2 and N. Wood3
1Pfizer Inc, New York, NY, USA, 2Schwarz BioSciences GmbH, Monheim, Germany, and 3Pfizer Inc, Sandwich, UK
Objective: Fesoterodine is a new, once-daily, oral, antimuscarinic agent indicated for the treatment of overactive bladder. It undergoes rapid and extensive metabolism by plasma esterases to form its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The sustained-release formulation of fesoterodine delivers 5-HMT with linear, dose-proportional pharmacokinetics (PK) suitable for once-daily dosing. This study was designed for the definitive assessment of the effect of food on 5-HMT PK using the commercial formulation of fesoterodine. Methods: In this randomized, open-label, single-dose, 2-way, crossover study, fesoterodine 8 mg was administered orally to healthy subjects in either a fed (after a high-fat, high-calorie breakfast) or fasted state. Blood samples for PK were drawn up to 36 hours after dosing. Primary endpoints for food effect assessment were area under the concentration-versus-time curve up to the last sample (AUC0-tz), and maximum plasma concentration (Cmax) for 5-HMT. Adverse events, vital signs, hematology, clinical chemistry, and electrocardiograms were monitored for safety assessment. Results: A total of 16 healthy male subjects enrolled and completed the study. Mean values of both primary PK parameters of 5-HMT (AUC0-tz and Cmax) were approximately 19% higher after fesoterodine administration in the fed versus the fasted state. The upper limits of the corresponding 90% confidence intervals for the “fed/fasted” ratios of AUC0-tz (104%, 137%) and Cmax (94%, 149%) were not included in the prespecified acceptance range (80%, 125%) for concluding “no food effect.” Secondary PK variables, (i.e. time to maximum plasma concentration terminal elimination half-life and mean residence time), did not differ markedly between the fed and fasted states. Fesoterodine was well tolerated, and adverse events were mild, with no apparent difference in frequency between fed and fasted states. Conclusions: The hypothesis of “no food effect” could not be statistically confirmed; however, only modest increases of approximately 19% were observed for Cmax and AUC0-tz of 5-HMT. This magnitude of PK effects is unlikely to be of clinical relevance based on Phase 2 and 3 clinical experience with fesoterodine, supporting its administration without regard to meals.Correspondence to:
B. Malhotra, PhD, Director
Clinical Sciences
Pfizer Inc
685 3rd Ave
New York, NY 10017, USA
Email: bimal.k.malhotra@pfizer.com
Biosimilars
Biosimilarity of HX575 (human recombinant epoetin alfa) and epoetin beta after multiple subcutaneous administration
F. Sörgel, U. Thyroff-Friesinger, A. Vetter, B. Vens-Cappell and M. Kinzig
Abstract
F. Sörgel1, U. Thyroff-Friesinger2, A. Vetter2, B. Vens-Cappell3 and M. Kinzig1
1IBMP-Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, 2Clinical Research, Hexal AG, Holzkirchen, and 3Scope International, Hamburg, Germany
Objective: To compare the steady-state pharmacokinetics and pharmacodynamics following multiple subcutaneous administration of a new erythropoiesis stimulating agent (HX575, Binocrit®, Sandoz GmbH, Holzkirchen, Germany) with that of epoetin beta (NeoRecormon®, Roche Ltd., Welwyn Garden City, UK). Methods: An open, randomized, parallel group study was conducted in 80 healthy adult males. Subjects were randomized to multiple subcutaneous doses of 100 IU/kg body weight of HX575 or epoetin beta three-times-weekly for 4 weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratios of hematological characteristics were used as surrogate parameters for efficacy evaluation. Results: The pharmacokinetic profiles after multiple doses were similar for both treatments. HX575 was bioequivalent to epoetin beta with respect to the rate and extent of exposure of exogenous epoetin, as indicated by the ratios (90% confidence intervals) of AUCtau (96.1 (86.4 – 106.9)) and Cmax,ss (98.5 (85.2 – 113.9)). The hematological profiles of both treatments were similar as determined from the population mean curves and the AUECHb ratio (90% confidence interval] (99.2 (97.7 – 100.7)), the primary endpoint of this study. Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected at any time. Conclusions: HX575 and epoetin beta were bioequivalent with respect to their steady-state pharmacokinetic profile and pharmacodynamic action. These results support the conclusion that HX575 and epoetin beta will be equally efficacious and may be interchangeable as therapy.Correspondence to:
Prof. F. Sörgel
Department of Research
IBMP-Institute for Biomedical and Pharmaceutical Research
Paul-Ehrlich-Straße 19
90562 Nürnberg-Heroldsberg, Germany
Email: ibmp@osn.de
Adverse Drug Reactions
Clarithromycin-induced mania in a child
T. Fidan and V. Fidan
Abstract
T. Fidan and V. Fidan
Ataturk University, Faculty of Medicine Child Psychiatry, Erzurum, Turkey
Clarithromycin is a macrolide antibiotic widely used in children with respiratory infections. Mania is an extremely rare psychiatric side effect. A pediatric case of typical manic symptoms associated with clarithromycin-use and resembling those in adults is presented. It was notable that the patient had no genetic predisposition.Correspondence to:
T. Fidan
Ataturk University
Faculty of Medicine Child Psychiatry
25240 Erzurum, Turkey
Email: tulincps@hotmail.com
Bioavailability Section
Significance of the biopharmaceutical properties of tramadol sustained-release formulations for chrono-pharmacologically optimized treatment of pain from various sources
A. Warnke, B. Schug, F. Vanderbist and H. Blume
Abstract
A. Warnke1, B. Schug1, F. Vanderbist2 and H. Blume1
1SocraTec R&D GmbH, Oberursel, Germany, and 2Laboratoires SMB SA, Brussels, Belgium
Tramadol is currently one of the most frequently used opioid analgesics in the world. Objective: The objective of this study was to investigate the rate and extent of tramadol bioavailability following evening versus morning intake of an extended-release pellet system designed for once daily administration. Moreover, the suitability of the preparation for chrono-adjusted pharmacotherapy was to be investigated. Methods: 18 male and female volunteers were enrolled in the study and treated with 200 mg tramadol extended-release capsules, which were to be taken in the fasted state between 7:30 and 8:00 a.m. or p.m., respectively. The parent compound and its O-desmethyl-metabolite were analyzed in plasma samples using a LC-MS/MS procedure. Results: Maximum exposure of tramadol (geometric means of Cmax-values) was determined as 289.3 ng/ml after morning and 283.1 ng/ml after evening administration. Extent of tramadol exposure (geometric means of AUC0-48-values) was calculated as 4,802.5 ng × h/ml after morning and 4,767.0 ng × h/ml after evening administration. Also tmax-values were comparable after morning and evening administration (9.00 vs. 9.50 hours). Statistical analyses, based on conventional bioequivalence approach, revealed no evidence of any impact of the time-point of administration on the biopharmaceutical performance of the dosage form investigated here. Conclusions: Bioavailability of the extended-release tramadol capsules for once daily administration is not affected by the time-point of administration. Total and maximum exposure of the product was bioequivalent after intake in the morning and at night. Thus, the time-point of administration may be adjusted to the patient’s needs without any significant change in the in-vivo performance.Correspondence to:
A. Warnke
SocraTec R&D GmbH
Feldbergstraße 27-29
61440 Oberursel, Germany
Email: andre.warnke@socratec-pharma.de
Bioavailability Section
Comparative bioavailability study of two salbutamol tablets in healthy adult volunteers
Z. Chik, R.C. Basu, R. Pendek, T.C. Lee and Z. Mohamed
Abstract
Z. Chik1, R.C. Basu1, R. Pendek2, T.C. Lee3 and Z. Mohamed1
1Department of Pharmacology, 2Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur and 3Info Kinetic Sdn. Bhd., University Science Malaysia, Penang, Malaysia
This study was carried out to compare the rate and extent of absorption of a generic salbutamol in oral dosage form (Brethmol, 4mg) with the proprietary equivalent product (Ventolin®, 4mg), in healthy adult subjects, under fasting conditions. The study was a single dose, randomized, two way crossover study with a four-week washout period. It involved 22 healthy volunteers who received a single dose (4mg) of the test and the reference products after an overnight fast of at least 10 hours. Blood samples were collected at pre-dose and a serial of 14 samples were collected from each of the subject from 1h until 48 h post-dose. Plasma concentrations of salbutamol were analyzed using GCMS method. The mean AUC0-¥ values were 91.26 and 96.45 h.ng/ml for reference and test product, respectively. The mean Cmax values were 12.26 and 12.38 ng/ml and the mean tmax values were 2.80 and 2.33 hours for reference and test product, respectively. Analysis of variance showed that the 90% confidence intervals on the relative difference of the ratio for the AUC0-¥ and the Cmax for the test and reference products were contained within the bioequivalence limit (80 – 125%) (Cmax: 89.8 – 110.5% and AUC0-¥: 91.6 – 121.5%). There was no statistically significant difference for the tmax between the test and reference formulations (p = 0.30). The test formulation was found to be bioequivalent to the reference formulation with regard to AUC0-¥ and Cmax. There was no statistically significant difference in Brethmol and Ventolin® tmax. In conclusion, Brethmol and Ventolin® are bioequivalent in healthy subjects.Correspondence to:
Z. Chik
Department of Pharmacology
Faculty of Medicine
University of Malaya
50603 Kuala Lumpur, Malaysia
Email: zamrichik@ummc.edu.my
