Volume 47, No. 3/2009(March)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Drug Utilization
Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors: Part C Special Pharmacology
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
General practitioners, Association of Statuatory Health Insurance Physicians in Hesse (Kassenärztliche Vereinigung in Hessen (KVH) Frankfurt (Main)), Germany
The part “Special pharmacology of the aged” of this guideline contains recommendations for typical conditions in the family doctors practice: in the January issue 2009 dementia and Morbus Parkinson, in this issue osteoporosis and urinary incontinence and in the next issue rectal incontinence and obstipation.
This issue of the IJCPT contains the third part of the Pharmacotherapy guidelines for the aged by family doctors for family doctors. Part 3: Osteoporosis and urinary incontinence. Osteoporosis is a systematic disease characterized by low bone mass and declining bone structure. Exercise, adequate diet, nicotine abstinence as well as reduction of alcohol consumption may counteract the progression of the disease. Osteoporosis manifests in bone fractures with minimal trauma. Attention must be given to the risk of falling, e.g., by avoiding drugs that increase the risk of falling: e.g., psychotropic agents, analgesic drugs and antiarrhythmic agents. Specific osteoporosis medication e.g. calcium, vitamin D, biphosphonates and SERM (selective estrogen receptor modulators) is evaluated by family doctors according to indication, dosage, contraindications, long-term therapy and nature of any fracture. Duration of therapy is at least 3 – max. 5 years followed by reassessment of indication. There are 3 types of urine incontinence (urge-, stress-, and overflow-incontinence). Another standardization of urinary incontinence follows dysfunctions of the pelvic floor: detrusor muscle-dependent, due to sphincter spasm, prostate gland dependent. Urge incontinence with a dysfunction of the detrusor muscle is the most common type. Mixed types are frequent. Non-drug measures (e.g. pelvic muscle training, bladder training, toilet training are first choice treatments. Drug therapy (estrogen, imipramine) are without proven effect.Correspondence to:
Dr. L. von Ferber, PD; Auf dem Ufer 7, 40593 Düsseldorf, Germany
Email: Liselotte.vonFerber@uni-duesseldorf.de
Clinical Trials
Accuracy assessments of quantitative diagnostic tests for clinical research
Abstract
R. Atiqi1, C. van Iersel1 and T.J. Cleophas1,2,3
1Albert Schweitzer Hospital, Dordrecht Netherlands, 2European College of Pharmaceutical Medicine, Lyon France, 3Department Statistics and Circulation, Boston, MA, USA
Background: Clinical research is impossible without accurate diagnostic tests. The methods for assessing accuracy of quantitative diagnostic tests are not routinely used by the scientific community. Objective and methods: To review the advantages and disadvantages of methods that could be used for that purpose. Using real data examples we review seven possible methods. Results and conclusions: Simple linear regression testing the presence of a significant correlation between the new test data (x-axis data) and the control test data (y-axis data) is not accurate for testing the validity of a novel quantitative diagnostic test. Accurate methods using linear regression include the following. First, from y = a + b x, test the hypothesis that b is statistically significantly larger than zero, than test the hypothesis that b = 1.000 and a = 0.000. Second, if “the b = 1.000 and a = 0.000 hypothesis” cannot be confirmed, then use as criterion for validation a squared correlation-coefficient r2 or intraclass correlation of > 95%, or a relative residual variance of < 5%. If the new test is validated this way, then the predicted control-test-values are calculated from the equation y = a + bx. The above three methods assume uncertainty of the new test data, but not of the control test data. Deming regression, Passing-Bablok regression, paired Student’s t-tests, and Altman-Bland plots assume uncertainty of both the new test and the control test. This is rarely a condition for validation, and carries the risk of unneeded loss of sensitivity of testing. However, if the control test is not the gold standard test and it is decided to account the uncertainty of the control test, then Passing-Bablok regression is the only method that adjusts for non-normal data as frequently observed in practice.Correspondence to:
Prof. T.J. Cleophas, MD, PhD; c/o Dept Medicine, Albert Schweitzer Hospital, Box 444, 3300 AK Dordrecht, Netherlands
Email: a.j.m.cleophas@asz.nl
Adverse Drug Reactions
Drug exposure and perceived adverse drug events reported by liver-transplant patients
Abstract
G. Espinasse1,2, N. Kamar4,5, C. Hurault2, B. Suc4, G. Fourtanier3, J.L. Montastruc1,2, L. Rostaing4,6 and H. Bagheri1,2
1Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, 2Laboratoire de Pharmacologie Médicale et Clinique, Unité de Pharmacoépidémiologie, EA3696, Université Paul Sabatier, Faculté de Médecine Toulouse, 3Service de Chirurgie Générale et Digestive, Centre Hospitalier Universitaire, Hôpital Rangueil, Toulouse, 4Unité de Transplantation d’Organes, Centre Hospitalier Universitaire, Hôpital Rangueil, Toulouse, 5INSERM U858, IFR 31, Toulouse Cedex 9, and 6INSERM U563, IFR 30, Toulouse Cedex, France
Introduction: Posttransplant patient outcome and quality of life are affected by different factors, such as post-graft context, psychological state, and polymedication. Many surveys have been carried out to study immunosuppressant ADRs, and have mainly used a questionnaire completed by patients, but few have asked patients about their drug exposure. The aim of this study is to describe drug exposure and adverse drug events (ADEs) reported by liver-transplant patients (LTP). Methods: This observational, retrospective study assessed questionnaires from LTPs concerning demographic data, drug exposure, and ADEs. Results: 118 LTPs exposed to 5.9 (± 2.8) drugs with immunosuppressive regimens, consisting mainly of tacrolimus (79.3%), cyclosporine (18.1%), or sirolimus (2.6%), were also exposed to antihypertensive drugs (43.2%), protonpump inhibitors (30.5%), statins (28.8%), drugs acting on bile composition (26.3%), and diuretics (19.5%). 1,389 ADEs were reported: 30.1% neurological, 13.4% cutaneous, 12.4% hematological, 11.1% digestive, 10.1% osteomuscular, 6.6% cardiovascular, and 16.3% others. Significantly more ADEs were reported by patients exposed to cyclosporine than those receiving tacrolimus (p < 0.05). Patients with a transplant for < 18 months had more tremors and those with a transplant for > 79 months reported more hirsutism, gingival hypertrophia, and arterial hypertension. Conclusions: This study shows the value of patient-reporting via structured interviews for both drug exposure and ADEs, and the importance of this approach to complement total data collection.Correspondence to:
H. Bagheri, PhD; Service de Pharmacologie Clinique, Faculté de Médecine, 37 Allées Jules-Guesde, 31000 Toulouse, France
Email: bagheri@cict.fr
Adverse Drug Reactions
Ciprofloxacin-related acute severe myalgia necessitating emergency care treatment: a case report and review of the literature
Abstract
S. Eisele1,4, E. Garbe2,3, M. Zeitz1, T. Schneider1 and R. Somasundaram1
1Department of Gastroenterology, Charité Campus Benjamin Franklin, Berlin, 2Department of Clinical Epidemiology, Bremen, Institute for Prevention Research and Social Medicine, University Bremen, 3Department of Clinical Pharmacology, Charité Campus Mitte, Berlin, and 4Department of Gastroenterology, Klinikum Großhadern, University of Munich, Germany
Objective: To report a case of an uncommon and up to date unpublished peracute and overwhelming muscle pain following administration of ciprofloxacin. Case summary: A 58-year-old male developed fulminating musculoskeletal pain associated with third-time exposure to ciprofloxacin administered for treatment of chronic otitis media. Symptoms resolved slowly after intense combined analgetic therapy and cessation of ciprofloxacin therapy. 24 h after ciprofloxacin discontinuation the symptoms had completely disappeared and no more analgetic treatment was needed. Laboratory values, especially muscle enzymes, did not reveal any pathological pattern. The patient’s past medical history highlighted reproducible side effects with both systemic and local administration of ciprofloxacin including milder symptoms of the musculoskeletal system. Discussion: Common side effects of fluoroquinolones include gastrointestinal, central nervous and allergic reactions, but also more uncommon reactions such as tendonitis and rhabdomyolysis. In our case, there had been no signs of rhabdomyolysis. Besides an elevated IgE level no clinical signs of a true anaphylactic reaction associated with release of mast cell mediators had been observed. A pharmacokinetic interaction between ciprofloxacin and the patient’s comedication carbamazepine is unlikely to be the responsible mechanism, since fluoroquinolones inhibit cytochrome P450 isoenzyme CYP1A2 but not CYP3A4 which metabolizes carbamazepine. Conclusion: To our knowledge, this is the first report describing fulminating musculoskeletal pain following administration of ciprofloxacin without any signs of rhabdomyolysis. Physicians should notice that there is a variety of adverse reactions of this usually well-tolerated agent and they should be aware of unusual complaints of their patients who receive fluoroquinolone treatment.Correspondence to:
Prof. Dr. R. Somasundaram; Medizinische Klinik I, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
Email: rajan.somasundaram@charite.de
Pharmacokinetics
In vitro and in vivo pharmacokinetic characteristics of clazosentan, an intravenous endothelin receptor antagonist, in humans
Abstract
P.L.M. van Giersbergen1, A. Treiber2 and J. Dingemanse1
Departments of 1Clinical Pharmacology and 2Preclinical Pharmacokinetics and Metabolism, Actelin Pharmaceuticals Ltd., Allschwil, Switzerland
Objective: In this study, the distribution, metabolism and excretion of the endothelin receptor antagonist clazosentan were investigated. Subjects and methods: 4 healthy male subjects received an intravenous 3-h infusion at a rate of 0.2 mg/kg/h of 14C-labeled clazosentan and blood, urine and feces samples were collected for a period of 8 days. Experiments were performed to investigate the plasma protein binding, the binding to red blood cells and the inhibition potential of cytochrome P450 isoenzymes of clazosentan. Results: Clazosentan was mainly excreted unchanged into feces whereas about 15% of the radioactive dose was recovered in urine. No metabolites representing more than 5% of total radioactivity were identified. No relevant inhibition of the human cytochrome P450 isoenzymes, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4, was observed in vitro at clazosentan concentrations largely exceeding those observed in clinical trials. In human blood, clazosentan was highly bound to plasma proteins and did hardly penetrate into red blood cells. Conclusion: The primary route of excretion of clazosentan was via the feces, mainly as unchanged drug.Correspondence to:
J. Dingemanse, PhD; Actelion Pharmaceuticals Ltd., Gewerbestr. 16, 4123 Allschwil, Switzerland
Email: jasper.dingemanse@actelion.com
Pharmacokinetics
Daptomycin elimination by CVVH in vitro: evaluation of factors influencing sieving and membrane adsorption
Abstract
C.C. Wagner1, I. Steiner2 and M. Zeitlinger1
1Department of Clinical Pharmacology and 2Center for Biomolecular Medicine and Pharmacology Institute of Pharmacology, Medical University of Vienna, Austria
Objective: Knowledge on the elimination of antibiotics by extracorporeal hemofiltration is a prerequisite for appropriate antimicrobial dosing in patients with renal failure. The present study set out to determine the clearance of the novel lipopetide antibiotic daptomycin from human whole blood by continuous venovenous hemofiltration (CVVH) in vitro. In addition, factors influencing daptomycin sieving and membrane adsorption were investigated. Methods: A recirculation model using different solvent media was established and daptomycin was added to the simulated blood circuit at varying concentrations. The concentration of daptomycin over time in the modelled blood compartment and the ultrafiltrate was measured by high performance liquid chromatography (HPLC). Results: Mean Sieving coefficients (SCs) of daptomycin over time were calculated to 0.98 ± 0.05, 0.33 ± 0.02 and 0.40 ± 0.03 at a baseline concentration of 60 µg/ml in Ringer lactate, Ringer lactate containing human albumin and in human whole blood, respectively. SCs of daptomycin in protein-containing media were higher than the free fraction in plasma of approximately 10%. Neither concentration of daptomycin nor addition of a second antibiotic showed significant impact on the SC. Adsorption of daptomycin to synthetic surfaces proved moderate and saturable, resulting in loss of around 20% of the amount initially added to the artificial blood circuit. Conclusion: In our in vitro setting the calculated clearance of daptomycin from whole blood exceeded the physiological clearance described for individuals with normal renal function. Investigation of clearance by CVVH in vivo seems necessary. Until sufficient clinical data are available for patients undergoing CVVH, monitoring of daptomycin concentrations in this population might be recommended in order to avoid sub-therapeutic exposure to daptomycin.Correspondence to:
Prof. M. Zeitlinger; Department of Clinical Pharmacology, Vienna University Hospital, Medical University of Vienna, Währinger Gürtel 18 – 20, 1090 Vienna, Austria
Email: markus.zeitlinger@meduniwien.ac.at
Bioavailability Section
Single-dose randomized, open-label, 2-way crossover bioequivalence study of clopidogrel 75 mg tablet in healthy volunteers under fasting conditions
Abstract
A. Filipe1, S. Almeida1,2, A.C. Franco Spínola1, R. Neves1, M. Tanguay3, C. Jiménez4 and E. Shink3
1Medical Department, Grupo Tecnimede, Abrunheira, Sintra, Portugal, 2Department of Pharmacology and Therapeutics, Universidad Autónoma de Barcelona, and 3Anapharm 2500, Québec, Canada, Anapharm Europe S.L., Barcelona, Spain
Aim: This study aimed to assess the bioequivalence of 2 formulations of 75 mg clopidogrel hydrogen sulphate film-coated tablet, under fasting conditions. Subjects and methods: 64 healthy subjects, age ranging from 19 to 55 years, were enrolled in a single-centre, randomized, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 24 h post dosing. Clopidogrel and clopidogrel carboxylic acid levels were determined by reverse-phase high-performance chromatography coupled to tandem mass spectrometry detection, LC-MS-MS method. Pharmacokinetic parameters used for bioequivalence assessment were the AUClast (area under the concentration-time curve from time zero to time of last observed nonzero concentration) and the Cmax (maximum observed concentration). These parameters were determined from the clopidogrel concentration data using non-compartmental analysis as well for clopidogrel carboxylic acid concentration data. Resuts: The 90% CI (90% confidence intervals), obtained by analysis of variance (ANOVA) were within the predefined ranges (80.00 – 125.00%) for both analytes. Conclusion: Bioequivalence between test and formulations, under fasting conditions, was concluded both in terms of rate and extent of absorption.Correspondence to:
A. Filipe; Medical Department, Grupo Tecnimede,
Zona Industrial da Abrunheira, R. Da Tapada Grande, No. 2 Abrunheira, 2710-089 Sintra, Portugal
Email: dmed.ct@tecnimede.pt
Bioavailability Section
Bioequivalence study of a new oral topotecan formulation, relative to the current topotecan formulation, in patients with advanced solid tumors
Abstract
R.L. Oostendorp1, J. Loftiss2, S. Goel3, D.A. Smith2, M.M. Dar2, P.O. Witteveen4, R.B. Cohen5, L.D. Lewis6, S. Kurian7, A. Patnaik8, H. Rosing9, J.H. Beijnen9,10, E.E. Voest4, H. Burris11 and J.H.M. Schellens1,10
1Department of Medical Oncology, The Netherlands Cancer Institute, The Netherlands, 2GlaxoSmithKline, Research Triangle Park, NC, USA, 3Montefiore Medical Center Bronx, NY, USA, 4Department of Medical Oncology, University Medical Center Utrecht, The Netherlands, 5Fox Chase Cancer Center Philadelphia, PA, USA, 6Dartmouth Medical School and Dartmouth-Hitchcock Medical Center Lebanon, NH, USA, 7Mary Babb Randolph Cancer Center Morgantown, WV, USA, 8Cancer Therapy and Research Center San Antonio, TX, USA, 9Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands, 10Faculty of Science, Department of Pharmaceutical Sciences, Division of Biomedical Analysis, University Utrecht, The Netherlands, and 11Sarah Cannon Research Institute Nashville, TN, USA
Objective: The aims of this study were to investigate the bioequivalence of a new oral topotecan formulation (i.e., proposed commercial formulation) relative to the current oral formulation (formulation used in previous clinical trials), the effect of food on the absorption and disposition of the new oral topotecan and its safety and tolerability in patients with advanced solid tumors. Patients and methods: This was a multi-center, pharmacological Phase I, multiple-dose, randomized, open-label, cross-over bioequivalence study. In the bioequivalence part, 85 patients were randomized to receive either a 4 mg (4 × 1 mg) dose of the new or current formulation on Days 1 or 8. In the food-effect part, 23 patients received a 4 mg (4 × 1 mg) dose of the new formulation in a fasted and fed state. Total topotecan and topotecan lactone were determined and pharmacokinetic data were analyzed by non-compartmental method. Results: Bioequivalence was demonstrated as the 90% confidence intervals of the ratio of the new to current formulation for both the area under the plasma concentration-time curve (AUC) and the maximal drug concentration (Cmax) for topotecan lactone were contained within the 0.8 – 1.25 boundary. The AUC and Cmax were similar in the fed and fasted state whilst food delayed the tmax for topotecan lactone and total topotecan. Safety data were collected on all subjects enrolled (n = 108) and were consistent with observations from previous studies of oral topotecan. All subjects experienced at least one adverse event, the majority of which were graded as mild to moderate in severity. Conclusion: The new oral topotecan formulation demonstrated bioequivalence to the current formulation and demonstrated it can be administered to patients with solid tumors in the fed or fasted state with similar systemic exposure.Correspondence to:
R.L. Oostendorp, MSc; The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Email: r.oostendorp@nki.nl
Bioavailability Section
Comparison of bioavailability of two ubidecarenone products in healthy Korean volunteers
Abstract
E.Y. Kang1, J.W. Choi2, H.S. Gwak1 and I.K. Chun2
1Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, 2College of Pharmacy, Dongduk Women’s University, Seoul, Korea
Objective: This study aimed to evaluate the bioavailability of two pharmaceutical products of ubidecarenone (coenzyme Q10, CoQ10). Materials: Two brands (brand A and brand B) of commercial CoQ10 hard capsules. Methods: Two brands of CoQ10 capsules were administered at 100 mg dose to two groups of healthy volunteers, respectively, and blood samples were withdrawn at predetermined time intervals and assayed by a validated HPLC method with an electrochemical detector. Results and conclusions: Intra- and inter-day precision and inter-day accuracy were acceptable for all quality control samples including the lower limit of quantitation of 50 ng/ml. Recovery of CoQ10 from human plasma was greater than 98.2%. CoQ10 was stable in human plasma under various storage conditions. This method was applied to a pharmacokinetic study after oral administration of CoQ10 hard capsules to healthy volunteers. The intrinsic CoQ10 concentrations were measured for three consecutive days before drug administration, which were ranged between 0.68 and 0.79 µg/ml, and there was no statistically significant difference between groups. In brand A, the plasma concentration after administration of CoQ10 was not higher than the intrinsic level, indicating that no significant drug absorption occurred, whereas considerably higher concentrations were obtained with brand B. The dissolution rates of brand A and B after 3 h were 0.35 ± 0.09 and 1.27 ± 0.16%, respectively. From the adjusted concentration-time curve, the AUC and t1/2 of brand B were calculated to be 11.51 ± 5.76 µg × h/ml and 21.7 h, respectively. A mean Cmax of 0.32 ± 0.1 µg/ml was obtained at 7.9 h. In conclusion, it was found that bioavailability of CoQ10 was significantly different depending on the formulations, and dissolution could be one of the important factors affecting CoQ10 absorption.Correspondence to:
I.K. Chun, PhD; Division of Life and Pharmaceutical Sciences, Ewha Woman’s University, 11-1 Daehyun-Dong Seodaemun-G4, Seoul 120-750, Korea
Email: hsgwak@ewha.ac.kr
Bioavailability Section
Relative bioavailability and pharmacokinetic study of omeprazole 20 mg enteric-coated tablet in healthy Bangladeshi volunteers
Abstract
A. Hasan1, M. Abul Kalam Azad2, M.A. Ullah1, A.H.M. Mahbub Latif3 and A. Hasnat1
1Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, 2Department of Pharmaceutical Technology, Faculty of Pharmacy, and 3Institute of Statistical Research and Training, University of Dhaka, Dhaka, Bangladesh
Objective: Introduction of omeprazole constituted a break through in the management of acid-related gastric disorders. Omeprazole effectively suppresses the gastric acid secretion in the parietal cells of the stomach. It is a widely prescribed proton pump inhibitor in Bangladesh. The increasing number of omeprazole containing products available in the market raises questions of therapeutic equivalence and/or generic substitution which are yet to be conducted on the Bangladeshi population. The aim of the study is to assess the relative bioavailability and pharmacokinetic properties of two oral formulations of 20 mg omeprazole tablet, namely LOSEC® as reference product and Losectil DR as test product using serum data. Materials and methods: The randomized, two-way crossover study was conducted on 24 healthy male subjects in compliance with the Declaration of Helsinki and ICH Guidelines. Subjects were assigned to receive Losectil DR (Test) and LOSEC (Reference) as a single dose of 20 mg tablet under fasting conditions, following a washout period of 1 week. After oral administration, blood samples were collected at various time intervals and analyzed for omeprazole concentrations using a validated HPLC method. The pharmacokinetic parameters were determined by a non-compartmental method. Results: From serum data, the obtained values for test and reference products were 593.05 ± 84.85 and 607.92 ± 67.07 ng/ ml for Cmax; 1756.71 ± 287.29 and 1786.90 ± 280.17 ng-h/ml for AUC0–24; 1889.26 ± 286.46 and 1929.18 ± 284.33 ng-h/ml for AUC0–¥, respectively. No statistically significant differences were observed between two formulations by analyzing different pharmacokinetic parameters in terms of period, sequence and formulation. From the paired t-test, no significant differences between two formulations were observed (p > 0.05). The 90% CIs of Cmax, AUC0–24 and AUC0–¥ were found to be 91.59 – 122.60%, 101.86 – 116.78% and 102.77 – 116.68%, respectively, which are within the FDA accepted limits for bioequivalence (80 – 125%). Conclusion: Finally it can be concluded that both products are bioequivalent in terms of rate and extent of drug absorption and therefore interchangeable.Correspondence to:
Dr. A. Hasnat, PhD; Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka-1000, Bangladesh
Email: ahasnat99@yahoo.com
Erratum
