Volume 45, No. 9/2007(September)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Review
Are women appropriately represented and assessed in clinical trials submitted for marketing authorization? A review of the database of the European Medicines Agency
M. Müllner, S. Vamvakas, M. Rietschel and B.J. van Zwieten-Boot
Abstract
M. Müllner, S. Vamvakas, M. Rietschel and B.J. van Zwieten-Boot
1Austrian Medicines and Medical Devices Agency/AGES PharmMed, Vienna, Austria, 2European Medicines Agency, Pre-Authorization of Medicines for Human Use, Scientific Advice and Orphan Drugs, Canary Wharf, London, UK and 3College Ter Beoordeling van Geneesmiddelen, Den Haag, The Netherlands
Objective: There is concern that patients included in trials do not represent the true patient population and women in particular may selectively be excluded. We looked at trial data submitted to the European Medicines Agency (EMEA) by drug companies to achieve marketing authorization in Europe between 2000 and 2003. Methods: We reviewed the EMEA database and included the main studies for the risk/benefit assessment (pivotal trials) submitted between 2000 and 2003. Results: In pivotal trials submitted to the EMEA there was no, or generally clinically negligible, evidence for gender bias; however, women were underrepresented in hypertension, diabetes and hepatitis B trials, and overrepresented in rheumatoid arthritis and allergic conjunctivitis. Conclusions: In trials submitted for marketing authorization to the EMEA gender bias was not a serious problem.Correspondence to:
Prof. Dr. med. M. Müllner AGES PharmMed, Schnirchgasse 9, 1030 Vienna, Austria
Email: marcus.muellner@ages.at
Therapeutics
Budesonide administered using chlorofluorocarbon and hydrofluoroalkane pressurized metered-dose inhalers: pharmacokinetics, pharmacodynamics and clinical equivalence
D. Singh, A. Tutuncu, I. Lohr, M. Carlholm and T. Polanowski
Abstract
D. Singh, A. Tutuncu, I. Lohr, M. Carlholm and T. Polanowski
1Respiratory Pharmacology, South Manchester University Hospitals Trust, University of Manchester, Manchester, UK, 2SkyePharma AG, Muttenz, Switzerland, 3AstraZeneca R&D, Lund, Sweden
Objective: The traditional chlorofluorocarbon (CFC) propellants used in pressurized metered-dose inhalers (pMDIs) have unacceptable environmental effects and are being replaced by alternatives such as hydrofluoroalkanes (HFAs). However, there is a need to ensure that pMDIs with these novel propellants are as effective and safe as their older counterparts. Materials and methods: Single-dose pharmacokinetic and multiple high-dose Phase I studies in healthy volunteers and randomized, controlled 12-week Phase III clinical trials in children, adolescents and adults with mild-to-moderate asthma have been performed to compare the efficacy and safety of HFA-based budesonide inhaler therapy with the traditional CFC-based pMDI. Results: The pharmacokinetic study in 40 persons showed comparable characteristics of CFC and HFA pMDIs, with good dose-proportionality, at doses of 400, 800 and 1,600 µg. The high-dosage (1,600 µg/day) study in 48 subjects showed both inhaler types to be similar in terms of effects on hypothalamic-pituitary-adrenal axis function over 4 weeks. The pediatric clinical study involved 159 children and showed noninferiority of the HFA pMDI in terms of 12-week change in forced expiratory volume in 1 sec, other spirometric parameters and symptomatic measures. The adolescent/adult study in 321 subjects also showed similarity between the two formulations, in terms of 12-week primary endpoint (changes in morning peak expiratory flow rates) and other lung function and symptom measures. Both formulations were well-tolerated, with no safety issues being identified for the novel HFA inhaler in any study. Conclusion: Budesonide HFA pMDI is pharmacokinetically and clinically comparable to the traditional CFC-based inhaler, with similar safety profile.
Correspondence to:
Dr. D. Singh
Senior Lecturer Respiratory Pharmacology, Manchester University, South Manchester University Hospitals Trust, Manchester, UK
Email: dsingh@meu.org.uk
Therapeutics
Monitoring paracetamol metabolism after single and repeated administration in pediatric patients with neoplastic diseases
S. Koling, G. Hempel, C. Lanvers, J. Boos and G. Würthwein
Abstract
S. Koling, G. Hempel, C. Lanvers, J. Boos and G. Würthwein
1Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, 2Department of Pharmaceutical and Medical Chemistry, University of Münster, 3Coordinating Center for Clinical Trials (KKS), University Hospital Münster, Germany
Introduction: Paracetamol (PCM) is frequently used in pediatric patients with neoplastic disease. It is metabolized mainly by conjugation, but at therapeutic concentrations, a small fraction of the drug undergoes oxidative metabolism via cytochrome P450 forming the hepatotoxic intermediate N-acetyl-p-benzo-quinone-imine (NAPQI) which is usually conjugated with glutathione and excreted as paracetamol mercapturate and paracetamol cysteine. Objective: The aim of this monitoring study was to evaluate PCM metabolism with minimal intervention during routine treatment with single and repeated administration in patients undergoing antineoplastic therapy. Method: A total of 107 urine samples collected 4 – 12 h after PCM administration from 29 children undergoing antineoplastic treatment, and 10 children without antineoplastic treatment were analyzed for PCM, PCM glucuronide (PCM-G), PCM sulfate (PCM-S), PCM mercapturate (PCM-M) and PCM cysteine (PCM-C). Results: The median (range) percentages for metabolites in urine were: a) in children with and without chemotherapy after the first administration: PCM: 0 (0 – 100) and 4 (0 – 11)%, PCM-G: 55 (0 – 88) and 51 (18 – 68)%, PCM-S: 30 (0 – 73) and 32 (22 – 57)%, PCM-(M+C): 13 (0 – 52) and 9 (0 – 24)%, respectively; b) after repeated administration in children with chemotherapy: PCM: 0 (0 – 51)%, PCM-G: 42 (7 – 100)%, PCM-S: 28 (0 – 70)%, PCM-(M+C): 24 (0 – 66)%. Conclusion: The pattern of PCM excretion in children undergoing antineoplastic treatment regimens is highly variable. Repeated administration is associated with a significant increase in the products of oxidative metabolism. This might indicate an increase in metabolism via the hepatotoxic NAPQI.Correspondence to:
Dr. S. Koling Abteilung für Pädiatrische Hämatologie und Onkologie, Universitätskinderklinik Münster, Albert-Schweitzer Straße 33, 48129 Münster, Germany
Email: skoling@uni-muenster.de
Pharmacodynamics
Marked elevation in homocysteine and homocysteine sulfinic acid in the cerebrospinal fluid of lymphoma patients receiving intensive treatment with methotrexate
A. Becker, S. Vezmar, M. Linnebank, H. Pels, U. Bode, U. Schlegel and U. Jaehde
Abstract
A. Becker, S. Vezmar, M. Linnebank, H. Pels, U. Bode, U. Schlegel and U. Jaehde
1Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, 2Department of Neurology, University of Bonn, 3Department of Neurology, Ruhr-Universität Bochum, and 4Children’s Hospital, University of Bonn, Germany
Objective: Interference of methotrexate (MTX) with the metabolism of homocysteine may contribute to MTX neurotoxicity. In this pilot study we measured the concentration of homocysteine and related metabolites in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma undergoing intensive treatment with MTX. Material and methods: CSF samples from lymphoma patients (n = 4) were drawn at the end of high-dose MTX infusions (3 – 5 g/m2/24 h, HDMTX) and one day after intraventricular injections of MTX (3 mg, ICVMTX) or cytarabine (30 mg) and analyzed for homocysteine, cysteine, sulfur-containing excitatory amino acids (cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid and homocysteic acid), S-adenosylmethionine, 5-methyltetrahydrofolate and MTX. The concentration of homocysteine, cysteine and sulfur-containing excitatory amino acids were also measured in the CSF of a reference population not exposed to MTX. The Wilcoxon signed rank-test and the Friedman test were used to compare concentrations of homocysteine and its metabolites at various time-points during chemotherapy. Comparison of patient and control samples were performed using the Mann-Whitney U-test. Allelic variants of homocysteine metabolism previously shown to influence MTX neurotoxicity (MTHFR c.677C>T, MS c.2756A>G and Tc2 c.776C>G) were also analyzed. Results: After application of HD- and ICVMTX, the CSF homocysteine concentrations in the lymphoma patients were markedly elevated and significantly higher than those in the control group (p < 0.05, Mann-Whitney U-test), whereas 5-methyltetrahydrofolate was depleted. A rapid elevation of homocysteine sulfinic acid, a sulfur-containg amino acid which was not detected in the CSF of the control group, was observed. One patient developed confluent white matter brain changes visible using MRI. This patient had the lowest concentration of S-adenosylmethionine in the CSF and carried two risk alleles for MTX neurotoxicity. Conclusions: In this pilot study, MTX administered either intravenously or intraventricularly, induced marked biochemical alterations in the CSF. Whether these changes can be used to predict MTX-induced neurotoxicity at an early stage in treatment needs to be elucidated in larger clinical trials.Correspondence to:
Prof. Dr. U. Jaehde
Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
Email: u.jaehde@uni-bonn.de
Pharmacoeconomics
Cost comparison analysis: pentaerythrithyl tetranitrate (PETN) and isosorbide dinitrate (ISDN) prescribed to diabetic patients in primary care practices in Germany
A. Icks, B. Haastert, W. Rathmann, D. Schröder-Bernhardi and G. Giani
Abstract
A. Icks, B. Haastert, W. Rathmann, D. Schröder-Bernhardi and G. Giani
1Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center at Heinrich Heine University, Düsseldorf, and 2IMS Health, Frankfurt/Main, Germany
Introduction: Both pentaerythrithyltetranitrate (Pentalong, PETN) and isosorbide dinitrate (ISDN) are commonly used in the therapy of ischemic heart disease (IHD). However, little is known about the therapeutic patterns in diabetic patients and no comparative data are available regarding the prescription costs of these two substances. Thus, the aim of this investigation was to compare the costs for PETN and ISDN therapy in diabetic patients in primary care. Material and methods: All continuously treated patients aged >= 40 years with diabetes (antidiabetic agents) and IHD or angina pectoris (ICD codes) and newly started on PETN or ISDN therapy (index date) in the period 2000 – 2005 were selected from a database containing data from 400 practices throughout Germany (Disease Analyzer, IMS Health). Prescriptions costs for PETN and ISDN, as well as costs for cardiovascular comedication, were determined for the period 183 days before and after the index date, and that changes in costs after the index date were calculated. Differences in costs between the two groups were evaluated using multivariate regression, adjusting for age, sex and comorbidity. Patients in Eastern (n = 137, age 71 ± 10 years, 55% male) and Western Germany (n = 212, age 73 ± 9 years, 50% male) were analyzed separately since there is a longer history of PETN use in Eastern Germany. Results: Significantly more patients were treated with PETN in Eastern Germany (61 vs. 11%, p < 0.05). The patient groups treated with PETN and ISDN differed with respect to sex and comorbidity. PETN therapy was more expensive than ISDN therapy in both German regions (adjusted cost differences were 10 and 17 Euro). However, when comedication was taken into account, a smaller cost increase after the index date was observed in the PETN group than in the ISDN group (non-significant cost savings of 43 and 52 Euro after adjustment for Western and Eastern Germany, respectively). Conclusion: PETN therapy tends to produce a saving in costs compared to ISDN therapy in diabetic patients when costs for comedication are taken into account and after adjustment for age and comorbidity. The prescription patterns in Eastern and Western Germany and the patient characteristics of those receiving PETN and ISDN differed, indicating differences in patients selection and prescribing by physicians in the two regions.Correspondence to:
A. Icks, MD, DrPH, MPH German Diabetes Center, Institute of Biometrics and Epidemiology, Auf’m Hennekamp 65, 40225 Düsseldorf, Germany
Email: icks@ddz.uni-duesseldorf.de
Drug Interactions
Drug interactions between tacrolimus and phenytoin in Japanese heart transplant recipients: 2 case reports
K. Wada, M. Takada, T. Ueda, H. Ochi, T. Kotake, H. Morishita, A. Hanatani and T. Nakatani
Abstract
K. Wada, M. Takada, T. Ueda, H. Ochi, T. Kotake, H. Morishita, A. Hanatani and T. Nakatani
Departments of 1Pharmacy and 4Organ Transplantation, National Cardiovascular Center, Osaka, 2Division of Practical Pharmacy, Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, 3Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto, Japan
Objective: The purpose of the study was to demonstrate how the interaction between phenytoin and tacrolimus (FK 506) can be managed clinically and to characterize the change in FK 506 levels after discontinuation of phenytoin in two Japanese heart transplant recipients with different dosing periods of phenytoin. Methods: A drug interaction between phenytoin and FK 506 was investigated in 2 patients. The concentration-dose ratios (CDR: trough blood FK 506 level (ng/ml)/FK 506 dose (mg/day) on the previous day) were calculated as an index of the induction of the CYP3A4 enzyme during and after phenytoin therapy. Results: About 2- to 3-fold dosages of FK 506 were required to maintain the required blood level when phenytoin was used concomitantly in the two cases examined. The FK 506 dose was constant within 21 days after discontinuing phenytoin in Patient 1 who had 36 days of phenytoin therapy. In Patient 2 with 21-day phenytoin therapy, the FK 506 doses and CDR varied for 10 days after discontinuing phenytoin, and expected FK 506 C0 levels were achieved within 11 days. Conclusions: The persistence of CYP induction after discontinuing phenytoin is dependent on the history of administration and, perhaps, on the dosing period in particular.Correspondence to:
Dr. K. Wada Department of Pharmacy, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita-city, Osaka 565-0873, Japan
Email: kwada@hsp.ncvc.go.jp
