Volume 45, No. 1/2007(January)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Molecular Target Therapy
Safety of Phase I clinical trials with monoclonal antibodies in Germany – the regulatory requirements viewed in the aftermath of the TGN1412 disaster
Abstract
B. Liedert, S. Bassus, C. Schneider, U. Kalinke and J. Löwer
Paul-Ehrlich Institute, Federal Agency for Sera and Vaccines, Langen, Germany
This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for preclinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires re-evaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.Correspondence to:
Dr. B. Liedert; Paul-Ehrlich Institute, Federal Agency for Sera and Vaccines, Paul-Ehrlich-Straße 51 – 59, 63225 Langen, Germany
Email: liebe@pei.de
Pharmacodynamics
Effect of locally applied trapidil on norepinephrine- and dinoprost-evoked hand vein constriction in healthy men
Abstract
W. Sziegoleit, K. Dannenberg, P. Presek and E. Thomas
1Section Clinical Pharmacology, Institute of Pharmacology and Toxicology, Martin Luther University Halle-Wittenberg, and 2Rodleben Pharma GmbH, Dessau-Rodleben, Germany
Objective: In this study the effect of locally administered trapidil on human hand veins was examined. Subjects: 10 healthy male volunteers aged 20 – 30 years were included. Method: The dorsal hand vein compliance technique was used. In a cross-over design the influence of locally infused trapidil (mainly 5 – 400 µg/min) on hand veins preconstricted with either norepinephrine (adrenoceptor agonist) or dinoprost (prostaglandin F2a) was investigated. Preconstriction reduced the vein diameter by about 80% with continuous local infusion of individually determined doses of norepinephrine in the range 11 – 1,000 ng/min and dinoprost in the range 90 – 5,600 ng/min. Blood pressure, cardiac function (electrocardiogram) and skin temperature of the hand infused were monitored. Results: Locally applied trapidil produced a dose-dependent dilation of hand veins preconstricted with norepinephrine and dinoprost. The corresponding ED50 values of trapidil did not differ significantly on an intraindividual comparison. Clinically important side effects with the drugs used were not observed. Conclusions: The results indicate that trapidil has a direct dilating action on superficial veins in humans. This effect is apparently achieved without involvement of adrenoceptors or prostanoid receptors in venous smooth muscle.Correspondence to:
Prof. Dr. W. Sziegoleit; Sektion Klinische Pharmakologie, Martin-Luther-Universität, 06097 Halle, Germany
Email: beatrice.buehligen@medizin.uni-halle.de
Therapeutics
Clinical effects of erdosteine in the treatment of acute respiratory tract diseases in children
Abstract
F. Balli, B. Bergamini, P. Calistru, E.P. Ciofu, R. Domenici, G. Doros, D. Dragomir, I. Gherghina, F. Iordachescu, G. Murgoci, D. Orasanu, D. Plesca, A. Vaccaro and R. Assereto
1Department of Gynecology, Obstetrics and Pediatry, University of Modena, Italy, 2Infectious and Tropical Diseases Hospital “Prof. Dr. Victor Babes”, 3Clinical Emergency Hospital for Children “Grigore Alexandrescu”, Bucharest, Romania, 4Pediatric Unit, Hospital “Campo di Marte”, Lucca, Italy, 5III Pediatric Clinic, Faculty of Medicine, University of Medicine and Pharmacy, Timisoara, Romania, 6Clinical Hospital for Children “Prof. Dr. Victor Gomoiu”, Bucharest, 7II Pediatric Clinic, Institute of Mother and Child Protection “Alfred Rusescu”, Bucharest, 8Clinical Emergency Hospital for Children “Marie Sklodowska Curie”, Bucharest, 9National Institute of Pneumology “Marius Nasta”, Bucharest, Romania, 10Edmond Pharma Research Department, Milano, Italy
Erdosteine has positive effects on mucus rheology and transport due to the active metabolite (Metabolite I) which contains a free thiol group. Erdosteine inhibits bacterial adhesiveness and has antioxidant properties. A synergistic effect of erdosteine with various antibiotics has been demonstrated in pharmacological and clinical studies. The present study was multicenter, randomized, double-blind and placebo-controlled. The aims of the study were to compare a combination of erdosteine with amoxicillin against an amoxicillin-placebo combination in pediatric patients with acute lower respiratory tract disease. A total of 158 patients (78 in the erdosteine group and 80 in the placebo group) were treated for 7 ± 2 days. The efficacy parameters were cough (primary), polypnea, rhonchi, rales and body temperature (all measured at baseline, on Day 3 and at the end of treatment). Safety was assessed by strictly monitoring the occurrence of adverse events and using standard laboratory parameters. The results of the intention-to-treat analysis showed that the severity of cough was decreased by 47% at Day 3 in the erdosteine group with a statistically significant difference compared to placebo, the difference was still significant at the final visit. The decrease in the severity of rales was significantly greater at Day 3 in the erdosteine group than in the placebo group. The incidence of polypnea and rhonchi in the two groups showed similar decreases, an improvement mainly due to the antibiotic. No adverse events occurred and no adverse changes in laboratory parameters were observed. It is concluded that the combination of erdosteine and amoxicillin is a safe medication which is clinically superior to that of the antibiotic combined with placebo, especially in regard to the effects on cough.Correspondence to:
R. Assereto, MD; Edmond Pharma Srl, Via G.B. Grassi 15, 20157 Milano, Italy
Email: tecdept@calao.it
Drug Utilization
Treatment of mental health problems in general practice: a survey of psychotropics prescribed and other treatments provided
Abstract
E. van Rijswijk, M. Borghuis, E. van de Lisdonk, F. Zitman and C. van Weel
1Department of General Practice, University Medical Center St. Radboud, Nijmegen, 2Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
Objective: Real-life data on the treatment of patients with mental health problems are important as a reference to evaluate care and benchmarking. This study describes the treatment of mental health problems in general practice as diagnosed by general practitioners (GP). Material and methods: Data on mental health problems were available from structured psychiatric interviews in the general population and data on mental health problems diagnosed by general practitioners. Pharmacological and non-pharmacological treatment data were taken from patients records held electronically in general practices. Results: GPs diagnosed a mental health problem in 13.2% of the 1,756 cases examined and 86% of these patients were treated by the GPs themselves. Of the 16% referrals, the majority were referred within primary care. Nearly all patients with a mental health problem received counseling or advice from their GP. Half of the patients with a medication-related disorder, a (single) mood disorder or an (single) anxiety disorder and all patients with a combined anxiety and depressive disorder received a prescription for psychotropic drugs (antidepressants and/or benzodiazepines). Nearly all patients with a sleep disorder received a prescription for benzodiazepine. In patients with psychosocial problems, 20% received benzodiazepines. Conclusion: The majority of mental health problems, when professionally treated, are treated in primary care. More than half the patients are treated with antidepressants and/or benzodiazepines. Most patients also receive supportive counseling or advice.Correspondence to:
E. van Rijswijk, MD, PhD; Department of General Practice, University Medical Center St. Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Email: H.vanRijswijk@ hag.umcn.nl
Drug Utilization
Prescription of benzodiazepines and antidepressants to outpatients attending a Japanese university hospital
Abstract
M. Nakao, T. Takeuchi and E. Yano
1Department of Hygiene and Public Health, Teikyo University School of Medicine, and 2Division of Psychosomatic Medicine, Teikyo University Hospital, Tokyo, Japan
Objective: Excessive benzodiazepine use is a public health concern from clinical and economical perspectives. Although more benzodiazepines are prescribed in Japan than in any other country, no hospital-based report has documented this phenomenon. Therefore, this study compared the prescription frequency of benzodiazepines with that of selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and other antidepressants in a single Japanese hospital over 1 year. Material: The annual prescription of benzodiazepines was assessed with that of antidepressants using an electronic database of medical records for outpatients at a Japanese tertiary care hospital affiliated with a private university with approximately 600,000 outpatient visits annually. Method: Groups of departments were analyzed separately (i.e. internal medicine, surgery, neurology, psychiatry, and others). The ratio of the number of prescriptions of anxiolytic benzodiazepines to that of SSRI and SNRI was calculated among the department groups and used as one of indicators comparing the prescriptions of benzodiazepines with those of antidepressants. Results: Of 644,444 hospital prescriptions, 6.1% were for anxiolytic benzodiazepines, and 5.8% were for hypnotic benzodiazepines. Regarding antidepressants, 1.6% of prescriptions were for SSRIs/SNRIs, 0.8% were for tricyclic antidepressants, and 1.5% were for other antidepressants. Of the benzodiazepine prescriptions, 26.8% were written by the internal medicine group. The ratio of the number of prescriptions for anxiolytic benzodiazepines to that for SSRI and SNRI was highest in the department of internal medicine (ratio = 13.0), followed by surgery (7.6), neurology (4.8), and psychiatry (2.5). With the department of psychiatry as the reference, the tendency to prescribe an anxiolytic benzodiazepine rather than an SSRI or SNRI was statistically significant in the remaining four department groups, after controlling for the effects of patient age and sex in a multiple logistic regression analysis. Conclusions: Benzodiazepine prescriptions in the Japanese hospital were far more common than prescriptions for antidepressants such as SSRIs and SNRIs, especially in internal medicine. Multi-institutional studies are needed to address this issue in Japanese hospitals, as well as in hospitals in other countries.Correspondence to:
M. Nakao, MD; Department of Hygiene and Public Health, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi, Tokyo 173-8605, Japan
Email: mnakao@med.teikyo-u.ac.jp
Pharmacokinetics
Reboxetine and cytochrome P450 – comparison with paroxetine treatment in humans
Abstract
U.D. Kuhn, M. Kirsch, U. Merke, A.-M. Eberhardt, B. Wenda, I. Maurer, S. Härtter, C. Hiemke, H.-P. Volz and A. Balogh
1Institute of Clinical Pharmacology, 2Institute of Psychology, 3Department of Psychiatry, Friedrich Schiller University, Jena, 4Department of Psychiatry, University Mainz and 5Hospital for Psychiatry and Psychotherapy Schloß Werneck, Werneck, Germany
Objectives: The noradrenaline-selective antidepressant reboxetine in vitro is a weak inhibitor of both cytochrome P450 (CYP) 2D6 and CYP3A4. Thus, in this study the pharmacokinetics of reboxetine in relation to pharmacogenetics and the effects of reboxetine compared to paroxetine treatment on the CYP2D6 and CYP3A4 phenotype were analyzed in healthy control subjects. Methods: Healthy male volunteers were treated with either 6 mg reboxetine (n = 26) or 30 mg paroxetine (n = 25). On Days 10/11 of treatment, serum concentrations of the antidepressants were measured and pharmacokinetic parameters calculated. Volunteers were phenotyped at the end of treatment and after at least 3 weeks washout (true phenotype) using 30 mg dextromethorphan (DM) hydrobromide given orally and measuring DM and metabolites in serum 2 h after intake. CYP2D6 and CYP2C19 genotypes were determined in parallel. Results and conclusion: Reboxetine serum concentrations showed no correlation with the CYP2D6 genotype and the CYP2D6 phenotype, whereas paroxetine concentrations showed some dependence on CYP2D6. In contrast to in vitro investigations, indicating a major role of CYP3A4 in reboxetine metabolism, reboxetine concentrations in serum showed no correlation with the respective DM metabolic ratios. There was also no correlation between paroxetine concentrations and the CYP3A4 phenotype data. The CYP2C19 genotype (only heterozygosity) had no influence on reboxetine and paroxetine pharmacokinetics. There were only minor changes in the DM metabolite pattern on treatment with reboxetine and no evidence of enzyme inhibition was obtained. In contrast and as expected, paroxetine strongly inhibited CYP2D6. Thus, reboxetine treatment has no effect on the CYP2D6 genotype and no clinically relevant drug interactions involving CYP2D6 are anticipated.Correspondence to:
Dr. U.D. Kuhn; Institute of Clinical Pharmacology, Friedrich Schiller University Jena, Medical Faculty (Universitätsklinikum), Dornburger Straße 159, 07740 Jena, Germany
Email: urs.kuhn@med.uni-jena.de
Pharmacokinetics
Comparison of plasma and saliva concentrations of levetiracetam following administration orally as a tablet and as a solution in healthy adult volunteers
Abstract
R.L. Lins, C. Otoul, F. De Smedt, R. Coupez and A. Stockis
1Stuivenberg Hospital, SGS Clinical Research Unit, Antwerp, and 2UCB S.A., Braine l’Alleud, Belgium
Objective: Concentrations in saliva, as an alternative to concentrations in blood, can be advantageous for the monitoring of antiepileptic agents. This study assesses the relationship between saliva and plasma concentrations of levetiracetam after administration orally as a solution and as a tablet. The possibility that saliva concentrations of the drug are altered by contamination in the buccal cavity was also examined. Methods: 4 healthy male subjects received a single 750 mg oral dose of levetiracetam as a 10% solution and 4 subjects received three 250 mg tablets (750 mg). Levetiracetam concentrations in plasma and saliva were monitored for 24 hours post dose. Results: In subjects receiving the levetiracetam solution, maximum saliva concentrations were observed at the first collection point (15 min) after administration and these were 19 – 74 times higher than corresponding plasma levels. The mean saliva/plasma ratio rapidly decreased thereafter, becoming stable after 4 hours. In subjects receiving tablets, levetiracetam concentration profiles for saliva paralleled the plasma concentration profiles with a fairly constant saliva/plasma concentration ratio throughout the 24-hour sampling period. A significant linear correlation between levetiracetam saliva and plasma concentrations was demonstrated (Pearson r = 0.88; p < 0.001 for tablet (n = 35) and r = 0.87; p < 0.001 for solution at times ³ 4 hours post-dose (n = 20)). The saliva to plasma concentration ratio was 1.11 (95% confidence interval: 0.99 – 1.22) following tablet intake, and 1.55 (95% CI: 1.34 – 1.77) following oral solution (³ 4 hours post dose). Conclusions: Using saliva to monitor therapeutic exposure to levetiracetam is feasible beginning 15 minutes after tablet intake but beginning 4 hours after intake of an oral solution.Correspondence to:
A. Stockis, PhD; UCB S.A., Chemin du Foriest, 1420 Braine l’Alleud, Belgium
Email: armel.stockis@ ucb-group.com
Pharmacokinetics
Impaired clearance of phenacetin in hepatic cirrhosis and fibrosis
Abstract
Z.Q. Qu, X.D. Li, H.L. Liu, P. He, X. Zhang and M.C. Wu
1Eastern Hepatobiliary Surgery Hospital and 2Cancer Institute, Second Military Medical University Shanghai, 3Ninth People’s Hospital Affiliated to School of Medicine, Shanghai Jiaotong University, Shanghai, China
Objective: CYP450 1A2 is constitutively expressed in liver. Phenacetin O-de-ethylation is a marker reaction for CYP450 1A2 activity. In this paper, the metabolism of phenacetin has been studied in patients with chronic hepatitis B or cirrhosis secondary to a hepatitis B virus infection. The possibility of using the phenacetin test in the evaluation of liver function in these subjects has also been tested. Subjects and methods: Phenacetin pharmacokinetics and the recovery of its urinary metabolites were studied in 8 normal subjects, 16 patients with chronic hepatitis B and 12 patients with cirrhosis. The phenacetin test was performed in 18 normal subjects and 52 hepatocellular carcinoma (HCC) patients. The test was repeated in HCC patients after treatment with transcatheter arterial chemoembolization (TACE). Results: Compared with normal controls, phenacetin apparent clearance decreased by 47.0% (p < 0.05) and 78.7% (p < 0.01) in patients with chronic hepatitis B and cirrhosis, respectively. The recovery of phenacetin O-de-ethylated metabolites decreased by 24.6 and 72.4% (p < 0.01). 46 of 52 HCC patients (88.4%) had an abnormal phenacetin test before TACE, where the ratio of plasma total acetaminophen to phenacetin was below the lower limit of the normal control range. The ratio was less than 50% of normal controls in 6 HCC patients who had a deterioration in liver function from Child-Pugh class A to Child-Pugh class B after TACE. Conclusion: The metabolism of phenacetin is impaired in patients with chronic hepatitis B and cirrhosis. The phenacetin test can predict the susceptibility of liver function to TACE in HCC patients.Correspondence to:
Dr. P. He; Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China
Email: heping303@yahoo.com.
PK Modeling
Antacid interaction with new quinolones: dose regimen recommendations based on pharmacokinetic modeling of clinical data for ciprofloxacin, gatifloxacin and norfloxacin and metal cations
Abstract
K. Miyata, H. Ohtani, M. Tsujimoto and Y. Sawada
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Objective: New quinolones (NQs) are widely used to treat various infections. However, concomitant oral administration of metal cations may decrease absorption of NQs and consequently decrease their blood concentration and pharmacological effect. A convenient approach to avoid this interaction is to separate the dosages by a certain interval. In this study, we aimed to develop a novel pharmacokinetic model to describe NQs-metal cation interactions in order to estimate the optimal dosing interval. Methods: Plasma concentration-time profiles of NQs after administration without or with metal cations at various dosing intervals were collected from the literature and analyzed with a pharmacokinetic model incorporating the formation of NQs-metal cations complex. The model was fitted to the reported time profiles of ciprofloxacin (CPFX) plasma concentration after concomitant administration with aluminum hydroxide/magnesium hydroxide antacid (Al/Mg antacid; Maalox, Maalox70) at various dosing intervals to obtain the pharmacokinetic parameters of CPFX. Model analysis was also carried out for gatifloxacin (GFLX) and norfloxacin (NFLX). Results: The developed model could adequately explain the interactions in all the combinations investigated. The model predicted, in the cases of usual doses of CPFX with Maalox, GFLX with Maalox70 and NFLX with sucralfate, that the NQ should be administered 4.5, 4.5 and 3.5 hours after, or 1, 1 and 0.5 hours before the administration of metal cations, respectively, to ensure 90% of control absorption. Conclusions: The developed model can adequately describe the extent of interaction between NQs and metal cations, and should be clinically useful to design dosage regimens to circumvent the interaction.Correspondence to:
Prof. Y. Sawada; Present address: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Email: sawada@ md.f.u-tokyo.ac.jp
