Volume 49, No. 6/2011(June)
|
 Int. Journal of Clinical Pharmacology and Therapeutics
The online-version will be updated before the print-version of this Journal is published. Upon request we will send the password and user name by e-mail. The online-service is only available for subscribers of the print-version, if proof of purchase is submitted.
The use of the online-version will be charged with an extra fee (additional to the subscription of the print-version).
The service can be used until December 31st of the year of subscription.
|
| Full Issue Price: 30.00$ |
 |
Original Research
Metabolism and excretion of a novel p38 MAP kinase inhibitor pamapimod in healthy male subjects
X. Zhang, S. Fettner, E. Winter, M. Masjedizadeh and G. Hisoire
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (345-352)
Metabolism and excretion of a novel p38 MAP kinase inhibitor pamapimod in healthy male subjects
X. Zhang, S. Fettner, E. Winter, M. Masjedizadeh and G. Hisoire
Hoffmann-La Roche Inc., Nutley, NJ, USA
Objective: This study investigated the pharmacokinetics, excretion, and metabolism of pamapimod following a single oral dose in healthy male subjects. Materials: Nonradio-labeled pamapimod was supplied as bulk powder, [14C]-labeled pamapimod was supplied as ethanol solution. Pamapimod, metabolic synthetic standards, and the internal standard were supplied by Roche. Methods: This was an open-label, singledose mass balance study. Healthy male subjects received a single oral dose of 300 mg [14C]-labeled pamapimod. Quantification of pamapimod and metabolites was determined by a validated liquid chromatography/tandem mass spectrometry method (LC/MS/ MS). Urine, blood, and feces were collected for metabolic profiling and radioactivity analysis. Profiling was done using high performance liquid chromatography (HPLC)/ LC/MS/MS. Radioactivity determination was by liquid scintillation counting. Results: Six subjects completed the study. Mean Cmax was 4,120 ng/ml at tmax of 2.8 h, and mean AUCinf was 19,800 ng·h/ml. The t1/2 of pamapimod was 7.2 h. Mean drug recovery was 100 ± 2% by 120 h, of which 76.5% was recovered in urine and 23.9% in feces. Unchanged pamapimod accounted for 15.3% excreta, indicating metabolism is the major elimination pathway. Five metabolites were identified in plasma, urine, and feces. In urine, 41.1% of the dose was excreted as carboxylate metabolite (RO4498496), 19.2% as lactol metabolite (RO4493992), and 12.5% as pamapimod. In feces, 18.5% was excreted as RO4498496, 2.8% as pamapimod. Conclusions: The majority of dose was renally cleared. Urinary and fecal metabolites accounted for > 80% radioactivity. These results indicate hepatic metabolism followed by renal excretion is the major elimination pathway of pamapimod.Correspondence to:
X. Zhang, PhD
Department of Clinical Pharmacology
Hoffmann-La Roche Inc.
340 Kingsland Street
Nutley, NJ 07110, USA
Email: amy.zhang@roche.com
Original Research
The influence of propiverine hydrochloride on cardiac repolarization in healthy women and cardiac male patients
F. Donath, M. Braeter and C. Feustel
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (353-365)
The influence of propiverine hydrochloride on cardiac repolarization in healthy women and cardiac male patients
F. Donath1, M. Braeter2 and C. Feustel2
1SocraTec R & D GmbH, Erfurt, and 2APOGEPHA Arzneimittel GmbH, Dresden,
Germany
Objective: Two comprehensively designed mono-centric ECG studies were performed to investigate the influence of propiverine hydrochloride and its main metabolite propiverine-N-oxide on cardiac function with regard to QTc prolongation, QTc dispersion and T-wave shape. Methods: The first study was conducted on 24 healthy females, followed by a second study on 24 male patients with coronary heart disease (CHD) and a pathological Pardee-Q-wave in the ECG. Both studies were placebo-controlled and compared the effects of single (30 mg s.i.d.) and multiple dosing (15 mg t.i.d.) of propiverine hydrochloride in a crossover design over 6 and 13 days, respectively. In CHD patients, the ECG was recorded under standardized exercise stress conditions. Results: An effect of propiverine on cardiac safety in healthy women and male patients with CHD could not be determined by the evaluation of QTc intervals derived from ECG under the following conditions: (1) single dosage; (2) steady-state and elevated dosage; (3) healthy female volunteers and male CHD patients; (4) resting and stress conditions in CHD patients. Moreover, other ECG parameters like QT dispersion, T-wave shape, and U-wave occurrence were not affected by propiverine compared to placebo after single or repeated dosing to reach steady-state conditions. Conclusion: These results reflect and confirm preclinical data as well as clinical observations on hundreds of volunteers and numberless patients suffering from overactive bladder syndrome and neurogenic detrusor overactivity who were treated with propiverine hydrochloride over nearly three decades in Europe and Japan.Correspondence to:
Dr. C. Feustel
APOGEPHA Arzneimittel GmbH
Clinical Research & Development
Kyffhäuserstraße 27
01309 Dresden, Germany
Email: cfeustel@apogepha.de
Original Research
Effects of bovine milk ingestion on urinary excretion of oxypurinol and uric acid
M. Kurajoh, T. Ka, C. Okuda, A. Yamamoto, Z. Tsutsumi, H. Koyama, Y. Moriwaki and T. Yamamoto
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (366-370)
Effects of bovine milk ingestion on urinary excretion of oxypurinol and uric acid
M. Kurajoh, T. Ka, C. Okuda, A. Yamamoto, Z. Tsutsumi, H. Koyama, Y. Moriwaki and T. Yamamoto
Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
Objective: Although allopurinol is a xanthine oxidase inhibitor, its overall effect may be due to the action of oxypurinol, a metabolite of allopurinol and another xanthine oxidase inhibitor, since the biological half-life of oxypurinol is longer than that of allopurinol. Oxypurinol shares a renal transport pathway with uric acid and ingestion of bovine milk increases the urinary excretion of uric acid. Therefore, we investigated whether its ingestion promotes the urinary excretion of oxypurinol. Subjects/methods: Bovine milk (15 ml/kg body weight) was administered to 6 healthy subjects who took allopurinol (300 mg) 12 h prior to ingestion. In addition, a control experiment was performed with the same subjects using the same protocol, except for the ingestion of water instead of bovine milk. Blood and urine samples were collected before and after bovine and water ingestion. Results: In the bovine milk ingestion experiment, the urinary excretion values of oxypurinol and uric acid were increased by 18% and 38%, respectively, and the fractional excretion values of oxypurinol and uric acid were increased by 20% and 40%, respectively, whereas those did not change in the control experiment. In addition, the concentration of alanine and sum of concentrations of amino acids were increased by 16% and 20%, respectively, in the bovine milk ingestion experiment. Conclusion: These results suggest that bovine milk ingestion promotes the urinary excretion of oxypurinol as well as uric acid by increasing amino acid concentration.Correspondence to:
T. Yamamoto, MD
Division of Endocrinology and Metabolism
Department of Internal Medicine
Hyogo College of Medicine
Mukogawa-cho 1-1
Nishinomiya, Hyogo 663, Japan
Email: tetsuya@hyo-med.ac.jp
Original Research
Population pharmacokinetics of amikacin in a Korean clinical population
S.B. Jang, Y.J. Lee, M.S. Park, Y.G. Song, J.-H. Kim, H.K. Kim, B.S. Ahn and K. Park
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (371-381)
Population pharmacokinetics of amikacin in a Korean clinical population
S.B. Jang1, Y.J. Lee1, M.S. Park2, Y.G. Song3, J.-H. Kim4, H.K. Kim5, B.S. Ahn5 and K. Park1
1Department of Pharmacology and 2Pediatrics, 3Internal Medicine, 4Laboratory
Medicine in Gangnam Severance Hospital, 5Department of Pharmacy in Gangnam
Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
Objective: This study aimed at investigating the influence of demographic and clinical covariates on the population pharmacokinetics of amikacin in Korean patients from routinely collected therapeutic drug monitoring data. Materials and methods: Pharmacokinetics was studied in 305 adult Korean patients who received amikacin 125 – 1,000 mg once-daily or everyother- day. Peak and trough plasma levels of steady state were measured. Patients were randomized into an index dataset (n = 197) and a validation dataset (n = 108). Covariates were selected in a step-wise approach using NONMEM 7 software. The predictive performance of the model was evaluated by the percent prediction error and the percent coverage of 95% population prediction interval. Results: The covariates significantly influencing amikacin pharmacokinetics were creatinine clearance (p < 0.0001) and ward setting (p = 0.0017) for clearance, and body weight (p < 0.0001) and presence of cholecystitis (p = 0.0135) for volume of distribution. The estimates of pharmacokinetic parameters for a typical individual were 2.82 l/h for clearance, and 18.04 l for volume of distribution. Inter-individual variability (CV%) was 31% for clearance. The mean (SD) of percent prediction errors was 2.1 (26.4)% for peak and –121.5 (460.3)% for trough concentrations. Percent coverage of 95% PPIs for peak and trough concentrations were above 80%. Conclusions: The population pharmacokinetic model developed in this study may be used as a basis for finding optimal amikacin dosing in a Korean patient population without a significant bias. Further studies will be needed to validate these results.Correspondence to:
Kyungsoo Park, MD, PhD
Department of Pharmacology
Yonsei University
College of Medicine
134 Shinchon-dong, Seodaemun-gu,
Seoul 120-752, South Korea
Email: kspark@yuhs.ac
Original Research
Tardive dyskinesia in the treatment of schizophrenia: the findings of the Research on Asian Psychotropic Prescription Pattern (REAP) survey (2001 – 2009)
Y.-T. Xiang, C.-Y. Wang, T.-M. Si, E.H.M. Lee, Y.-L. He, G.S. Ungvari, H.F.K. Chiu, S.-Y. Yang, M.-Y. Chong, C.-H. Tan, E.-H. Kua, S. Fujii, K. Sim, K.H. Yong, J.K. Trivedi, E.-K. Chung, P. Udomratn, K.-Y. Chee, N. Sartorius and N. Shinfuku
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (382-387)
Tardive dyskinesia in the treatment of schizophrenia: the findings of the Research on Asian Psychotropic Prescription Pattern (REAP) survey (2001 – 2009)
Y.-T. Xiang1,2, C.-Y. Wang2, T.-M. Si3, E.H.M. Lee1, Y.-L. He4, G.S. Ungvari5, H.F.K. Chiu1, S.-Y. Yang6, M.-Y. Chong7, C.-H. Tan8, E.-H. Kua8, S. Fujii9, K. Sim10, K.H. Yong10, J.K. Trivedi11, E.-K. Chung12, P. Udomratn13, K.-Y. Chee14, N. Sartorius15 an
1Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, 2Beijing
Anding Hospital, Capital Medical University, 3Institute of Mental Health, Peking University,
Beijing, 4Shanghai Mental Health Center, Shanghai, China, 5The University of
Notre Dame Australia/Marian Center, Perth, Australia, 6Taipei City Hospital, Taipei,
7Kaohsiung Chang Gung Memorial Hospital and School of Medicine, Chang Gung
University, Taiwan, 8National University of Singapore, Singapore, 9Hyogo Institute for
Traumatic Stress (HITS), Kobe, Japan, 10Institute of Mental Health, Bangkok View,
Singapore, 11Department of Psychiatry, C.S.M. Medical University UP (erstwhile K.G.
Medical University) Lucknow, India, 12National Seoul Hospital, Seoul, Korea,
13Prince of Songkla University, Songkhla, Thailand, 14Department of Psychiatry and
Mental Health, Tunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital,
Malaysia, 15University of Geneva, Geneva, Switzerland, and 16School of Human
Sciences, Seinan Gakuin University Fukuoka, Japan
Objective: The aim of the study was to survey the frequency of tardive dyskinesia (TD) in patients with schizophrenia and its demographic and clinical correlates in selected Asian countries. Method: A total of 6,761 hospitalized schizophrenia patients in nine Asian countries and territories were examined from 2001 to 2009. TD was evaluated as “present” or “absent” according to the clinical judgment of experienced psychiatrists. The patients’ socio-demographic and clinical characteristics and the prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. Results: The frequency of TD in the whole sample was 5.0% with wide variations between countries (0 – 14.9%). Multiple logistic regression analysis showed that the following variables were independently associated with TD: study time, study site, older age, male gender, more severe negative and extrapyramidal symptoms and less anticholinergic drugs. Conclusions: A generally low frequency of TD in Asian schizophrenia patients with inter-ethnic variations was recorded. It is unclear whether the low prevalence of TD compared with Western data is real or the result of it being insufficiently recognized.Correspondence to:
Dr. Yu-Tao Xiang
Department of Psychiatry
Chinese University of Hong Kong
Ground Floor, Multicentre
Tai Po Hospital
Tai Po, N.T., Hong Kong
Email: xyutly@gmail.com
Original Research
Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects
N. McCracken, G. Lahu and T.D. Bethke
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (388-396)
Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects
N. McCracken, G. Lahu and T.D. Bethke
Nycomed GmbH, Konstanz, Germany
Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved for the treatment of severe COPD. The pharmacological effect is mediated mainly by its active metabolite roflumilast N-oxide. Objective: This doubleblind, 2-period cross-over study was conducted to investigate the potential effects of concomitant roflumilast on pharmacokinetics and pharmacodynamics of warfarin and vice versa. Materials and methods: A total of 24 healthy adults was enrolled into the study. Once-daily oral doses of roflumilast (500 μg) or placebo were given for 12 days, with subjects receiving both treatments one after the other; single oral doses of (R,S)-warfarin (25 mg) were administered on Day –14 and Day 8 of both periods. Warfarin enantiomer concentrations, prothrombin time (PT), and clotting factor activity (Factor VII, only) as well as concentrations of roflumilast and roflumilast N-oxide were measured in plasma. Results: There was no clinically relevant pharmacokinetic or pharmacodynamic interaction between warfarin and roflumilast. Exposure over 120 h (area under the curve, AUC0–120) with “Test” (warfarin plus roflumilast) and “Reference” (warfarin plus placebo) treatment for Factor VII (geometric mean ratio 102.1% (90% confidence interval: 99.7 – 104.7%)) and excess AUC0–120 for PT (99.3% (92.3 – 106.9%)) were unchanged. Conclusions: Pharmacokinetic parameters including maximum plasma concentration (Cmax) and AUC0–∞ of (R)-, (S)-warfarin, roflumilast, and roflumilast N-oxide were unaffected by co-administration.Correspondence to:
Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestr. 4, 78467 Konstanz, Germany
Email: thomas.bethke@nycomed.com
Original Research
The negative impact of rebate contracts on the health care of patients with depression in Germany
K. Kostev, S. Fuchs, C. Bauer and U. May
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (397-402)
The negative impact of rebate contracts on the health care of patients with depression in Germany
K. Kostev1, S. Fuchs2, C. Bauer3 and U. May3
1Center of Excellence Patient Data, IMS Health GmbH & Co. OHG, Frankfurt a. M.,
2Health Economics and Outcomes Research, IMS Health GmbH & Co. OHG,
Nürnberg, and 3Bundesverband der Arzneimittel-Hersteller e.V., Bonn, Germany
Background: Aim of this study was to show the negative consequences of rebate contracts on health care of patients with depression. Negative consequences were defined as therapy withdrawal, increased resource utilization and the frequency of switch-back to initial pharmaceutical product in patients with conversion to a rebate pharmaceutical. Methods: This retrospective analysis was performed combining the information of 3 databases including information about 20 millions patients and 80% of all prescriptions in Germany. The time period of observation started 1 year before the initiation of rebate contracts. Observation time was 2 years. This study included adults (> 18 years) with an antidepressive drug therapy and who had a statutory health insurance with rebate contracts on antidepressive pharmaceuticals. Results: The mean persistence was 329 days for patients, who were switched to a rebate product compared to 365 days for patients who stayed on the initial drug therapy (p < 0.0001). 29.9% of the patients who were converted to a rebate product switched back to the initial antidepressive drug therapy within 1 year. 1,871 additional patients would be hospitalized due to the conversion to a rebate pharmaceutical that caused direct inpatient costs amounting to 19.9 million EUR per year in Germany. Conclusions: Despite the above limitations this analysis presents a clear association between the initiation of rebate contracts and a negative impact on health care of patients with an antidepressive drug therapy.Correspondence to:
Dr. K. Kostev
Center of Excellence Patient Data
IMS Health GmbH & Co. OHG
Darmstädter Landstr. 108
60598 Frankfurt am Main, Germany
Email: kkostev@de.imshealth.com
Case Report
Successful treatment of gallbladder neuroendocrine carcinoma with combined chemo-radiotherapy: A case report and literature review
P.-C. Lin, Y.-C. Lai, J.-I. Lai, S.-Y. Hsu and W.-S. Wang
Abstract
In ter na tional Jour nal of Clin i cal Phar ma col ogy and Ther a peu tics, Vol. 49 – No. 6/2011 (403-408)
Successful treatment of gallbladder neuroendocrine carcinoma with combined chemo-radiotherapy: A case report and literature review
P.-C. Lin1,2, Y.-C. Lai1,2, J.-I. Lai1,2, S.-Y. Hsu3 and W.-S. Wang2,4
1National Yang-Ming University School of Medicine, 2Department of Medicine,
National Yang-Ming University Hospital, 3Kaohsiung Medical University and
4Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan,
Republic of China
Neuroendocrine tu mors (NETs) oc cur in the bronchopulmonary sys tem. Extrapulmonary NETs are rare and are con - sid ered to ac count for 2.5 – 5% of all NETs, with more than 60% of these tu mors oc cur - ring along the gas tro in tes ti nal tract, in clud ing primary NET of the gall blad der. Pri mary NETs of the gall blad der have been clas si fied as carcinoid, neuro endo crine car ci noma or het er o ge neous car ci noma. Cur rently, the main treat ment of neuro endo crine car ci noma re mains sur gery. The role of ra dio ther apy and che mo ther apy is un de fined be cause of the pau city of data. In ad vanced cases, che mo - ther apy has been pre scribed with such ef fec - tive agents as cisplatin, carbo platin, etoposide and paclitaxel. Here we re port a case of a 64-year-old Tai wan ese male pa tient with neuroendocrine car ci noma of the gall bladder who received com bined chemo- radiotherapy (CCRT) with cisplatin, 5- fluor ouracil and leuco vorin (PFL) from June 2009 un til now, and whose dis ease is sta ble. CCRT with PFL may be a pos si ble reg i men for high-grade neuroendocrine carcinoma of the gall bladder.Correspondence to:
P.-C. Lin, MD
Department of Medicine
National Yang-Ming University Hospital
No. 152, Xin-Min Road,
I-lan, 26042 Taiwan
Email: nicklin1103tw@ya hoo.com.tw
Bioavailability Section
Comparative pharmacokinetics and bioequivalence of two tablet formulations of 2 mg risperidone in healthy Thai male volunteers
N. Khorana, S. Maphanta, O. Lohitnavy, A. Srichaiya and J. Sayasathid
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 6/2011 (409-414)
Comparative pharmacokinetics and bioequivalence of two tablet formulations of 2 mg risperidone in healthy Thai male volunteers
N. Khorana1,2, S. Maphanta1,3, O. Lohitnavy1,3, A. Srichaiya1 and J. Sayasathid4
1Bioequivalence Test Center, 2Department of Pharmaceutical Chemistry and Pharmacognosy, 3Department of Pharmaceutical Practice, Faculty of Pharmaceutical Sciences, 4Naresuan University Hospital, Naresuan University, Phitsanulok, Thailand
Background: Risperidone is an atypical antipsychotic drug with potent serotonin and moderate dopamine antagonistic properties. It possesses good bioavailability following oral administration. Risperidone is primarily converted by the cytochrome P450 2D6 (CYP2D6) and 3A4 (CYP3A4) enzymes to 9-hydroxyrisperidone, its active metabolite with equivalent potency to the parent compound. Objective: This study aimed to compare the pharmacokinetics and determine bioequivalence of two risperidone immediate release oral tablets, a test formulation (Risperidone GPO® or “Test”) and a reference formulation (Risperdal® or “Reference”). Method: A single-dose, randomized, fasting, 2-period, 2-sequence, crossover study design with a 2-week washout period was conducted in 23 healthy Thai male volunteers. Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 h following an oral administration of 2 mg risperidone. The plasma concentrations of risperidone and 9-hydroxyrisperidone were determined by using a validated HPLC method. Pharmacokinetic parameters of Test and Reference were obtained by noncompartmental analysis. Results: The 90% confidence intervals for Test/Reference ratios of the pharmacokinetic parameters (Cmax, AUC0–t and AUC0–∞) of both risperidone and its active metabolite (9-hydroxyrisperidone) fell within the acceptable bioequivalence range (80 – 125%) according to ASEAN guideline. Conclusion: The two risperidone formulations are bioequivalent. The test formulation may be used for generic substitution where applicable.Correspondence to:
N. Khorana
Department of Pharmaceutical Chemistry and Pharmacognosy
Faculty of Pharmaceutical Sciences
Naresuan University
Phitsanulok, Thailand 65000
Email: nantakak@nu.ac.th
