Volume 48, No. 11/2010(November)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original Research
Microdialysis feasibility investigations with the non-hydrophilic antifungal voriconazole for potential applications in nonclinical and clinical settings
F. Simmel and C. Kloft
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (695-704)
Microdialysis feasibility investigations with the non-hydrophilic antifungal voriconazole for potential applications in nonclinical and clinical settings
F. Simmel and C. Kloft
Department of Clinical Pharmacy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle, Germany
Objective: This study aimed at investigating the feasibility and validity of the microdialysis technique for the non-hydrophilic antifungal voriconazole, in settings for established concentric and new linear catheters. Optimal conditions for application of microdialysis in in vivo studies including steady-state conditions were to be elaborated. Materials and methods: For in vitro microdialysis investigations, a robust and easy-to-handle system was developed permitting standardized physiological-like conditions. Various experiments on the influence of flow-rate (0.4 – 10.0 µl/min), voriconazole concentration (1.0 – 50.0 µg/ml) on relative recovery were performed. Additionally, the mass transfer coefficient r of voriconazole was estimated (WinNonlin™). Results: In vitro microdialysis experiments suggested sufficient voriconazole concentrations in the dialysate for (non-)clinical investigations. The stability of voriconazole was confirmed over 10 h (37 °C). A flow-rate dependency was shown (optimum: 2.0 µl/min) and r was estimated to be 0.09 mm/min and 0.11 mm/min for concentric and linear catheters, respectively. Relative recovery in delivery/recovery experiments was independent of the voriconazole concentration ranging from 96.0% to 97.8%/93.8% to 100.2% (CV 1.7%/ 0.5%) indicating unhampered passage of voriconazole through the catheter. Investigations mimicking steady-state suggested voriconazole concentration of 100 – 200 µg/ml for in vivo catheter calibration solutions. Conclusion: The results demonstrate the feasibility and validity of the microdialysis technique in clinically-mimicked settings despite the higher lipophilicity of voriconazole and support the application of the technique in vivo.Correspondence to:
Prof. Dr. C. Kloft
Department of Clinical Pharmacy
Institute of Pharmacy
Martin-Luther-Universität Halle-Wittenberg
Wolfgang-Langenbeck-Straße 4
06120 Halle, Germany
Email: charlotte.kloft@pharmazie.uni-halle.de
Original Research
Sources and predictors of home-kept prescription drugs
Z. Klemenc-Ketis and J. Kersnik
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (705-707)
Sources and predictors of home-kept prescription drugs
Z. Klemenc-Ketis1,2 and J. Kersnik1,2
1Department of Family Medicine, Medical School, University of Maribor, Maribor, and 2Department of Family Medicine, Medical School, University of Ljubljana, Ljubljana, Slovenia
Objective: To examine the extent of home-kept prescription drugs in the general population and to identify the predictors for a higher number of prescription drugs kept in people’s homes. Methods: The study included a random stratified sample of 1,000 Slovenian inhabitants. Participants answered a self-administered questionnaire regarding sources and contents of their home pharmacies. The main outcome measure was the presence and the number of home-kept prescription drugs. Results: The response rate was 41%. At least one prescription drug in the home pharmacy was kept by 298 (75.4%) of the respondents, average number of prescription drugs was 3.1 ± 3.3. The majority of the respondents (319, 77.8%) bought the drugs for self-medication in pharmacies. Almost a quarter of the respondents obtained them from relatives and friends (82, 20.0%). Multivariate logistic regression analysis showed that a visit to a clinical specialist in the previous year and high blood pressure were independent predictors for the presence of any home-kept prescription drug. Multivariate linear regression analysis also showed that rural and suburban living areas, a visit to a clinical specialist, a need for a home visit by a doctor in the past year, and the presence of diabetes, high blood pressure, asthma or depression are independent predictors for a higher number of home-kept prescription drugs. Conclusion: Doctors have to take into account that their patients keep several prescription drugs in their home pharmacies. These patients are potential providers to their friends and relatives of potentially unsafe drugs for self-medication.Correspondence to:
Z. Klemenc-Ketis
Kersnikova cesta 1
3320 Velenje, Slovenia
Email: zalika.klemenc-ketis@uni-mb.si
Original Research
Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer
M. Ranson, R.H. Wilson, J.M. O’Sullivan, M. Maruoka, A. Yamaguchi, R.A. Cowan, J.P. Logue, H. Tomkinson, N. Tominaga, H. Swaisland, S. Oliver and M. Usami
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (708-717)
Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer
M. Ranson1, R.H. Wilson2, J.M. O’Sullivan2, M. Maruoka3, A. Yamaguchi4, R.A. Cowan1, J.P. Logue1, H. Tomkinson5, N. Tominaga6, H. Swaisland5, S. Oliver5 and M. Usami7
1Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Manchester, 2Center for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK, 3Chiba Cancer Center, Chiba, 4Harasanshin Hospital, Fukuoka, Japan, 5AstraZeneca, Alderley Park, Macclesfield, UK, 6AstraZeneca KK, and 7Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
Objective: To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing. Methods: In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days’ once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days’ once-daily dosing. Results: Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0 – 36.3 ml/min in Japanese patients and 7.8 – 29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9 – 29.1 l in Japanese patients and 9.6 – 23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7 – 18.8 h in Japanese patients and 5.0 – 22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations. Conclusions: There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC.Correspondence to:
Prof. M. Ranson
Department of Medical Oncology
University of Manchester
Christie Hospital NHS Trust
Wilmslow Road, Withington
Manchester, M20 4BX, UK
Email: Malcolm.Ranson@christie.nhs.uk
Original Research
Imaging inflammation in stroke using magnetic resonance imaging
F. Chauveau, T.H. Cho, Y. Berthezène, N. Nighoghossian and M. Wiart
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (718-728)
Imaging inflammation in stroke using magnetic resonance imaging
F. Chauveau1,2, T.H. Cho1,2, Y. Berthezène1,2, N. Nighoghossian1,2 and M. Wiart1
1CNRS, UMR 5220, Inserm, U630, Insa de Lyon, Creatis, Bron, and 2Université de Lyon, Lyon 1, France
Stroke is the third leading cause of death, after myocardial infarction and cancer, and the leading cause of permanent disability in Western countries. Although anti-inflammatory drugs have shown very promising results in preclinical rodent studies, they appeared to be ineffective against stroke in clinical trials. In this context, non-invasive detection of inflammatory cells after brain ischemia could be helpful (i) to select patients who may benefit from anti-inflammatory treatment, and/or (ii) to target an adequate individualized therapeutic time window. Magnetic resonance imaging (MRI) coupled with injection of iron oxide nanoparticles, a contrast agent taken up by macrophages ex vivo and in vivo, appears to be a promising tool for this purpose. This review focuses on the use of this technique to image inflammation in pre-clinical and clinical studies of stroke. Despite current limitations, MRI of inflammation may become an important tool for the investigation of novel ischemic stroke therapeutics targeting inflammation.Correspondence to:
M. Wiart, PhD
Hopital Neuro-cardiologique
Laboratoire Creatis UMR CNRS 5220 - U630 Inserm
Service de Radiologie (B13)
28, avenue du Doyen Lepine
69677 Bron cedex, France
Email: wiart@creatis.univ-lyon1.fr
Original Research
Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes
M. Inada, M. Sato, S. Morita, K. Kitagawa, K. Kawada, A. Mitsuma, M. Sawaki, K. Fujita and Y. Ando
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (729-734)
Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes
M. Inada1, M. Sato1, S. Morita1, K. Kitagawa1, K. Kawada1, A. Mitsuma1, M. Sawaki1, K. Fujita2 and Y. Ando1
1Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, and 2Department of Medical Oncology, Saitama International Medical Center-Comprehensive Cancer Center, Saitama Medical University, Saitama, Japan
Objective: Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. Methods: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and glutathione-S-transferases pi 1 (GSTP1) genes. Results: For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. Conclusions: Our results suggest that ERCC1, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients’ sensitivity to neuropathy.Correspondence to:
M. Inada, MD
Department of Clinical Oncology and Chemotherapy
Nagoya University Hospital
65 Tsurumai-cho, Showa-ku
Nagoya, Aichi 466-8560 Japan
Email: m-inada@med.nagoya-u.ac.jp
Original Research
Co-prescription of gastroprotective agents in patients taking non-selective NSAIDs or COX-2 selective inhibitors: analysis of prescriptions
L. Pasina, A. Nobili, M. Tettamanti, E. Riva, U. Lucca, R. Piccinelli, L. Defendi, L. Perego, S. Lucifora and C. Bulla
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (735-743)
Co-prescription of gastroprotective agents in patients taking non-selective NSAIDs or COX-2 selective inhibitors: analysis of prescriptions
L. Pasina1, A. Nobili1, M. Tettamanti1, E. Riva1, U. Lucca1, R. Piccinelli2, L. Defendi2, L. Perego2, S. Lucifora2 and C. Bulla2
1Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, and 2Local Health Authority, Bergamo, Italy
Objective: To evaluate the prevalence of co-prescription of GPAs (proton pump inhibitors – PPIs and H2-receptor antagonists) and non-selective NSAIDs or COXIBs in patients registered under the local health authority (LHA) of Bergamo, a city in the north of Italy. Methods: A drug utilization analysis was done using the Bergamo prescription Health Services Electronic Database. All patients aged 35 years or older who had received at least one prescription during 2004 for non-selective NSAIDs and/or COXIBs were divided into three groups: occasional, chronic and new users. Results: Among chronic users, 44.8% were treated with non-selective NSAIDs, 11.6% with COXIBs, and 43.6% with both (mixed NSAIDs). For new users, non-selective NSAIDs were prescribed to 82.7%, COXIBs and mixed NSAIDs to 10.8% and 6.5%. PPIs were co-prescribed to 7.1% of COXIB users and 5.8% of non-selective NSAID occasional users. Among chronic users, the figures were 15.6% and 14%. For new users, prescriptions for COXIBs were associated with less use of GPA for patients who received the first and last prescription for NSAIDs and GPAs on the same day, while for patients who became chronic users COXIBs did not reduce the probability of co-prescription of a GPA: the number of co-prescribed medications and antithrombotics or corticosteroids were independent predictors of GPA use. Conclusions: COXIBs seem to be used in patients at high risk of GI toxicity. However, the fear of GI adverse reactions and the uncertain safety profile of COXIBs leads many physicians to boost the gastroprotection by prescribing a PPI.Correspondence to:
L. Pasina, PharmD
Laboratory for Quality Assessment of Geriatric Therapies and Services
Drug Information Service for the Elderly
Istituto di Ricerche Farmacologiche “Mario Negri”
Via Giuseppe La Masa, 19
20156 Milano, Italy
Email: pasina@marionegri.it
Original Research
Pharmacokinetic study of the oral administration of procaterol hydrochloride hydrate 50 µg in healthy adult Japanese men
H. Kobayashi, M. Masuda, E. Kashiyama, N. Koga, Y. Yasuda, T. Shibutani, K. Endo, T. Funaki and T. Miyamoto
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (744-750)
Pharmacokinetic study of the oral administration of procaterol hydrochloride hydrate 50 µg in healthy adult Japanese men
H. Kobayashi1, M. Masuda2, E. Kashiyama3, N. Koga2, Y. Yasuda2, T. Shibutani2, K. Endo2, T. Funaki2 and T. Miyamoto4
1Shinanozaka Clinic, Shinanokai, Medical Corporation, 2Department of Clinical Research and Development, Division of New Product Evaluation and Development, Otsuka Pharmaceutical Co., Ltd., 3Department of Drug Metabolism and Pharmacokinetics, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., and 4Japan Clinical Allergy Research Institute, Tokyo, Japan
Background: The pharmacokinetics of procaterol, a selective β2-adrenergic agonist with a high intrinsic efficacy in man, could not be determined in humans when the drug was launched because of the low therapeutic dose and the low sensitivity of the analytical methods available at the time. However, a recently established analytical method using LC-MS/MS has been refined to enable the determination of the pharmacokinetic profile of procaterol and its metabolites in humans. Methods: Procaterol hydrochloride hydrate 50 µg was administered orally to 8 healthy adult Japanese men. Plasma and urine samples collected from the subjects were analyzed by use of LC-MS/MS for procaterol and its metabolites. Results: Following the oral administration of procaterol hydrochloride hydrate 50 µg, the plasma concentration of procaterol reached a Cmax of 136.4 pg/ml at ~1.44 h post-dose. The mean apparent terminal elimination half-life was ~3.83 h. DM-251 and DM-252, glucuronides of the optical isomers of procaterol, were the main metabolites and both were present in plasma at higher levels than procaterol in the plasma. The 24 h urinary excretion rates of unchanged procaterol, DM-251 and DM-252 were 15.7%, 12.4% and 11.2% of the procaterol administered, respectively. Conclusion: This study describes the pharmacokinetic profiles of procaterol and its metabolites following the oral administration of procaterol hydrochloride hydrate 50 µg. Procaterol and its glucuronides were found at high levels in the plasma and urine.Correspondence to:
N. Koga, MS
Department of Clinical Research and Development
Division of New Product Evaluation and Development
Otsuka Pharmaceutical Co., Ltd.
Shinagawa Grand Central Tower 13F
2-16-4 Konan, Minato-ku, Tokyo, 108-8242 Japan
Email: Kogan@otsuka.jp
Original Research
Effects of probenecid on the pharmacokinetics of mizoribine and co-administration of the two drugs in patients with nephrotic syndrome
Y. Utsunomiya, Y. Hara, H. Ito, H. Okonogi, Y. Miyazaki, Y. Hashimoto and T. Hosoya
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (751-755)
Effects of probenecid on the pharmacokinetics of mizoribine and co-administration of the two drugs in patients with nephrotic syndrome
Y. Utsunomiya1, Y. Hara1, H. Ito1, H. Okonogi1, Y. Miyazaki1, Y. Hashimoto2 and T. Hosoya1
1Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, and 2Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
Probenecid (PRB) is an agent that reduces the systemic level of uric acid, and has the ability to inhibit the renal tubular secretion of agents that are co-administered with it. In this study, we evaluated the effects of PRB co-administered with mizoribine (MZR) on the pharmacokinetics (PK) of MZR in 12 patients with nephrotic syndrome. The elimination rate constant (kel) was used as an indicator of changes in the PK of MZR when the secretion of MZR was inhibited by co-administration of PRB, in order to determine the extent to which MZR was influenced by PRB. In 4 of the 12 patients studied, kel decreased and the biological half-life (t1/2) of MZR was prolonged when co-administered with PRB, in comparison with the values when MZR was used alone, thus revealing that the PK of MZR was influenced by PRB. Co-administration of PRB with MZR appears to be effective in prolonging the biological half-life of MZR and enhancing its effect in patients with nephrotic syndrome, although further studies will be required to determine the optimal dosage of PRB and renoprotective effects.Correspondence to:
Y. Utsunomiya, MD, PhD
Division of Kidney and Hypertension
Department of Internal Medicine
The Jikei University, School of Medicine
3-25-8, Nishi-Shimbashi, Minato-ku
Tokyo, 105-8461 Japan
Email: yutsu@jikei.ac.jp
Original Research
Night-time bioavailability of levodopa/carbidopa/entacapone is higher compared to controlled-release levodopa/carbidopa
M. Kuoppamäki, A. Sauramo, K. Korpela, M. Vahteristo, M. Kailajärvi, T. Lehtinen and J. Ellmén
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (756-760)
Night-time bioavailability of levodopa/carbidopa/entacapone is higher compared to controlled-release levodopa/carbidopa
M. Kuoppamäki1,2, A. Sauramo1, K. Korpela1, M. Vahteristo1, M. Kailajärvi3, T. Lehtinen3 and J. Ellmén1
1Orion Pharma, Espoo/Turku/Kuopio, 2Department of Neurology, University of Turku, and 3Clinical Research Services Turku (CRST), Turku, Finland
Objective: Controlled-release levodopa/carbidopa (CR-LC) is often used to provide prolonged control of night-time motor symptoms in patients with Parkinson’s disease (PD). Levodopa/carbidopa/entacapone (LCE) provides higher bioavailability of levodopa compared with levodopa/carbidopa formulations and has been shown to be effective in PD patients with wearing-off symptoms. The aim of this study was to compare the bioavailability of levodopa after a single evening dose (administered at 10 p.m.) of LCE 200 or CR-LC 200. Methods: This was an open-label, randomized, crossover study in healthy subjects. The main pharmacokinetic (PK) parameters were AUC, Cmax, C6h and t1/2 of levodopa. Results: A single evening dose of LCE 200 was associated with significantly better bioavailability compared with CR-LC 200. In line with increased bioavailability of levodopa, LCE 200 induced more nausea. Conclusions: The results of this study demonstrate that a single bedtime dose of LCE 200 provides higher bioavailability of levodopa compared to CR-LC 200.Correspondence to:
M. Kuoppamäki, MD, PhD
Orion Pharma
P.O. Box 425
20101 Turku, Finland
Email: mikko.kuoppamäki@orionpharma.com
Original Research
Different persistence on initial basal supported oral therapy in Type 2 diabetics is associated with unequal distributions of insulin treatment regimens under real-life conditions in Germany
M. Pfohl, F-W. Dippel, K. Kostev, S. Fuchs and W. Kotowa
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (761-766)
Different persistence on initial basal supported oral therapy in Type 2 diabetics is associated with unequal distributions of insulin treatment regimens under real-life conditions in Germany
M. Pfohl1, F-W. Dippel2, K. Kostev3, S. Fuchs3 and W. Kotowa3
1Evangelisches Bethesda-Johanniter-Klinikum GmbH, Duisburg, 2Sanofi-Aventis Deutschland GmbH, Berlin, and 3IMS HEALTH GmbH and Co. OHG, Frankfurt/Nuremberg, Germany
Objectives: Results from a representative German database and from two German health services research studies revealed an unequal distribution between basal supported oral therapy (BOT) and basal-bolus therapy (ICT) regimens in Type 2 diabetics treated with either insulin glargine (GLA) or human insulin (Neutral Protamine Hagedorn; NPH). This study assesses whether this unequal distribution could be caused by a different persistence on the initial BOT regimen. Methods: A Markov model was developed simulating the transition from BOT to ICT during a treatment course of 10 years. Data on persistence with BOT were obtained from the IMS® Disease Analyzer database. The model cohort consisted of German statutorily insured Type 2 diabetics starting a BOT either with insulin glargine or NPH insulin at a ratio of 1 : 1. Results: The number of Type 2 diabetics who switched from BOT to ICT differed between the two groups: After 2 years, 53% of glargine-treated patients and 31% of NPH-treated patients continued the BOT. After 6.5 years, all NPH-treated patients had switched to ICT. However, complete transition to ICT of glargine-treated patients occurred 1.75 years later. In the first quarter of Year 3, the model simulation resulted in BOT : ICT ratios comparable to those found in the real-world settings for GLA- and NPH-treated patients. Conclusions: The simulation indicates that the persistence on the initial basal supported oral therapy is associated with the resulting BOT : ICT ratio. Therefore, the unequal distribution between BOT and ICT of Type 2 diabetics treated with either insulin glargine or NPH insulin might be caused by different persistence on the initial BOT regimen.Correspondence to:
F.-W. Dippel, MSc
Health Economics and Outcomes Research
Sanofi-Aventis Deutschland GmbH
Potsdamer Straße 8, 10785 Berlin, Germany
Email: franz-werner.dippel@sanofi-aventis.com
Original Research
Factors influencing valproate pharmacokinetics in children and adults
S.M. Jankovic, J.R. Milovanovic and S. Jankovic
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (767-775)
Factors influencing valproate pharmacokinetics in children and adults
S.M. Jankovic, J.R. Milovanovic and S. Jankovic
Pharmacology Department, Medical Faculty, University of Kragujevac, Kragujevac, Serbia
Objective: The aim of the present study was to build population pharmacokinetic models for the clearance of valproate (VPA) in 2 separate populations of Serbian patients with epilepsy, children and adults. Methods: Analysis was performed using 65 and 63 steady-state concentrations of VPA collected from 58 children and 60 adult epileptic patients, respectively. Mean values for total body weight and age were 27.07 ± 13.08 kg and 7.21 ± 3.63 years in the pediatric population, and 69.67 ± 15.60 kg and 33.97 ± 16.41 years in the adult population. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. Results: The derived final models show that VPA clearance increased with total body weight of patients in both populations. However, the carbamazepine comedication was the main determinant of the final model in children whereas phenobarbitone comedication was the most important factor in the adult population. The magnitudes of these effects were +0.159 lh–1 and +0.539 lh–1 for carbamazepine and phenobarbitone, respectively. A significant decrease in interindividual and intraindividual variability was observed in the target populations. The pharmacokinetic models obtained were validated in groups of 15 epileptic patients, each showing good predictive performance of the model. Conclusions: The derived models describe well VPA clearance in terms of characteristics of Serbian pediatric and adult epileptic patients, offering a basis for rational individualization of VPA dosage regimens.Correspondence to:
J. R. Milovanovic, PhD
Pharmacology Department
Medical Faculty
University in Kragujevac
34000 Kragujevac, Serbia
Email: Jasminamilo@yahoo.com
Case Report
Stroke after treatment with bortezomib and dexamethasone in a Chinese patient with extramedullary relapse of multiple myeloma
H.F. Guo, H.L. Su, J.J. Mao, C. Sun, J. Wang and X. Zhou
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 11/2010 (776-778)
Stroke after treatment with bortezomib and dexamethasone in a Chinese patient with extramedullary relapse of multiple myeloma
H.F. Guo, H.L. Su, J.J. Mao, C. Sun, J. Wang and X. Zhou
Department of Hematology, Wuxi People’s Hospital, Nanjing Medical University, Wuxi, P.R. China
Thromboembolic complications commonly occur in patients with multiple myeloma (MM). The risk of such complications may be elevated by the use of immunomodulatory agents such as thalidomide and lenalidomide as initial therapy for MM. However, arterial thrombosis after treatment with bortezomib is rare. Herein we report a case of a 70-year-old Chinese male patient with extramedullary relapse of MM. After treatment with bortezomib and dexamethasone he developed a nonfatal thrombotic stroke. Administration of bortezomib and dexamethasone was then discontinued and he obtained partial remission.Correspondence to:
H.F. Guo, MD, PhD
Department of Hematology
Wuxi People’s Hospital
Nanjing Medical University
299 Qingyang Road 214023, Wuxi, China
Email: guohongf2000@yahoo.com.cn
Book Review
Handbook of Drug-Nutrient Interactions, 2nd Edition
R.W. Lissner and A.M. Waaga-Gasser
Abstract
Handbook of Drug-Nutrient Interactions, 2nd Edition
R.W. Lissner and A.M. Waaga-Gasser
