Volume 47, No. 10/2009(October)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Commentary on the contents of this issue
B.G. Woodcock
Original Research
Prevalence of fatal adverse drug reactions in hospitalized patients
A.J. Pardo Cabello*, L.G. González Contreras*, M.V. Manzano Gamero, F.J. Gómez Jiménez and E. Puche Cañas
Abstract
A.J. Pardo Cabello1*, L.G. González Contreras2*, M.V. Manzano Gamero1, F.J. Gómez Jiménez1 and E. Puche Cañas2
1Department of Medicine and 2Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain
Objective: The aims of the present study were to assess the prevalence of fatal adverse drug reactions (FADRs) in a hospitalized population, identify the drugs involved and investigate reported risk factors for these events. Methods: The study population of this retrospective, single-centre case study comprised 289 patients dying between 1 January 2004 and 31 December 2004 and registered in the Cause of Death Register of a teaching hospital. All compiled data were recorded by two observers especially trained to identify and report adverse drug reactions (ADRs). The degree of probability that the ADR led directly to death was determined by using WHO criteria and an adapted version of Naranjo’s score. Results: Among 289 deceased study subjects, 17 (5.9%) were suspected to have died from an ADR. The most common suspected FADRs were gastrointestinal hemorrhages (52.9%), central nervous system hemorrhages (17.6%), cardiac disorders (17.6%), drug-induced myelosuppression (6%) and antimicrobial-related enterocolitis (6%). The drugs most frequently implicated in a FADR were antithrombotic drugs (65%), nonsteroidal anti-inflammatory drugs (NSAIDs) (47%) and corticosteroids (29%). The only risk factors associated with FADRs in this population were multiple-drug therapy and the presence of platelet antiaggregants and NSAIDs, alone or associated. Conclusions: FADRs are an important cause of death in hospitalized patients. Hemorrhages were seen in a majority of the fatal reactions, and antithrombotic agents or NSAIDs were implicated in most of these events.Correspondence to:
Dr. L.G. González Contreras PhD
Department of Pharmacology
Faculty of Medicine
University of Granada
Avda. de Madrid 11, P.C.
18012 Granada, Spain
Email: lggonzal@ugr.es
Original Research
Leukocytoclastic vasculitis associated with insulin aspart in a patient with Type 2 diabetes
S. Marušic, V. Vlahovic-Palcevski and D. Ljubanovic
Abstract
S. Marušic1, V. Vlahovic-Palcevski2 and D. Ljubanovic3
1Department of Clinical Pharmacology, University Hospital Dubrava, Zagreb, 2Department of Clinical Pharmacology, University Hospital Centre Rijeka, University of Rijeka Medical School, Rijeka and 3Department of Pathology, University Hospital Dubrava, Zagreb, Croatia
Objective: To report a case of leukocytoclastic vasculitis associated with insulin aspart therapy. Case summary: A 56-year-old man was admitted to the Department of Endocrinology because of a poorly controlled Type 2 diabetes. In an attempt to reach a tight blood glucose control, an intensive diabetes management consisting of one evening dose of intermediate-acting NPH insulin and three preprandial doses of short-acting insulin aspart was introduced. Two weeks following insulin aspart introduction the patient developed palpable purpura on distal parts of the upper and lower limbs. Four days after the onset of purpura, a skin biopsy was preformed. Histological examination showed vasculitis with perivascular infiltrates of lymphocytes and erythrocyte extravasation. Direct immunofluorescence was negative. On the day the purpuric eruptions appeared, insulin aspart was substituted with regular human insulin. All skin lesions disappeared spontaneously within 8 days. Insulin aspart was not re-administered. Discussion: Other possible causes of vasculitis in this case were excluded by diagnostic tests. The temporal relationship between the insulin aspart administration and the occurrence of purpura, with no further episodes of skin eruptions after discontinuation of the drug, support the hypothesis of an insulin aspart caused vasculitis. Based on the Naranjo’s algorithm, the adverse drug reaction could be considered possible. Conclusion: Clinicians should be aware of the possibility of leukocytoclastic vasculitis occurring during insulin aspart treatment.Correspondence to:
S. Marušic, MD
Department of Clinical Pharmacology
University Hospital Dubrava
Av. Gojka Šuška 6
10000 Zagreb, Croatia
Email: srmarusic@inet.hr
Original Research
The influence of hepatic impairment on the pharmacokinetics of paliperidone
S. Boom, A. Thyssen, H. Crauwels, K.H. Molz, A. Cleton, L. Janssens, K. Talluri, and M. Eerdekens
Abstract
S. Boom1,4, A. Thyssen1, H. Crauwels1,5, K.H. Molz2, A. Cleton1,4, L. Janssens1, K. Talluri3,6 and M. Eerdekens1
1Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium, 2APEX GmbH, München, Germany, 3Johnson & Johnson Pharmaceutical Research & Development, Titusville, USA, 4Current address: Pharma-Plus, Rucphen, The Netherlands, 5Current address: Tibotec-Virco, Mechelen, Belgium and 6Current address: Compass Consulting International, Morrisville, NC, USA
Objectives: This study assessed the impact of hepatic impairment on the pharmacokinetics (PK) of paliperidone and its enantiomers. Methods: A single 1 mg dose of paliperidone immediate-release (IR) was administered to subjects with moderate hepatic impairment (n = 10) and demographically matched individuals with normal hepatic function (n = 10). Results: Plasma protein binding was lower in hepatically impaired subjects resulting in a 27% higher unbound fraction of paliperidone compared with healthy individuals. After correcting for the difference in plasma protein binding, unbound exposures were comparable between groups. All other PK parameters were similar between the two groups. Paliperidone IR was equally well tolerated in both groups. Conclusions: The impact of moderate hepatic impairment on paliperidone PK is not considered clinically relevant as the PK profile of unbound paliperidone is similar for subjects with moderate hepatic impairment and those with normal hepatic function. Dosage adjustments of paliperidone are not required in subjects with mild or moderate hepatic impairment.Correspondence to:
A. Thyssen, PhD
Johnson & Johnson Pharmaceutical Research & Development
A Division of Janssen Pharmaceutica N.V.
Turnhoutseweg 30, 2340 Beerse, Belgium
Email: ATHYSSEN@its.jnj.com
Original Research
Validity and representativeness of the “Disease Analyzer” patient database for use in pharmaco-epidemiological and pharmacoeconomic studies
H. Becher, K. Kostev and D. Schröder-Bernhardi
Abstract
H. Becher1, K. Kostev2 and D. Schröder-Bernhardi2
1Ruprecht-Karls-University, Heidelberg and 2IMS Health, Frankfurt am Main, Germany
Objectives: Patient and health care databases are available in many countries. These are often based on routinely collected diagnosis and prescription data. Various research questions, such as those related to pharmacoepidemiological health services or drug supply, can be evaluated on the basis of these databases. In Germany, the Disease Analyzer patient database is the largest database of its kind. Using various validity criteria, the representativeness of this database is examined with respect to variables relevant to pharmacoepidemiological and pharmacoeconomic studies. Methods: The Disease Analyzer patient database contains data on diagnoses, prescriptions, risk factors (such as smoking and obesity), and laboratory values for approximately 10 million patients from Germany, the UK, France, and Austria. The database also contains data from various groups of specialist physicians as well as from general practitioners and specialists for internal medicine. Data from physicians’ practices in Germany form the basis of this investigation. To check the validity and representativeness of the data, the distributions of several variables are analyzed. These variables refer partly to the physicians’ practices participating in the study and partly to the patients in these practices. The factors observed include prescriptions for generic drugs, the distribution of diagnostic groups among participating physicians’ practices, the distribution of patients according to health insurance fund, the most frequent products, the distribution of package sizes prescribed, and the age structure of patients with various incident cancer diagnoses. These factors were compared with available reference statistics. Results: The sampling methods for the selection of physicians’ practices appear to be appropriate. Prescription statistics for several drugs were very similar to available data from the pharmaceutical prescriptions report (Arzneimittelverordnungsreport). The age structures for given diagnoses in Disease Analyzer also agreed well with those from corresponding disease registries. Additional comparisons were also in good agreement with data from available sources. Conclusion: The analyses carried out in comparison with reference statistics find no indication of lack of representativeness or validity of the Disease Analyzer database. In principle, the database appears suitable for pharmacoepidemiological and pharmacoeconomic studies. Development and maintenance of large pharmacoepidemiological databases is needed for modern health services. Such databases allow assessment of health care quality and rare adverse drug effects.Correspondence to:
Dr. K. Kostev
Center of Excellence Patient Data, Germany
IMS Health GmbH & Co. OHG
Darmstädter Landstraße 108
60598 Frankfurt am Main, Germany
Email: kkostev@de.imshealth.com
Bioavailability Section
Comparative bioavailability of two formulations of sibutramine
A.C. Franco Spínola, S. Almeida, A. Filipe, R. Neves, Z. Abolfathi, M. Yritia and D. Anctil
Abstract
A.C. Franco Spínola1, S. Almeida1,2, A. Filipe1, R. Neves1, Z. Abolfathi3, M. Yritia4 and D. Anctil3
1Medical Department, Grupo Tecnimede, Abrunheira, Sintra, Portugal, 2Department of Pharmacology and Therapeutics, Universidad Autònoma de Barcelona, Spain, 3Anapharm, Québec, Canada, and 4Anapharm Europe S.L., Barcelona, Spain
This study was conducted in order to compare the bioavailability of two capsule formulations containing 15 mg of sibutramine, N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine hydrochloride monohydrate, 84485-00-7 CAS registry number. 62 healthy subjects were enrolled in a single-center, randomized, single-dose, open-label, 2-way crossover study, with a minimum washout period of 14 days. Plasma samples were collected up to 72.0 hours post-dosing. R-sibutramine, S-sibutramine, N-mono-desmethyl-sibutramine (M1) and N-di-desmethyl-sibutramine (M2) levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC/MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment were the area under the concentration-time curve from time zero to time of last non-zero concentration (AUC0-t) and the maximum observed concentration (Cmax). These parameters were determined from sibutramine enantiomers as well from M1 and M2 concentration data using non-compartmental analysis. The 90% confidence intervals obtained by analysis of variance were 89.25 – 122.88% for Cmax, 90.37 – 123.18% for AUC0-t and 91.20 – 122.38% for AUCinf for R-sibutramine and 88.27 – 124.08% for Cmax, 86.15 – 121.78% for AUC0-t and 88.02 – 120.96% for AUCinf for S-sibutramine. These results were all within the range of 80.00 – 125.00% established by regulatory requirements. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.Correspondence to:
A.C. Franco Spínola
Medical Department
Tecnimede S.A.
Zona Industrial da Abrunheira
Rua da Tapada Grande n.º2
Abrunheira, 2710-089 Sintra,
Portugal
Email: dmed.ct@tecnimede.pt
Bioavailability Section
Bioequivalence study of two meloxicam tablet formulations after single-dose administration in healthy Thai male volunteers
P. Tangsucharit, J. Kampan, S. Kanjanawart, D. Gaysonsiri, S. Vannaprasaht, S. Tiamkao, K. Phunikhom, S. Simasathiansophon, P. Puapairoj and W. Tassaneeyakul
Abstract
P. Tangsucharit, J. Kampan, S. Kanjanawart, D. Gaysonsiri, S. Vannaprasaht, S. Tiamkao, K. Phunikhom, S. Simasathiansophon, P. Puapairoj and W. Tassaneeyakul
Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Objectives: To compare the bioavailability of two meloxicam tablet formulations (MEL-OD®, Zydus Cadila Healthcare Limited, India, as a test formulation and Mobic®, Boehringer Ingelheim International GmbH, Germany, as a reference formulation) in healthy Thai male volunteers under fasting condition. Materials and methods: A randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover with a washout period of 2 weeks, was conducted in 26 healthy Thai male volunteers. Blood samples were collected 0, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 24, 36, 48, 72 and 96 h post dose. Plasma concentrations of meloxicam were determined using a validated HPLC method. The pharmacokinetic parameters of meloxicam were determined using a non-compartmental model. Results: The mean Cmax was 1,027.32 ± 251.91 and 1,151.89 ± 282.58 ng/ml while the mean AUC0-t was 34,024.31 ± 11,811.68 and 35,137.66 ± 11,970.47 ng• h/ml for the test and reference formulation, respectively. In addition, the mean AUC0-¥ for test formulation was 37,241.44 ± 14,888.85 ng• h/ml and for the reference formulation was 39,541.04 ± 16,624.64 ng• h/ml. The median tmax for the test and reference formulation was 4.50 (range 2.00 – 12.00) and 4.50 (range 3.00 – 10.00), respectively. The geometric means (90% confidence intervals) of the ratio for the log-transformed pharmacokinetic parameters, Cmax, AUC0-t and AUC0-inf were 0.8919 (82.58 – 96.32%), 0.9697 (89.46 – 105.10%) and 0.9525 (87.68 – 103.47%), respectively. Conclusions: It can be concluded that two meloxicam tablet formulations are bioequivalent both in term of rate and extent of absorption after single-dose administration under fasting condition.Correspondence to:
Dr. W. Tassaneeyakul
Department of Pharmacology
Faculty of Medicine
Khon Kaen University
Khon Kaen 40002, Thailand
Email: wichitt@kku.ac.th
Bioavailability Section
Bioequivalence study of low-dose diclofenac potassium tablet formulations
B. Hinz, A.M. Hug, G. Fotopoulos and M.S. Gold
Abstract
B. Hinz1, A.M. Hug2, G. Fotopoulos3 and M.S. Gold4
1Institute of Toxicology and Pharmacology, University of Rostock, 2Novartis Consumer Health, Munich, Germany, 3Novartis Consumer Health, Nyon, Switzerland, 4Novartis Consumer Health, Parsippany, NJ, USA
Background and aim: Diclofenac is a nonsteroidal antiinflammatory drug with potent analgesic and anti-inflammatory properties. An immediate-release formulation containing a low dose of 12.5 mg diclofenac-potassium (-K) is marketed as over the counter (OTC) medication in most European countries. An immediate-release formulation containing 25 mg diclofenac-K has now also been approved for OTC use. This study assessed the bioequivalence of two immediate-release diclofenac formulations when administered at the same dose. Subjects and methods: A randomized, crossover, open-label study was conducted in 29 healthy volunteers to assess the bioequivalence of single 25 mg dose of diclofenac-K in two formulations: 2 × 12.5 mg as film-coated tablets and 1 × 25 mg as sugar-coated tablet. Blood samples for pharmacokinetic analyses were obtained over 10 hours post administration. Results: Plasma time courses of diclofenac were similar for the tested formulations. Mean AUC¥ was 798 ± 281 ng × h/ml (mean ± SD) for the film-coated and 776 ± 249 ng × h/ml for the sugar-coated formulation, respectively. The 2-sided 90% confidence interval for the mean test/reference ratio of AUC¥ (95.5 – 107.5) fell within the predetermined equivalence range of 80 – 125%. Both formulations were rapidly absorbed; median time to maximal plasma concentration was 35 min in each group. Adverse events (peripheral erythema on the hand, headache, hypoesthesia) reported during the study were of mild severity and were considered as unlikely to be drug-related. Conclusion: The two diclofenac-K immediate release formulations were pharmacokinetically similar. It can be concluded that the new sugar-coated tablet formulation is equivalent to the available film-coated tablet formulation with respect to the extent of diclofenac absorption.Correspondence to:
Dr. B. Hinz
Institute of Toxicology and Pharmacology
University of Rostock
Schillingallee 70
18057 Rostock, Germany
Email: burkhard.hinz@med.uni-rostock.de
