Volume 48, No. 4/2010(April)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original Research
Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration
R. Bellmann, , G. Falkensammer*, C. Seger, S. Weiler, J. Kountchev** and M. Joannidis
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 4/2010 (243-249)
Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration
R. Bellmann1, 2, G. Falkensammer3*, C. Seger3, S. Weiler1, J. Kountchev2** and M. Joannidis2
1Clinical Pharmacokinetics Unit, Laboratory of Inflammation Research, 2Intensive Care Unit, Department of Internal Medicine I, Innsbruck Medical University, 3Central Institute for Medical and Chemical Laboratory Diagnostics, Innsbruck General Hospital, Innsbruck, Austria, *Present address: Krankenhaus der Elisabethinen, Linz, **Present address: Department of Internal Medicine, Kufstein District Hospital, Kufstein, Austria
Pharmacokinetics of teicoplanin (TP) was assessed in critically ill patients on continuous veno-venous hemofiltration (CVVH), in eleven patients, after the first dose and in another four after repeated administration. The TP peak concentration amounted to 55.44 ± 15.90 µg/ml and 81.28 ± 28.55 µg/ml (mean ± SD), the trough concentration 6.4 ± 1.7 µg/ml and 21.3 ± 5.0 µg/ml, the half-life 15.7 ± 5.7 and 35.1 ± 12.3 h, the apparent volume of distribution 0.84 ± 0.22 and 0.48 ± 0.09 l/kg and the TP clearance 39 ± 12 and 11 ± 4 ml/h/kg after the first dose and after repeated administration, respectively. The mean sieving coefficient of TP was 0.15. After a 1,200 mg loading dose, daily maintenance doses of 600 – 1,800 mg were required for achieving trough levels of 15 – 25 µg/ml. Therapeutic drug monitoring is indispensable during CVVH because of a considerable variability of TP pharmacokinetics.Correspondence to:
R. Bellmann, MD
Innsbruck Medical University
Department of Internal Medicine I
Anichstrasse 35
6020 Innsbruck, Austria
Email: romuald.bellmann@i-med.ac.at
Original Research
In-vitro and in-vivo characteristics of a modified-release double-pulse formulation for a water soluble drug
A. Avramoff and A.J. Domb
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 4/2010 (250-258)
In-vitro and in-vivo characteristics of a modified-release double-pulse formulation for a water soluble drug
A. Avramoff and A.J. Domb
Department of Medicinal Chemistry, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
Objective: The aim of the present study was to evaluate the in-vitro dissolution and in-vivo pharmacokinetic profile of a novel two-phase modified-release formulation for diltiazem hydrochloride, as a water-soluble drug. Materials and methods: The delivery system consisted of two tablets inserted into a capsule. Both tablets comprised a coated drug core-matrix. The coating of the first tablet was intended to produce a first phase with a relatively fast release profile, while that of the second tablet included a unique controlling membrane designed to achieve a delayed controlled-release profile. Three different formulations were tested for their dissolution profiles both in water media and in buffer with a pH of 6.8. These formulations were also evaluated for their pharmacokinetic profile in healthy volunteers after single administration of a 240 mg dose. Serial venous blood samples were collected over 36 h post administration to measure diltiazem levels by HPLC. In addition the in-ivo /in-vitro correlation (IVIVC) was calculated for these formulations. Results: The in-vitro characteristics of these formulations demonstrated a controlled release profile in both media but with different characteristics, as in Formulation 3 where faster dissolution profile obtained in water but slower one in pH 6.8 buffer. In-vivo the pharmacokinetic profile of these formulations showed that arabinogalactan containing formulations achieved plasma levels which allow a once daily administration. IVIVC calculation demonstrated that dissolution tested in buffer 6.8 media better correlates with the percent absorbed in-vivo and the best results were achieved with the formulation containing the highest amount of polysaccharide in the coating. Conclusion: It is concluded that the developed formulations achieved a controlled release profile both in-vitro and in-vivo which are suitable for once-daily administration.Correspondence to:
A. Avramoff, MPh
Department of Medicinal Chemistry
School of Pharmacy, Faculty of Medicine
The Hebrew University of Jerusalem
Jerusalem 91120, Israel
Email: avi.avramoff@dexcel.com
Original Research
Pharmacokinetics and the antiplatelet effect of a new clopidogrel formulation, clopidogrel besylate, in healthy subjects
J.-Y. Park, K.-A. Kim, J.-H. Ryu, G.-H. Lee, S.-H. Jeon and J.-S. Kim
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 4/2010 (259-269)
Pharmacokinetics and the antiplatelet effect of a new clopidogrel formulation, clopidogrel besylate, in healthy subjects
J.-Y. Park1, K.-A. Kim1, J.-H. Ryu2, G.-H. Lee2, S.-H. Jeon2 and J.-S. Kim2
1Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine and 2Central Research Institute, Hanlim Pharmaceutical Company, Ltd., Seoul, Korea
Background: Clopidogrel, a thienopyridine derivative, is an inhibitor of platelet aggregation induced by adenosine diphosphate (ADP). We compared the pharmacokinetics and the antiplatelet effect of two clopidogrel formulations (clopidogrel besylate (test) and clopidogrel bisulfate (reference)). Subjects and methods: The study was conducted in 40 healthy subjects in a randomized, open-label, 2-period crossover manner. Each subject received a single loading dose of 150 mg clopidogrel on Day 1 followed by a daily dose of 75 mg clopidogrel from Day 2 to Day 7. After the first dose blood samples for pharmacokinetic analysis of clopidogrel and SR26334 were collected over 24 h. The pharmacodynamic variables, i.e., the inhibition of ADP-induced platelet aggregation, were measured over 264 h. Results: No serious adverse events occurred during the study period. The mean plasma concentration-time profiles of clopidogrel and SR26334 for the two formulations were comparable. The 90% confidence intervals (CIs) for the log-transformed ratios for pharmacokinetic parameters (Cmax and AUC) of SR26334 fell within the predefined pharmacokinetic equivalence range of 80 – 125%. However, the upper limits of 90% CI of Cmax and AUC for clopidogrel exceeded the equivalence range. The two formulations showed similar antiplatelet profiles. The 90% CIs of ΔEmax and ΔAUEC of platelet aggregation inhibition fell within the equivalence range of 80 – 125%. Conclusion: Both clopidogrel formulations were well-tolerated. The study population showed no serious AEs. The test formulation proved pharmacokinetically non-inferior to the reference formulation. The test formulation showed an antiplatelet effect on ADP-induced platelet aggregation similar to the reference formulation. The two formulations were considered pharmacodynamically equivalent in terms of platelet aggregation inhibition.Correspondence to:
J.-Y. Park, MD, PhD
Dept. of Clinical Pharmacology and Toxicology
Anam Hospital, Korea University
College of Medicine
126-1, Anam-dong 5-ga, Sungbuk-gu
Seoul 136-705, Korea
Email: jypark21@korea.ac.kr
Original Research
Change of psychotropic drug prescription for schizophrenia in a psychiatric institution in Beijing, China between 1999 and 2008
F.-R. An, Y.-T. Xiang, C.-Y. Wang, G.-P. Zhang, H.F.K. Chiu, S.S.M. Chan, E.H.M. Lee and G.S. Ungvari
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 4/2010 (270-274)
Change of psychotropic drug prescription for schizophrenia in a psychiatric institution in Beijing, China between 1999 and 2008
F.-R. An1, Y.-T. Xiang1,2, C.-Y. Wang1, G.-P. Zhang1, H.F.K. Chiu2, S.S.M. Chan2, E.H.M. Lee2 and G.S. Ungvari2
1Beijing Anding Hospital, Capital Medical University, Beijing and 2Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China
Background: To date, no study has investigated how prescription patterns change over time in Chinese patients with schizophrenia. This study aimed to determine psychotropic drug prescription patterns and the use of electroconvulsive therapy (ECT) for schizophrenia and their changes over time in a large psychiatric institution in Beijing, China. Methods: The case notes of inpatients with schizophrenia were scrutinized to identify psychotropic drug prescription patterns and the use of ECT on November 10, 1999 and the same calendar day in 2008 and to compare the two surveys. Results: In 1999, 45.1% of inpatients with schizophrenia were on first-generation antipsychotic drugs (FGA), while 52.9% were on second-generation antipsychotic drugs (SGA). In 2008, the percentage of patients on FGAs decreased to 15.1%, while those on SGAs increased to 77.2%. The proportion of schizophrenia patients on mood stabilizers and antidepressants rose from 3.3% and 4.3% in 1999 to 18% and 9.5% by 2008, respectively. Use of ECT grew from 0.5% in 1999 to 5.6% by 2008. The proportion of schizophrenia patients not prescribed antipsychotic drugs changed from 5.6% in 1999 to 13.7% in 2008. Conclusions: The prescription pattern of psychotropic drugs changes considerably over time, even in the same clinical setting. Mental health professionals need to keep up with changes in the prescription patterns of psychotropic drugs in order to serve their patients at the best possible level. The socio-economic reasons for not prescribing antipsychotic drugs to schizophrenia patients should be further explored.Correspondence to:
Dr. Y.-T. Xiang
Department of Psychiatry
Chinese University of Hong Kong
Ground Floor, Multicentre, Tai Po Hospital
Tai Po, N.T., Hong Kong, PR China
Email: xyutly@cuhk.edu.hk
Original Research
High thiopurine metabolite concentrations associated with lymphopenia in inflammatory bowel disease (IBD) pediatric patients receiving aminosalicylates combined with azathioprine
T.-M.-H. Nguyen, C. Le Gall, A. Lachaux and R. Boulieu,
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 4/2010 (275-281)
High thiopurine metabolite concentrations associated with lymphopenia in inflammatory bowel disease (IBD) pediatric patients receiving aminosalicylates combined with azathioprine
T.-M.-H. Nguyen1, C. Le Gall2, A. Lachaux2 and R. Boulieu1, 3
1Département de Pharmacie Clinique, de Pharmacocinétique et d’Évaluation du Médicament, Université de Lyon, Lyon, 2Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron and 3 Laboratoire de Pharmacocinétique Clinique, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
Objective: Aminosalicylates are widely used with azathioprine in the treatment of IBD. The association results in an increase in 6-TGN levels in adults with IBD with a difference in the occurrence of myelotoxic effects. Scarce data are available in pediatric population. We proposed to investigate the effect of the coadministration of aminosalicylates on thiopurine concentrations in pediatric IBD patients. Materials and methods: Data from 71 patients treated for at least 1 y by azathioprine and aminosalicylates were recorded. 6-TGN and 6-MeMPN concentrations, blood cell counts and liver function tests were compared between patients taking and those not taking aminosalicylates. Results: Aminosalicylate therapy was associated with a significant increase in mean 6-TGN but also 6-MeMPN concentrations. In patients in remission, 6-TGN level was related to aminosalicylate dosage (r = 0.561, p = 0.010). Lymphopenia rate was higher in patients receiving combined therapy compared to monotherapy whereas a slight rise in leucopenia was found. Conclusions: This observation suggests that the higher frequency of lymphopenia may be associated with the elevated 6-TGN concentrations recovered in patients treated with aminosalicylates. This combination does not improve remission rate but could increase adverse effects especially lymphopenia.Correspondence to:
Prof. R. Boulieu
Université Lyon 1, ISPB
Département de Pharmacie Clinique,
de Pharmacocinétique et
d’Évaluation du Médicament
8 Avenue Rockefeller
69373 Lyon Cedex 08, France
Email: roselyne.boulieu@sante.univ-lyon1.fr
Original Research
Protopanaxatriol metabolites identified by LC-MS/MS after oral administration in mice
Y.-Z. Wang*, Y.-S. Wang*, S.-F. Chu, N.-H. Chen and J.-T. Zhang
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 4/2010 (282-290)
Protopanaxatriol metabolites identified by LC-MS/MS after oral administration in mice
Y.-Z. Wang1*, Y.-S. Wang2*, S.-F. Chu2, N.-H. Chen2 and J.-T. Zhang2
1Center for Drug Evaluation, State Food and Drug Administration, Haidion District, and 2Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Objective: 20(S)-Protopanaxatriol (Ppt), a well-known end metabolite of protopanaxatriol-type saponins, has recently been reported to have the same bioactivity as its prototype. Whether or not Ppt could be further metabolized into other compounds in vivo is still unknown. The present study is aimed to determine the structures of Ppt metabolites in mice. Materials: The metabolites were produced by intragastric gavage of Ppt in mice. The homogenate of small intestine was used for analysis after solid phase extraction. Methods: The metabolic profile of Ppt was investigated by using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), which were also used to identify the structures of metabolites. Accurate mass measurement using LC-time of flight MS was applied to determine the element composition of metabolites and thus to confirm their proposed structures. Results: One Phase I and three Phase II metabolites were detected at 1 h, 5 h, and 10 h after administration of Ppt, which were the same at the three time points. The Phase I metabolic changes observed included dehydrogenation and hydroxylation of the steroid-like structure, as well as formation of an ester bond at C-20 of the side chain. The Phase II metabolites involved conjugation to aminoethylsulfonic acid after hydrolysis of the ester bond. A possible biotransformation pathway was proposed. Conclusions: Ppt yielded four metabolites in vivo, and 1 h was enough to complete the biotransformation process of Ppt.Correspondence to:
Prof. J.-T. Zhang
Institute of Materia Medica
Chinese
Academy of Medical Sciences and Peking
Union Medical College
1 Xian Nong Tan Street
Beijing 100050, China
Email: zhangjt@imm.ac.cn
Bioavailability Section
Pharmacokinetic comparison and bioequivalence of two leflunomide formulations in humans: a single dose, randomized, open-label, two-way crossover study
J.-Y. Park, K.-A. Kim, Y.-H. Lee, S.-W Park, G.-H. Lee and J.-H Ryu
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 4/2010 (291-295)
Pharmacokinetic comparison and bioequivalence of two leflunomide formulations in humans: a single dose, randomized, open-label, two-way crossover study
J.-Y. Park1, K.-A. Kim1, Y.-H. Lee2, S.-W Park3, G.-H. Lee3 and J.-H Ryu3
1Departments of Clinical Pharmacology and Toxicology, and 2Rheumatology, Korea University College of Medicine and 3Central Research Institute, Hanlim Pharmaceutical Co., Seoul, Korea
Background and aims: Leflunomide is a disease-modifying antirheumatic drug (DMARD) with comparable efficacy to methotrexate in the treatment of rheumatoid arthritis. We compared the pharmacokinetic characteristics of two leflunomide formulations in healthy subjects and assessed whether these formulations were bioequivalent. Subjects and methods: A randomized, two-way, crossover study was conducted in 24 healthy male volunteers to compare the pharmacokinetics of two leflunomide formulations after administration of a single 20 mg dose of each drug with a 7 week washout period. Blood samples for the analysis of A77 1726, the main active metabolite of leflunomide, were obtained 624 h after drug administration. Results: After administering a single dose of 20 mg of each leflunomide formulation, the mean AUC0–t and Cmax values of A771726 were 487.3 ± 167.6 µg*h/ml and 2.24 ± 0.85 µg/ml for the reference formulation and 468.5 ± 148.6 µg*h/ml and 1.98 ± 0.45 µg/ml for the test formulation, respectively. The 90% confidence intervals of the test/reference mean ratios for AUC0-t, AUC0-∞, and Cmax fell within the predetermined equivalence range of 0.8 – 1.25. No serious adverse events occurred during the study period. Conclusions: The two leflunomide formulations showed similar pharmacokinetic profiles in terms of A77 1726, and the test formulation was found to be bioequivalent to the reference formulation with respect to the rate and extent of leflunomide absorption.Correspondence to:
J.-Y. Park, MD, PhD
Dept. of Clinical Pharmacology and Toxicology
Korea University College of Medicine
126-1, Anam-dong 5-ga, Sungbuk-gu
Seoul 136-705, Korea
Email: jypark21@korea.ac.kr
