Dustri Online Services

Abstract

Hier wird der Text (inkl. Abbildungen und Tabellen) dem Verlag gestellt.

Efficacy and tolerability of flupirtine in subacute/ chronic musculoskeletal pain – results of a patient level, pooled re-analysis of randomized, double-blind, controlled trials

M.A. Ueberall¹, G.H.H. Mueller-Schwefe² and B. Terhaag³

¹Institute for Quality Assurance in Pain Therapy and Palliative Care Medicine, Nuremberg, ²Palliative- and Pain Center, Göppingen and ³TEVA/AWD.pharma, Radebeul, Germany
Introduction: Flupirtine, a nonopioid analgesic without antipyretic or antiphlogistic properties, constitutes a unique class within the group of WHO-I analgesics. First approved in Germany on a national level in 1989, this selective neuronal potassium channel opener evolved rapidly into one of the most preferred analgesics for the treatment of musculoskeletal pain in some European countries. However, its use outside Europe was limited due to a discrepancy between the empirical application of the drug and supporting evidence. As a consequence, the German Pain Society commissioned an independent research institute to perform a pooled re-analysis of all available data from randomized controlled trials (including some trial not yet published). Methods: A retrospective pooled analysis of the individual patient data from 8 randomized controlled Phase III – IV clinical trials was carried out which included patients with sub-acute and chronic musculoskeletal pain. The efficacy and tolerability of flupirtine at dosages of 100 – 400 mg/d were compared to placebo and/or active comparators. Data were pooled by treatment and by subject. The primary endpoint was the average change in pain intensity for the overall maintenance period. Results: A total of 1,046 patients was evaluated for efficacy and 1,095 patients for safety. Based on 3,337 pain assessments, treatment with flupirtine and active comparators resulted in significant reductions in pain intensity compared to baseline beginning from Day 4 (flupirtine) and Day 5 (comparators) and continuing up to the end of the study period as well as during the overall maintenance period (all p < 0.001). Flupirtine prooved to be non-inferior to the active comparators (p < 0.001) but showed a superior tolerability profile with a significantly lower number of patients reporting treatment emergent adverse events (28.6 vs. 39.1%, p < 0.001) and a significantly lower percentage of patients who prematurely discontinued study medication due to these adverse events (7.1 vs. 11.7%, p = 0.013). Limitations: The limitations in the study were confined to those inherent in the retrospective and pooled analysis design. Conclusion: On the basis of this pooled analysis of individual data from 8 controlled clinical trials involving patients suffering from sub-acute/chronic musculoskeletal pain, the efficacy of flupirtine was superior to placebo across its effective and approved dosage range. Flupirtine was at least as active as the active comparators and showed a superior tolerability profile with a significantly lower treatment discontinuation rate.Correspondence to:
Michael A. Ueberall, MD
Medical Director
Institute for Quality Assurance in Pain Therapy and Palliative Care Medicine
Institute for Neurological Sciences, Algesiology and Pediatrics
Theodorstraße 1
90489 Nuremberg, Germany
Email: michael.ueberall@ifnap.de

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (648-655)

Thorough QT/QTc study of tocilizumab after single-dose administration at therapeutic and supratherapeutic doses in healthy subjects

S. Grange¹, C. Schmitt¹, L. Banken¹, B. Kuhn¹ and X. Zhang²

¹Hoffmann-La Roche AG, Basel, Switzerland, and ²Hoffmann-La Roche Inc., Nutley, NJ, USA
Objectives: The study was intended to determine whether tocilizumab has a threshold pharmacologic effect on cardiac repolarization as detected by QT/QTc prolongation on 12-lead electrocardiograms (ECGs) in healthy subjects. Methods: This was a multicenter, double-blind, placebo- and active-controlled, parallel group study. Healthy subjects received either an intravenous infusion of tocilizumab 10 mg/kg (n = 30) or 20 mg/kg (n = 31), oral moxifloxacin 400 mg (n = 31), or placebo (n = 29). Triplicate ECGs were obtained at predose, 2 h postdose on Day 1, and on Days 8, 15, and 29. Blood samples for pharmacokinetic analyses were collected at predose and up to 28 days postdose. Adverse events and laboratory safety tests were assessed throughout the study. Results: Estimated mean study-specific, heart rate-corrected QT interval change from timematched baseline versus placebo was negative at all time points (range –5.4 to –1.0 ms); the associated upper bound of the 1-sided 95% confidence limit was below threshold (10 ms). No clinically significant abnormalities in other electrocardiographic parameters were detected. No electrocardiographic abnormalities constituted an adverse event. After tocilizumab dosing, median time to maximum serum concentration was 2 h postdose; mean apparent terminal half-life was 9.3 ± 1.2 (10 mg/kg) and 12.1 ± 1.5 (20 mg/kg) days. Tocilizumab was well tolerated. Neutrophil counts decreased after tocilizumab administration, reaching a nadir 2 to 5 days after infusion. Mean neutrophil counts returned to baseline in the 10-mg/kg group and were near baseline in the 20-mg/kg group at the follow-up visit (Day 50 ± 2). Conclusions: There was no QT prolongation effect of clinical concern by tocilizumab at both the therapeutic (10 mg/kg) and the supratherapeutic (20 mg/kg) dose in healthy subjects.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

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (656-665)

Plasma pharmacokinetics of daptomycin in critically ill patients with renal failure and undergoing CVVHD

D. Khadzhynov¹, T. Slowinski¹, I. Lieker¹, C. Spies², B. Puhlmann², T. König², A. Uhrig³, K. Eggers⁴, H.-H. Neumayer¹, F. Traunmüller⁵,⁶, C. Joukhadar⁵,⁶ and H. Peters¹

¹Department of Nephrology, ²Department of Anaesthesia, ³Department of Infectious Disease, ⁴Department of Cardiology, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University Berlin, Germany, ⁵J&P MEDICAL RESEARCH Ltd., Vienna, Austria and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA, USA, and ⁶Medical University of Graz, Graz, Austria
Background: Daptomycin is a novel antibiotic with primarily renal elimination. Methods: In an open-label, prospective trial, the pharmacokinetics of daptomycin after single (8 mg/kg BW) and multiple intravenous doses (4 mg/kg BW) at steady state were determined in critically ill, dialysis-dependent patients treated with continuous veno-venous hemodialysis (CVVHD). Daptomycin levels were determined by HPLC. Subjects with normal renal function received one dose of 4 mg/kg BW of daptomycin. Results: In the normal controls, daptomycin administration resulted in a mean maximum concentration (C_max) of 60.7 ± 10.7 mg/l and an area under the time-versus-concentration curve from 0 to 24 h (AUC_0–24) of 402 ± 56 mg × h/l. In the CVVHD-treated patients, a loading dose of 8 mg/kg lead to C_max of 87.5 ± 15.0 mg/l, AUC_0–24 of 537 ± 97 mg × h/l and AUC_24–48 of 193 ± 69 mg × h/l, respectively. After multiple doses of 4 mg/kg every 48 h, C_max was 41.8 ± 5.0 mg/l, AUC_0–24 302 ± 43 mg × h/l and AUC_24–48h 102 ± 24 mg × h/l, respectively. Approximately 40% of the daptomycin dose administered was removed by CVVHD. Mean plasma half-lives of daptomycin in patients were 2 – 3 times longer than in healthy controls. Conclusions: The dosing regimen of 4 mg/kg TBW of daptomycin administered to CVVHD patients every 48 h is inappropriate to achieve effective antimicrobial plasma concentrations of daptomycin in the second half of the dosing interval (24 – 48 h). Doses of ≥ 4 mg/kg TBW administered intravenously every 24 h are necessary in CVVHD patients to assure that plasma daptomycin levels are comparably high to subjects with normal renal function and to avoid underdosing.Correspondence to:
H. Peters, MD
Department of Nephrology
Charité Universitätsmedizin Berlin
Humboldt University
Charitéplatz 1
10117 Berlin, Germany
Email: Harm.Peters@charite.de

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (666-671)

Antimicrobial effect of statins: organic solvents might falsify microbiological testing results

P. Matzneller¹, M. Manafi² and M. Zeitlinger¹

¹Department of Clinical Pharmacology, and ²Institute of Hygiene and Applied Immunology, Medical University of Vienna, Austria
Objectives: Statins possess a variety of pleiotropic effects. Direct antimicrobial effect of simvastatin and, to a smaller degree, fluvastatin, has been reported for Gram-positive bacteria. The present study investigated antimicrobial activity of all statins available on the European market on Gram-positive and -negative organisms, with particular attention on the possible impact of organic solvents on bacterial growth. Methods: Simvastatin was dissolved both in 100% methanol (simvastatin_100%) and in 5% methanol (simvastatin_5%), the latter solution requiring pH adjustment for solubility reasons. Antimicrobial activity of both simvastatin solutions and of five other statins was evaluated against Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213 by broth microdilution testing. In addition, time-kill curves of methanol alone, simvastatin_100% and simvastatin_5% were performed for S. aureus ATCC 29213. Results: Relevant antimicrobial activity was observed only for simvastatin100% when tested against S. aureus (MIC = 31 mg/l). MIC of simvastatin5% was more than 10-fold higher (500 mg/l). In analogy, time-kill rates of simvastatin against S. aureus decreased markedly when the methanol content in the test solutions was reduced. In both experimental settings, antimicrobial activity observed for pure methanol was only slightly inferior to that of simvastatin_100%. Conclusion: Previously published results about the antimicrobial effect of statins relied on the use of pure methanol as solvent. Present data indicate that the observed antimicrobial effect must be attributed, at least to a very large extent, to the solvent. Toxicity of solvents may influence microbiological evaluation of poorly water-soluble substances. pH adjustment to enhance solubility and thus reduce the need for using organic solvent might sometimes overcome this problem.Correspondence to:
Prof. Dr. M. Zeitlinger
Department of Clinical Pharmacology
Medical University of Vienna
Währinger Gürtel 18 –20
1090 Vienna, Austria
Email: markus.zeitlinger@meduniwien.ac.at

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (672-678)

Open label, three period, single sequence, study of 5, 25, 50 mg sertraline pharmacokinetics in healthy male Korean volunteers

M.K. Park, K.-H. Shin, K.-P. Kim, T.-E. Kim, S.H. Yoon, J.-Y. Cho, S.-G. Shin, I.-J. Jang and K.-S. Yu

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Background: Sertraline is a naphthalenamine derivative which has the effect of selective serotonin reuptake inhibition. It has been used for major depression, and obsessive compulsive disorder. This study was performed to evaluate the pharmacokinetic (PK) characteristics after the administration of low dose sertraline for the purpose of exploring an application of microdosing methods in PK studies. Methods: An open-label, three-period, single-sequence, dose-escalation study was performed in 6 healthy Korean male volunteers. Subjects were administered a single dose of 5 mg, 25 mg and 50 mg sertraline orally in each period, with 1 week washouts between periods. Blood samples were obtained up to 96 h after drug administration. Plasma concentrations were determined using high performance liquid chromatography-tandem mass spectrometry. PK parameters of sertraline were analyzed using non-compartmental methods. Results: A total of 6 subjects completed the study. After the administration of sertraline at 5 mg, 25 mg and 50 mg, the median t_max were 6.0, 6.0 and 4.0 h and the mean (SD) elimination half-lives were 31.9 (6.5), 27.2 (6.7) and 28.0 (6.6) h, respectively. The AUC and C_max increased dose-dependently. The dose-normalized mean (SD) AUC and C_max were different in each dosing group (p < 0.01) with 2.0 (0.8), 5.3 (1.2) and 6.0 (1.9) mg × hr/l/mg in the 5 mg, 25 mg and 50 mg groups for dose-normalized AUC, and 0.07 (0.01), 0.18 (0.05) and 0.21 (0.08) mg/l/mg in the 5 mg, 25 mg and 50 mg groups for dose-normalized C_max, respectively, which indicates a lack of dose proportionality. Conclusion: A lack of dose proportional properties was shown in the 5 mg dose relative to the 25 mg and 50 mg doses of sertraline. This shows that the PK parameters for low-dose sertraline could be different from those in clinical concentrations.Correspondence to:
K.-S. Yu, MD, PhD
Department of Pharmacology and Clinical Pharmacology
Seoul National University College of Medicine and Hospital
101 Daehak-ro, Jongno-gu
Seoul 110-744, Republic of Korea
Email: ksyu@snu.ac.kr

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (679-687)

A Phase I study to evaluate the pharmacokinetics of axitinib (AG-13736) in healthy Chinese volunteers

Y. Chen¹, J. Jiang², J. Zhang², M.A. Tortorici¹, Y.K. Pithavala¹, L. Lu³, G. Ni⁴ and P. Hu²

¹Pfizer Oncology, San Diego, CA, USA, ²Peking Union Medical College Hospital, ³Pfizer, Beijing, China, and ⁴Pfizer Inc, New London, CT, USA
Objective: To assess axitinib plasma pharmacokinetics and safety of single oral doses of axitinib under fed conditions in healthy Chinese volunteers. Materials and methods: This Phase I, open-label study evaluated single dosing of axitinib in 14 healthy Chinese volunteers. Axitinib was administered as 5-, 7-, and 10-mg doses under fed conditions in study periods 1, 2, and 3, respectively, followed by pharmacokinetic assessments and safety monitoring. A washout period ≥ 7 days was provided between successive axitinib doses. Blood samples were collected during each period up to 32 h post-dose for pharmacokinetic analysis. Axitinib plasma pharmacokinetic parameters were estimated using standard noncompartmental methods. Results: Estimates (geometric mean) of axitinib AUC_inf were 150, 251, and 321 ng × h/ml for doses of 5, 7, and 10 mg, respectively, reflecting a dose-proportional increase in AUC_inf (increments of 1 : 1.7 : 2.1 for dose increments of 1 : 1.4 : 2, respectively). Geometric mean estimates of maximum observed plasma concentration (C_max) were 33.5, 51.1, and 69.4 ng/ml, respectively, which also showed dose proportionality. Axitinib plasma pharmacokinetics was similar to those previously observed in healthy Caucasians, with geometric mean values (% geometric coefficient of variation) for axitinib plasma AUC_inf 150 ng × h/ml (62%) versus 125 ng × h/ml (60%), respectively. Axitinib was well tolerated, with no serious adverse events or discontinuations; one adverse event of mild abdominal distension was observed. Conclusions: In healthy Chinese subjects, single dosing of axitinib demonstrated dose-proportional pharmacokinetics. Axitinib pharmacokinetics in this population was similar to those previously observed in healthy Caucasians, suggesting a lack of ethnic differences.Correspondence to:
Dr. P. Hu
Peking Union Medical College Hospital
Chinese Academy of Medical Sciences
1 Shuaifuyuan Wangfujing
Beijing 100730, China
Email: pei.hu.pumc@gmail.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (688-694)

Pharmacokinetics and tolerability of probucol after multiple oral administrations in healthy volunteers

H. Jeon, S. Lee, T.-E. Kim, S.H. Yoon, S.-G. Shin, I.-J. Jang and K.-S. Yu

Department of Pharmacology and Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Background: Probucol is indicated for primary hyperlipidemia and for hypercholesterolemia with hypertriglyceridemia. The objective of this study was to evaluate the tolerability and pharmacokinetics of probucol by multiple oral administration in healthy Korean male subjects. Methods: This study was conducted by a randomized, openlabel, three-treatment, parallel-group design. A total of 30 subjects were randomly assigned to 1 of the 3 treatment groups were administered probucol orally at 250 mg once daily (QD) after breakfast (250 mg/d), at 500 mg once daily after breakfast (500 mg/d), or at 250 mg twice a day (b.i.d) after breakfast and dinner (500 mg/d) for 14 days. Serial samples of blood were collected and plasma drug concentrations were determined using liquid chromatography-tandem mass spectrometry (LC/MS/MS). For tolerability assessment, measurement of vital signs and electrocardiograms (ECG), clinical laboratory tests and physical examinations were performed. Results: At Day 13, the mean of the AUC_24h of probucol was 123,800 µg × h/l in the 250 mg QD group, 198,500 µg × h/l in the 500 mg QD group, and 244,700 µg × h/l in the 250 mg BID group. The mean accumulation index for AUC_24h (ratio of AUC_24h for Day 13 to that for Day 1) was 2.5 in the 250 mg QD group, 2.85 in the 500 mg QD group, and 4.21 in the 250 mg b.i.d. group. No clinically significant changes in ECG, including QTc prolongation were observed during the study period. All adverse events were mild and no clinically significant changes were observed in any other tolerability assessment, thus confirming tolerability for all regimens tested. Conclusions: This study provided data on the pharmacokinetics and tolerability of probucol by multiple oral administrations in healthy male volunteers.Correspondence to:
K.-S. Yu, MD, PhD
Department of Pharmacology and Clinical Pharmacology
Seoul National University College of Medicine and Hospital
101 Daehak-ro, Jongno-gu
Seoul 110-744, Korea
Email: ksyu@snu.ac.kr

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (695-699)

Use of hemodialysis after ingestion of a mixture of acids containing hydrofluoric acid

M. Antar-Shultz, S.I. Rifkin and C. McFarren

University of South Florida, Division of Nephrology and Hypertension, Tampa, FL, USA
Hydrofluoric acid (HF) is a highly toxic poison that can be rapidly fatal. Death usually results from the many systemic effects of dissociated fluoride ions, including hypocalcemia, hypomagnesemia, hyperkalemia, and direct cardiotoxicity. A patient is described who accidentally ingested a hydrofluoric acid-containing substance and who likely benefited from hemodialysis. His fluoride level post-dialysis was reduced by approximately 70% from a level drawn three hours prior to the initiation of hemodialysis. However, the single treatment did not reduce the fluoride level to normal. A review of the pathophysiology of hydrofluoric acid intoxication and the outcomes of prior exposures suggests that hemodialysis could play a vital role in the management of poisonings with fluoride-containing substances. However, the initial hemodialysis treatment should be prolonged beyond the standard four-hour session.Correspondence to:
M. Antar-Shultz, DO
University of South Florida
Division of Nephrology and Hypertension
12901 Bruce B. Downs Blvd, MDC 19
Tampa, FL 33612, USA
Email: antarshultz@hotmail.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (700-704)

Individual differences in prothrombin timeinternational normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports

F. Yamamuro¹, A. Miki², G. Kondo¹, T. Maeda¹, H. Satoh², S. Hori²,³ and Y. Sawada²

¹Department of Pharmacy Kumamoto City Hospital, ²Laboratory of Drug Informatics,
Graduate School of Pharmaceutical Sciences, and ³Interfaculty Initiative in Information Studies, Graduate School of Interdisciplinary Information Studies, The University of Tokyo, Tokyo, Japan
Objective: We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo). Case summaries: The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 – 3.0 before therapy but were elevated to values in the range of 3.79 – 4.92 within 8 – 17 days after initiating the coadministration of warfarin (1.5 – 3.5 mg/d) and S-1 (80 – 120 mg/d). When the drug interactions in Cases 1 – 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as “probable”. Discussion: The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone. Conclusion: It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered.Correspondence to:
Y. Sawada, PhD
Laboratory of Drug Informatics
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku
Tokyo, 113-0033 Japan
Email: sawada@mol.f.u-tokyo.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 11/2011 (705-708)

Systemic steroids in acute exacerbation of COPD – from guidelines to bedside

P.-H. Wang¹, S.-L. Cheng¹, H.-C. Wang², H.-T. Chang¹, Y.-L. Hsu¹, Y.-S. Chen¹ and C.-Y. Chang¹

¹Department of Internal Medicine, Far Eastern Memorial Hospital, and ²Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
The optimal steroid dosages in AECOPD are still under debate. Admission records of patients in our hospital from January to December 2008 due to a diagnosis of AECOPD were reviewed. More wheezing and tachypnea were noted in the patients with a maximal daily prednisolone dose more than 60 mg. The steroid dose was higher in AECOPD without pneumonia than those concurrent with pneumonia. Those who had concurrent pneumonia had a higher risk of nosocomial infections. The study reflects the heterogeneity of AECOPD and that steroid dosages were determined by the clinical evaluation of the severity of illness and bacterial infections.Correspondence to:
H-C. Wang, MD, PhD
Department of Internal Medicine
National Taiwan University Hospital, No. 7
Chung-Shan South Road
Taipei, Taiwan
Email: haochienwang@gmail.com

Shopping Overview
Type	Qtty	Price
Your basket is empty

Username:
Password:

Volume 49, No. 11/2011(November)