Volume 51, No. 3/2013(March)
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Original Research
Estimation of safe and effective dose of vancomycin in MRSA-infected patients using serum cystatin C concentrations
Yu-chun Chen, Jia-fu Feng, Bing Li, Ling Zhang and Yu-wei Yang
Price
42.00 $
Page No. 161
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (161-169)
Estimation of safe and effective dose of vancomycin in MRSA-infected patients using serum cystatin C concentrations
Yu-chun Chen1*, Jia-fu Feng2*, Bing Li3, Ling Zhang4 and Yu-wei Yang2
1Departmant of Pharmacy, Mianyang Central Hospital, 2Laboratory Medicine, 3The First Clinical College, Chongqing Medical University, and 4Kidney Internal Medical Department, Mianyang Central Hospital, Chongqing, China
*These authors contributed equally to this work.
Objective: To utilize serum cystatin C (CysC) concentration to identify the daily dosage regimen of vancomycin (Van) for the treatment of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Methods: Serum Van, CysC, and serum and urine creatinine (Cr) concentrations were detected in 65 MRSA-infected patients. The estimated glomerular filtration rate (eGFR), Cr clearance (CLcr) and Van clearance (CLvan) were calculated and the correlation equation between CysC and CLvan was obtained using mathematical methods. Finally, the daily dosage equation of Van was derived according to pharmacokinetic theory. Results: In the test sample, serum Cr was 183.27 ± 68.34 μmol/l, CLcr was 75.56 ± 30.02 ml/min, eGFR was 70.79 ± 40.79 ml/min, and serum CysC was 1.35 ± 0.61 mg/l. There was significant correlation between eGFR and CLcr (R2 = 0.8051, p = 0.000). Bland-Altman analysis showed an agreement of 96.9% (63/65) between eGFR and CLcr. eGFR was significantly correlated with CLvan (R2 = 0.8465, p = 0.000) and the correlation was significantly higher than that between CLvan and CLcr (R2 = 0.6367, p = 0.000). CysC fits a high correlated CLvan estimating equation (R2 = 0.9211, p = 0.000): CLvan(ml/min) = 64.4026 × (CysC)–1.1488. Accordingly, the predicted equation was created for calculation of the Van dosage to achieve the appropriate target steady-state serum concentration (Css): IR (the rate of continuous infusion, g/D) = 64.4026 × (CysC)–1.1488 × Css (mg/l) × (60/1,000) × 24. Conclusions: Serum CysC is a good marker of renal function in comparison with serum Cr for the dose determination of Van. CysC can estimate the daily dose of Van, and may improve therapeutic success rates of MRSA-infected patients. Correspondence to:
Jia-Fu Feng, MD, Laboratory Medicine, Mianyang Central Hospital, Sichuan 621000, China
Email: [email protected]
Original Research
Jolkinolide B from Euphorbia fischeriana Steud induces in human leukemic cells apoptosis via JAK2/STAT3 pathways
Jia-He Wang, Ke Zhang, Hui-Yan Niu, Lin-Hua Shu, Dong-Mei Yue, Dong-Yang Li and Ping He
Price
42.00 $
Page No. 170
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (170-178)
Jolkinolide B from Euphorbia fischeriana Steud induces in human leukemic cells apoptosis via JAK2/STAT3 pathways
Jia-He Wang1, Ke Zhang2, Hui-Yan Niu1, Lin-Hua Shu3, Dong-Mei Yue3, Dong- Yang Li4 and Ping He1
1Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, 2Department of Developmental Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 3Department of Pediatrics, Shengjing Hospital of China Medical University, and 4The 96th Class, 7-year Program of Clinical Medicine, China Medical University, Shenyang, China
Jolkinolide B from the roots of Euphorbia fischeriana Steud exhibits significant antitumor activities against several tumor lines. Previous study has shown that Jolkinolide B could induce apoptosis in human leukemia cells. However, the exact mechanism and signaling pathway involved in Jolkinolide B-induced apoptosis have not been fully elucidated. In the present study, we found that Jolkinolide B reduced cell viability and induced apoptosis in dose- and time-dependent manner in human leukemic HL-60 and THP-1 cells. The induction of apoptosis was accompanied by the downregulation of JAK2/STAT3. Our results also suggest that expression of Bcl-2 and mitochondrial cytochrome c was dosedependently reduced following Jolkinolide B-treated THP-1 and HL-60 cells, whereas Jolkinolide B up-regulated the expression of Bax and cytosolic cytochrome c. Moreover, we observed that Jolkinolide B treatment resulted in activation of caspase-3, -8, and -9. JSI-124, a STAT-3 inhibitor, was able to block the negative effect of Jolkinolide B on cell apoptosis. Taken together, our study for the first time suggests that Jolkinolide B is able to enhance apoptosis of human leukemic HL-60 and THP-1 cells, at least in part, through downregulation of JAK2/STAT3 and bcl-2, and upregulation of Bax and cytosolic cytochrome c. Moreover, the triggering of caspase-3, -8, and -9 activation mediated apoptotic induction.Correspondence to:
Jia-He Wang
Department of Geriatrics
Shengjing Hospital of China Medical University
Shenyang, 110004, PR China
Email: [email protected]
Original Research
Factors that contribute to clopidogrel resistance in cardiovascular disease patients: environmental and genetic approach
Sayer I. Al-Azzam, Karem H. Alzoubi, Omar F. Khabour, Mohammad B. Nusair, Hakam Al-Hadidi, Abdalla Awidi and Akram Saleh
Price
42.00 $
Page No. 179
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (179-186)
Factors that contribute to clopidogrel resistance in cardiovascular disease patients: environmental and genetic approach
Sayer I. Al-Azzam1, Karem H. Alzoubi1, Omar F. Khabour2, Mohammad B. Nusair1, Hakam Al-Hadidi3, Abdalla Awidi4 and Akram Saleh5
1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, 2Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, 3Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, 4Department of Medicine, and 5Department of Cardiology, Faculty of Medicine, University of Jordan, Amman, Jordan
Background and objective: Clopidogrel is a potent antiplatelet drug that reduces the risk of vascular events in patients with cardiovascular disease. However, several studies have shown that about a quarter of patients showed low or no response to clopidogrel therapy. In this study, factors that contribute to clopidogrel resistance were investigated in 270 cardiovascular disease patients from Jordan. Patients and methods: Clopidogrel resistance was determined through platelet aggregation analysis using the Multiplate analyzer®. Genetic factors (CYP2C19*2 and PON1 Q192R) were examined using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: The incidence of clopidogrel resistance among Jordanians is about 32%. Significant association between clopidogrel resistance and female gender, concomitant use of calcium channel blockers, and low HDL was found (p < 0.05). In addition, presence of CYP2C19*2 allele is strongly related to clopidogrel resistance (p < 0.001). However, lack of contribution to clipidogrel resistance was found for PON1 Q192R polymorphism, age, diabetes, hypertension, smoking and aspirin use (p > 0.05). Conclusion: Several factors might contribute to clopidogrel resistance including gender, concomitant use of calcium channel blockers, HDL and CYP2C19*2 polymorphism.Correspondence to:
Sayer I. Al-Azzam, PharmD, MSc, BCPS
Department of Clinical Pharmacy
Faculty of Pharmacy
Jordan University of Science and Technology
P.O. Box 3030, Irbid 22110, Jordan
Email: [email protected]
Original Research
Pharmacokinetics and safety of sirukumab following a single subcutaneous administration to healthy Japanese and Caucasian subjects
Yanli Zhuang, Zhenhua Xu, Dick E. de Vries, Qingmin Wang, Akira Shishido, Craig Comisar, Joyce A. Ford, Monica Keen, Meguru Achira, Yuko Tsukamoto, Kevin J. Petty, Hugh M. Davis and Honghui Zhou
Price
42.00 $
Page No. 187
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (187-199)
Pharmacokinetics and safety of sirukumab following a single subcutaneous administration to healthy Japanese and Caucasian subjects
Yanli Zhuang1, Zhenhua Xu1, Dick E. de Vries2, Qingmin Wang1, Akira Shishido3, Craig Comisar1, Joyce A. Ford1, Monica Keen1, Meguru Achira3, Yuko Tsukamoto3, Kevin J. Petty1, Hugh M. Davis1 and Honghui Zhou1
1Janssen Research & Development, LLC, Spring House, PA, USA, 2Janssen Biologics B.V., Leiden, The Netherlands, and 3Janssen Pharmaceutical K.K., Tokyo, Japan
Objective: Sirukumab (CNTO 136) is a human mAb with high affinity and specificity for binding to interleukin-6. This Phase 1 study evaluated the pharmacokinetics, immunogenicity, safety, and tolerability of sirukumab following a single subcutaneous (s.c.) administration in healthy male Japanese and Caucasian subjects. Methods: Japanese and Caucasian subjects were randomized to placebo or 25, 50, or 100 mg sirukumab. Blood samples were collected to measure serum sirukumab concentration and antibodies to sirukumab. Noncompartmental analysis and population pharmacokinetic modeling were conducted to characterize sirukumab pharmacokinetics. Adverse events were monitored at each visit. Results: 25 Japanese and 24 Caucasian subjects received sirukumab and were included in the pharmacokinetic evaluation. Mean Cmax and AUC0–∞of sirukumab increased in an approximately dose-proportional manner in both Japanese and Caucasian subjects. Median tmax was 3 –5 days after s.c. administration of sirukumab. Mean t1/2 was 15 –16 days in Japanese and 15 –18 days in Caucasian subjects. A one-compartment population pharmacokinetic model adequately described sirukumab pharmacokinetics following s.c. administration. The estimated population means for CL/F, V/F, and Ka were 0.54 ±0.03 l/day, 12.2 ±0.55 l, and 0.77 ±0.07 day–1, respectively. Race was not a significant covariate on CL/F or V/F. No subject was positive for antibodies to sirukumab. Adverse events were generally mild and did not appear to be dose-related or lead to study discontinuation. Conclusions: Sirukumab pharmacokinetics following subcutaneous administration was linear at doses ranging 25 –100 mg and was comparable between Japanese and Caucasian subjects. A single subcutaneous administration of 25, 50, or 100 mg sirukumab appeared to be well tolerated by both Japanese and Caucasian healthy male subjects.Correspondence to:
Honghui Zhou, PhD, FCP, Biologics Clinical Pharmacology, Janssen Research & Development, LLC, 1400 McKean Rd., Spring House, PA 19477, USA
Email: [email protected]
Original Research
Effect of food on the pharmacokinetics of darexaban, an oral direct factor Xa inhibitor, in healthy Japanese subjects
Takeshi Kadokura, Yuta Taniuchi, Hiroshi Inoue, Masako. Saito, Mioko Iwahana, Shunsuke Yamada, Akinori Urae and Mashio Nakamura
Price
42.00 $
Page No. 200
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (200-206)
Effect of food on the pharmacokinetics of darexaban, an oral direct factor Xa inhibitor, in healthy Japanese subjects
Takeshi Kadokura1, Yuta Taniuchi1, Hiroshi Inoue1, Masako Saito1, Mioko Iwahana1, Shunsuke Yamada1, Akinori Urae2 and Mashio Nakamura3
1Astellas Pharma Inc., 2Mediscience Planning Inc., Tokyo, and 3Department of Clinical Cardiovascular Research, Mie University Graduate School of Medicine, Mie, Japan
Background: Darexaban is a potent direct factor Xa (FXa) inhibitor developed for prophylaxis of venous and arterial thromboembolic disease. This drug is rapidly and extensively metabolized to darexaban glucuronide (YM-222714), which is a pharmacologically active metabolite. The potential effects of food on the harmacokinetics of darexaban glucuronide after darexaban administration were assessed in two studies. Methods: Both studies were conducted as open-label, two-way crossover studies. Healthy non-elderly Japanese male subjects received darexaban as a single 15 mg tablet (Study 1, n = 24) or a single 30 mg tablet (Study 2, n = 24). The geometric mean ratio (GMR) (fed/fasted) for AUClast and Cmax were evaluated as primary parameters. Results: GMR(fed/fasted) for AUClast emonstrated slight decreases as 0.797 (90% CI: 0.758 – 0.838) in Study 1 and 0.821 (90% CI: 0.752 – 0.896) in Study 2. For Cmax, the GMR was 0.908 (90%CI: 0.835 – 0.988) in Study 1 and 1.039 (90% CI: 0.953 – 1.131) in Study 2. There were no serious adverse events during the two studies. None was considered to be drug-related. Conclusion: These studies demonstrated that there was no clinically significant effect of food on the pharmacokinetics after administration of darexaban. We therefore conclude that darexaban can be administered without regard to food intake.Correspondence to:
Takeshi Kadokura
Astellas Pharma Inc
3-17-1, Hasune, Itabashi-ku, Tokyo, Japan
Email: [email protected]
Original Research
Genotype-phenotype variability in human CYP3A locus in Nepalese people residing in Bangladesh
Rajib Hassan, Syeda Sadia Ameen, Abdullah Al Maruf, Ananna Nandini, Humayra Tabin, Maizbha Uddin Ahmed, Mohammad Safiqul Islam, Muhammad Shahdaat Bin Sayeed and Abul Hasnat
Price
42.00 $
Page No. 207
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (207-214)
Genotype-phenotype variability in human CYP3A locus in Nepalese people residing in Bangladesh
Rajib Hassan1, Syeda Sadia Ameen1, Abdullah Al Maruf1, Ananna Nandini2, Humayra Tabin2, Maizbha Uddin Ahmed1, Mohammad Safiqul Islam1, Muhammad Shahdaat Bin Sayeed1 and Abul Hasnat1
1Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, and 2Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh
Objectives: The study has been designed to phenotype 200 Nepalese people residing in Bangladesh by measuring urinary ratio of 6β-hydroxycortisol/cortisol (metabolic ratio) and to genotype all the subjects for the presence of CYP3A4*1B, *2, *4, *5, *6, *10, *18, CYP3A5*3, and *6 alleles. Methods: Cortisol and 6β-hydroxycortisol were extracted and quantified from morning spot urine samples (n = 200) by HPLC. Genotyping was carried out using the extracted genomic DNA by amplification of target alleles by PCR. Amplified DNA was digested by appropriate restriction enzymes followed by gel electrophoresis and sequencing to identify the targeted alleles. Results: A wide ratio of 6β-hydroxycortisol/cortisol was found (0.71 – 10.61) with an average of 4.41. No sample (n = 200) was found positive for CYP3A4*1B, *2, *4, *5, *6, *10, *18, and CYP3A5*6 alleles. CYP3A5*1/*1, *1/*3, and *3/*3 genotype frequency were found to be 20%, 20%, and 60%, respectively. A significantly higher mean metabolic ratio (MR) ± SD (MR = 6.28 ± 3.43) was found for CYP3A5*1/*1 compared to both CYP3A5*1/*3 (MR = 3.68 ± 1.37) and CYP3A5*3/*3 (MR = 3.58 ± 1.95). Conclusion: This study demonstrates the absence of common CYP3A4 variant alleles in Nepalese people residing in Bangladesh whereas Nepalese people carrying the CYP3A5*1/*1 genotype appear to show a significantly higher 6β-hydroxycortisol/cortisol ratios compared to those with CYP3A5*3/*3 genotype.Correspondence to:
Prof. Dr. Abul Hasnat
Department of Clinical Pharmacy and Pharmacology
Faculty of Pharmacy, University of Dhaka
Dhaka – 1000, Bangladesh
Email: [email protected]
Short Report
In vivo evaluation of drug-drug interactions linked to UGT inhibition: the effect of probenecid on dalcetrapib pharmacokinetics
Pau Aceves Baldó, Judith Anzures-Cabrera and Darren Bentley
Price
42.00 $
Page No. 215
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (215-218)
In vivo evaluation of drug-drug interactions linked to UGT inhibition: the effect of probenecid on dalcetrapib pharmacokinetics
Pau Aceves Baldó, Judith Anzures-Cabrera and Darren Bentley
Roche Products Ltd, Welwyn Garden City, UK
Objective: To assess the effect of the UGT inhibitor probenecid on the pharmacokinetics of dalcetrapib, an investigational drug whose pharmacologically active thiol form undergoes glucuronidation (fm UGT ≥ 0.25). Materials and methods: A two-way crossover study in 20 healthy subjects. Subjects received a single 600 mg dose of dalcetrapib with or without probenecid (500 mg 4 times daily for 6 days). Results: AUC∞ and Cmax of dalcetrapib thiol were increased by 14% and 21%, respectively, by co-administration of probenecid. Conclusions: This case study illustrates the difficulty in predicting clinically relevant drug-drug interactions for UGT substrates based only on the fraction metabolized by glucuronidation.Correspondence to:
Darren Bentley, PhD
Roche Products Ltd.
Welwyn Garden City, AL7 1TW, UK
Email: [email protected]
Case Report
Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate
Johann von Felden, Matteo Montani, Kerstin Kessebohm and Felix Stickel
Price
42.00 $
Page No. 219
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (219-223)
Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate
Johann von Felden1, Matteo Montani2, Kerstin Kessebohm3 and Felix Stickel1
1Department of Visceral Surgery and Medicine, Inselspital, 2Institute of Pathology and 3Center for Clinical Pharmacology and Pharmacovigilance, University of Berne, Switzerland
Introduction: Herbal and dietary supplements are widely used as measures to improve and preserve health and well-being. Among the bestselling preparations are dietary supplement containing glucosamine and chondroitine sulfate taken to improve symptoms of osteoarthritis. Methods and results: We here present a case of a male patient with biopsy-proven acute and severe autoimmune hepatitis subsequent to intake of a preparation containing glucosamine and chondroitine sulfate. Response to steroids was favorable and resulted in complete remission of the patient. Diagnostic work-up of the case revealed no other possible cause of liver injury, and causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) resulted in a possible causal relationship between intake of glucosamine and chondroitine sulfate and the adverse hepatic reaction. Conclusion: The present case recalls that products containing glucosamine and chondroitine sulfate can occasionally cause acute liver injury mimicking autoimmune hepatitis, and reminds of the potential dangers of compounds with poor efficacy and ill-defined safety records.Correspondence to:
Felix Stickel, MD
Department of Visceral Surgery and Medicine
Inselspital, University of Berne
Murtenstrasse 35, 3010 Berne, Switzerland
Email: [email protected]
Case Report
A case of thrombotic thrombocytopenic purpura associated with bupropion
Neriman Defne Altintas, Seval Izdes, Sibel Yucel, Murat Suher and Imdat Dilek
Price
42.00 $
Page No. 224
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (224-227)
A case of thrombotic thrombocytopenic purpura associated with bupropion
Neriman Defne Altintas1, Seval Izdes2, Sibel Yucel3, Murat Suher4 and Imdat Dilek5
1Medical Intensive Care Unit, Ankara Ataturk Training and Research Hospital, 2University of Yildirim Beyazit, Ankara Ataturk Training and Research Hospital, Department of Anesthesiology and Reanimation, 3Department of Anesthesiology and Reanimation, 4Department of Internal Medicine, and 5Ankara Ataturk Training and Research Hospital, Department of Hematology, Ankara, Turkey
Objective: To report a case of bupropion-associated thrombotic thrombocytopenic purpura (TTP) syndrome. Case summary: A 55-year-old man was admitted with complaints of diarrhea, acute renal failure, and confusion ~ 54 days after bupropion initiation for smoking cessation. Subsequently he had a tonic-clonic seizure and had to be intubated because of altered consciousness. Laboratory findings were compatible with microangiopathic hemolytic anemia. He was diagnosed as TTP for which the Naranjo adverse drug reaction probability scale indicated a probable relationship with bupropion (a score of 5). He was treated with plasma exchange, systemic corticosteroids, hemodialysis and recovered fully. Discussion: Bupropion is an anti-depressant drug also indicated for smoking cessation. It has widely reported neuropsychiatric and allergic adverse effects; however, TTP associated with bupropion has only been reported once. The clinical course of TTP in this case was compatible with TTP related to acute, immune mediated drug toxicity, which suggests that auto-antibodies might have been responsible. Conclusions: Given the fact that the clinical condition is compatible with acute, immune-mediated TTP syndrome, we suggest bupropion deserves evaluation for auto-antibody induction. Prescribers should be aware of the possible risk of thrombocytopenia and TTP.Correspondence to:
Neriman Defne Altintas, MD
Ankara Ataturk Training and Research Hospital
Medical Intensive Care Unit
Kenedy Cad. 72/13, 06660, Küçükesat, Ankara, Turkey
Email: [email protected]
Case Report
Thrombocytopenia induced by both aspirin and clopidogrel in the same patient
Yunzhen Hu, Min Yuan and Xiaoyang Lu
Price
42.00 $
Page No. 228
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (228-231)
Thrombocytopenia induced by both aspirin and clopidogrel in the same patient
Yunzhen Hu1, Min Yuan2 and Xiaoyang Lu1
1Department of Pharmacy, and 2Department of Neurology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Aspirin and clopidogrel are used widely as antiplatelet agents due to their efficacy, safety, and tolerability. In rare cases, these agents can cause thrombotic thrombocytopenic purpura, but no report has documented severe thrombocytopenia in response to both drugs in the same patient. A 73-yearold female developed severe thrombocytopenia following treatment with clopidogrel. Platelet count recovered within 6 months of drug withdrawal without additional thrombopoietic therapies. Seven months after the last dose of clopidogrel, thrombocytopenia recurred on aspirin therapy. Again, platelet count rebounded gradually and independently. This case suggests that some patients who experience thrombocytopenia in response to one antiplatelet agent may react similarly to other antiplatelet agents.Correspondence to:
Xiaoyang Lu
Department of Pharmacy
The First Affiliated Hospital
College of Medicine, Zhejiang University
Hangzhou, China
Email: [email protected]
Letter to the Editor
The financial impact of computer systems-based approaches to reducing repeat drug exposure in patients with known drug allergies
Wuan-Jin Leu, Hsiang-Yin Chen, Hsiu-Yu Chien, Hui-Ping Liu, Chuang-Chin Chiueh and You-Meei Lin
Page No. 232
Abstract
Intern. Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 3/2013 – Letter to the editor
The financial impact of computer systems-based approaches to reducing repeat drug exposure in patients with known drug allergies
Wuan-Jin Leu1,2, Hsiang-Yin Chen2,3, Hsiu-Yu Chien1,2, Hui-Ping Liu1,2, Chuang-Chin Chiueh1,2 and You- Meei Lin1,2
1Department of Pharmacy, Shuang Ho Hospital, 2School of Pharmacy, College of Pharmacy, and 3Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Correspondence to:
You-Meei Lin, RPh, MS
Department of Pharmacy, Shuang Ho Hospital
Taipei Medical University, No.291
Zhongzheng Rd., Zhonghe District
New Taipei City, 23561, Taiwan
Email: [email protected]
Bioavailability Section
Bioequivalence study of a novel orodispersible tablet of meloxicam in a porous matrix after single-dose administration in healthy volunteers
Milko Radicioni, Sandra Connolly, Federico Stroppolo, Gabriele Granata, Luca Loprete and Chiara Leuratti
Price
42.00 $
Page No. 234
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (234-243)
Bioequivalence study of a novel orodispersible tablet of meloxicam in a porous matrix after single-dose administration in healthy volunteers
Milko Radicioni1, Sandra Connolly2, Federico Stroppolo3, Gabriele Granata3, Luca Loprete1 and Chiara Leuratti4
1CROSS Research S.A., Arzo, Switzerland, 2MDS Pharma Services (now Celerion), Early Clinical Research, Neptune, NJ, USA, 3Alpex Pharma S.A., Mezzovico, and 4CROSS S.A., Arzo, Switzerland
Background: Meloxicam is a non-steroidal anti-inflammatory drug, indicated for osteoarthritis exacerbations, rheumatoid arthritis and ankylosing spondylitis symptomatic treatment. Objective: To compare the bioavailability of a 15 mg meloxicam orodispersible tablet (ODT) and a reference 15 mg tablet in healthy volunteers. Methods: Two randomized, crossover, bioequivalence studies were conducted. In both studies, 28 volunteers were randomly assigned to receive test ODT and reference tablet formulations in single dose under fasting conditions in two study periods, with a 7-day (Study I) or 14-day (Study II) wash-out between administrations. Blood samples were collected at pre-specified times. Pharmacokinetic parameters were obtained by noncompartmental analysis. Bioequivalence was assumed if the 90% confidence interval of the test/reference ratio of the least-squares means for Cmax, AUC0–t and AUC0–∞were within the 80.00 –125.00% range, according to the current guidelines. Results: All 28 subjects in Study I and 26 subjects in study II completed the study and were included in the analysis. The 90% confidence intervals of the geometric means ratios for the logtransformed Cmax, AUC0–t and AUC0–∞were 87 – 96%, 88 – 96% and 87 – 96% in Study I, and 99 – 105%, 98 – 104% and 108 – 120% in Study II. Test product was characterized by a slightly earlier tmax than the reference, i.e., 4.9 ± 1.1 vs. 5.8 ± 2.6 hours in Study I (p = 1.000) and 3.8 ± 2.0 vs. 4.8 ±1.6 hours in Study II (p = 0.0054). The two drugs were well tolerated. Conclusions: Test and reference formulations met the regulatory criteria for bioequivalence in the fasting healthy volunteers enrolled.Correspondence to:
Dr. Chiara Leuratti
Cross S.A.
via L. Lavizzari 18
6850 Mendrisio, Switzerland
Email: [email protected]
Bioavailability Section
Bioequivalence assessment of a pregabalin capsule and oral solution in fasted healthy volunteers: a randomized, crossover study
Howard N. Bockbrader, Christine W. Alvey, Brian W. Corrigan and Louis L. Radulovic
Price
42.00 $
Page No. 244
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (244-248)
Bioequivalence assessment of a pregabalin capsule and oral solution in fasted healthy volunteers: a randomized, crossover study
Howard N. Bockbrader, Christine W. Alvey, Brian W. Corrigan and Louis L. Radulovic
Parke Davis Pharmaceutical Research, Ann Arbor, MI, USA (at the time the study was conducted)
Objective: To determine the oral bioavailability of a pregabalin capsule relative to a pregabalin solution. Methods: This was an open-label, randomized, crossover study in 12 healthy volunteers. Pharmacokinetics were compared for a 100-mg capsule and a 100-mg capsule dissolved in water, administered fasted. Results: Mean Cmax and AUC0–∞ for the capsule were within 2% of those for the solution (3.8 vs. 3.7 μg/ml and 26.7 vs. 27.0 μg×h/ml, respectively). The 90% confidence intervals for the ratios of Cmax and AUC0–∞ fell fully within 80 – 125%. Conclusions: A 100-mg pregabalin capsule is bioequivalent to a pregabalin solution (100-mg capsule dissolved in water).Correspondence to:
Dr. Howard Bockbrader
BEP Analyses
2749 Trailwood Lane
Ann Arbor, MI 48015, USA
Email: [email protected]
Bioavailability Section
Comparative bioavailability of two moxifloxacin tablet products after single dose administration under fasting conditions in a balanced, randomized and cross-over study in healthy volunteers
Sirimas Kanjanawart, Dhanu Gaysonsiri, Katcharin Phunikom, Sontaya Simasathiansopon, Panot Tangsucharit, Suda Vannaprasaht, Thanawat Kaewkamson and Wichittra Tassaneeyakul
Price
42.00 $
Page No. 249
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (249-254)
Comparative bioavailability of two moxifloxacin tablet products after single dose administration under fasting conditions in a balanced, randomized and cross-over study in healthy volunteers
Sirimas Kanjanawart1,2, Dhanu Gaysonsiri1, Katcharin Phunikom1, Sontaya Simasathiansopon1, Panot Tangsucharit1, Suda Vannaprasaht1,2, Thanawat Kaewkamson1 and Wichittra Tassaneeyakul1,2
1Department of Pharmacology, and 2Research and Diagnostic Center for Emerging Infectious Diseases, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Moxifloxacin, a 4th generation of fluoroquinolones, is a broad spectrum antibacterial agent against respiratory tract pathogens, including Gram-positive and Gramnegative bacteria, anaerobic bacteria and atypical respiratory tract pathogens. In order to evaluate the efficacy and safety of generic moxifloxacin products, the bioequivalence of these generic products with an approved reference formulation should be demonstrated. Thus, the aim of this study was to compare the rate and extent of absorption of a new generic film coated moxifloxacin tablet product (Rapiflox®, Atlantic Laboratories Corporation Ltd., Bangkok, Thailand) with that of a reference product (Avelox®, Bayer Health Care AG, Leverkusen, Germany) when given as a single dose. A crossover study was performed in 20 healthy Thai volunteers. The subjects received either a 400 mg tablet of the reference or test product after overnight fasting. Blood samples were collected at pre-dose (0 hour) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 34 hours post-dose. Moxifloxacin plasma level was measured by a validated HPLC method with fluorescence detector. Pharmacokinetic parameters were calculated using a non-compartmental model. The geometric mean of maximum concentration (Cmax) of the test product was 4,069.64 ng/ml, with median time to achieve maximum concentration (tmax) at 2 hours (range 0.25 – 6.00 hours), while the geometric mean Cmax and median tmax of the reference product was 4,211.98 ng/ml and 2.00 hours (range 0.25 – 8.00 hours). Furtherrmore, the geometric means of AUC0–tlast and AUC0–∞ for the test product were 49,731.66 and 51,865.89 ng×h/ml while those of the reference product were 51,927.97 and 54,455.93 ng×h/ml. The geometric mean of the ratios of Test/Reference for the logtransformed Cmax, AUC0–tlast and AUC0–∞ of moxifloxacin and their 90% CIs were 96.62% (83.21 – 112.19%), 95.77% (87.07 – 105.34%) and 95.24 (86.52 – 104.85%), respectively. Therefore, it can be concluded that these two moxifloxacin tablet products were bioequivalent in healthy Thai volunteers under fasting condition.Correspondence to:
Dr. Sirimas Kanjanawart
Department of Pharmacology
Faculty of Medicine
Khon Kaen University
Khon Kaen, 40002, Thailand
Email: [email protected]
Bioavailability Section
Pharmacokinetic comparison of two 4 mg tablet formulations of tizanidine
Mutasim Al-Ghazawi, Mamoun Alzoubi and Bashar Faidi
Price
42.00 $
Page No. 255
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 3/2013 (255-262)
Pharmacokinetic comparison of two 4 mg tablet formulations of tizanidine
Mutasim Al-Ghazawi1,2, Mamoun Alzoubi2 and Bashar Faidi3
1Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, 2Pharmaquestjo, and 3Pharma International Company Amman, Jordan
Objectives: To assess the bioequivalence of two Tizanidine 4 mg tablet formulations (Tizanidine® of the Pharma International company, as test product, and Sirdalud® of Novartis as a reference product), and to investigate possible effects of smoking on pharmacokinetics of tizanidine. Methods: A single-blind, randomized, single dose, two treatment, two-period, two-sequence, crossover bioequivalence study with 1 week washout period in 36 healthy volunteers. The drug was administered with 240 ml of water after 10-hour overnight fasting. After dosing, serial blood samples were collected for a period of 14 hours. Plasma harvested from blood was analyzed for tizanidine by a newly developed method using HPLC coupled with an MS/MS detector. The limit of quantitation of tizanidine was 0.080 ng/ml. Matrix-based calibration curves were linear over the range 0.080 – 8.00 ng/ml for tizanidine. The between- day coefficient of variation for quality control samples was less than 10%. Results: The average bioavailability measures and pharmacokinetic parameters of the two tizanidine tablets were as follows: peak plasma concentration, Cmax, was 1.21 ± 0.84 ng/ml and 1.28 ± 1.11 ng/ml for Tizanidine PIC® and Sirdalud®, respectively. The time to peak plasma concentrations tmax were 0.83 ± 0.43 and 1.01 ± 0.5 hours, while the plasma half-life (t1/2) values were 1.20 ± 0.84 and 1.29 ± 0.57 hours. The area under the plasma concentration-time profiles AUC0→last were 2.53 ± 2.10 ng×h/ml and 2.46 ± 2.23 ng×h/ ml, whereas the AUC0→∞were 2.81 ± 2.27 ng×h/ml and 2.75 ± 2.37 ng×h/ml for Tizanidine PIC® and Sirdalud®, respectively. The mean residence time (MRT) values were 2.16 ± 0.693 hours and 2.33 ± 0.65 hours. The 90% confidence intervals for test/reference ratio of Cmax, AUC0→last and AUC0→∞ were found within the acceptable limits of 0.00 –125.00%, consequently no significant difference was found between the test and reference. Conclusion: Based on the pharmacokinetic and statistical results, it was concluded that; Tizanidine PIC® 4 mg tablets is bioequivalent to Sirdalud® 4 mg tablets of Novartis and smoking decreases Cmax and AUC of tizanidine.Correspondence to:
Mutasim Al-Ghazawi
Department of Biopharmaceutics and Clinical Pharmacy
Faculty of Pharmacy, University of Jordan
P.O. Box 925819, Amman 11942, Jordan
Email: alghazam @ju.edu.jo
