Volume 55 (2017), No. 2/2017(February)
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Original Research
CYP3A4*1G and CYP3A5*3 genetic polymorphisms alter the antihypertensive efficacy of amlodipine in patients with hypertension following renal transplantation
Yun Huang, Gaiyan Wen, Yao Lu, Jia Wen, Ying Ji, Xiaowei Xing, Ying Li, Juan Wen, and Hong Yuan
Price
42.00 $
Page No. 109
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (109-118)
CYP3A4*1G and CYP3A5*3 genetic polymorphisms alter the antihypertensive efficacy of amlodipine in patients with hypertension following renal transplantation
Yun Huang*, Gaiyan Wen*, Yao Lu, Jia Wen, Ying Ji, Xiaowei Xing, Ying Li, Juan Wen, and Hong Yuan
Center for Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, China
Objective: Previous studies have determined that CYP3A and multidrug resistance protein 1 (MDR1) polymorphisms can affect the pharmacokinetics and pharmacodynamics of amlodipine in both healthy subjects and those with early hypertensive renal disease. In the current study, our objective was to analyze the association between the CYP3A4*1G, CYP3A5*3, and MDR1 C3435T gene polymorphisms and the antihypertensive efficacy of amlodipine in hypertensive patients after renal transplantation. Materials: Blood samples were collected from 76 patients on amlodipine therapy (5 mg/d). Methods: The CYP3A4*1G, CYP3A5*3, and MDR1 C3435T genetic polymorphisms were detected using both polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and gene sequencing. Subsequently, antihypertensive effects were analyzed according to genotype, and blood pressure values were measured and recorded weekly. Results: Four weeks of treatment with amlodipine was sufficient to successfully control blood pressure in 79% of patients. The efficacy of amlodipine in patients with the CYP3A5*3*3 genotype was significantly higher than that in patients with other CYP3A5 genotypes (p < 0.05). In addition, the reduction in diastolic blood pressure (DBP) in patients with the CYP3A5*3*3 and CYP3A4*1G*1G genotypes was significantly higher than that in patients with other CYP3A5 and CYP3A4 genotypes, respectively (p < 0.05). Furthermore, we found that linkage disequilibrium exists between the CYP3A4 *1G and CYP3A5*3 alleles and observed that the most significant reduction in DBP occurred in patients with the *1/*1 and *3/*3 genotype. Conclusions: Our study demonstrates that amlodipine treatment may effectively control blood pressure (BP) for hypertensive patients following renal transplantation. Additionally, we found that the CYP3A5*3 polymorphism affects the antihypertensive efficacy of amlodipine in Chinese hypertensive patients after renal transplantation.
*These authors contributed equally to this work.Correspondence to:
Hong Yuan, MD, PhD, F.A.C.C
Center of Clinical Pharmacology (Department of Cardiology)
The Third Xiang-Ya Hospital
Central South University
138 Tong-Zi-Po Road, Changsha, Hunan 410013, China
Email: [email protected]
Original Research
Treatment persistence in the use of basal insulins in Poland and Germany
Wolfgang Rathmann, Marcin Czech, Edward Franek, Karel Kostev
Price
42.00 $
Page No. 119
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (119-125)
Treatment persistence in the use of basal insulins in Poland and Germany
Wolfgang Rathmann1, Marcin Czech2, Edward Franek3, Karel Kostev4
1Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Duesseldorf, Germany,
2Real World Evidence, IMS Health, Warsaw, 3Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland, and 4Epidemiology, IMS Health, Frankfurt am Main, Germany
Aims: To compare short-term basal insulin therapy persistence and its predictors in Poland and Germany. Methods: Persistence was defined as proportions of patients remaining on the initial basal insulin (analogs: Poland: n = 6,889, Germany: n = 454,067; neutral protamine Hagedorn (NPH) insulins: Poland: n = 50,761, Germany: n = 226,064) over 2 years based on nationwide prescription databases (LRx; IMS Health) in Poland and Germany from 2013 to 2015. Persistence was evaluated by Kaplan-Meier curves (log-rank tests). Risk of discontinuation of initial basal insulin was investigated using Cox regression models adjusting for age, sex, comedication with other glucose-lowering agents and baseline or comedication with antihypertensives, lipid-lowering drugs, antidepressants, and antiepileptics. Results: In Poland, 2-year persistence was 83.0% in analog insulin and 73.3% in NPH users (p < 0.001). In Germany, persistence was also higher in patients with analog insulins (92.6% vs. 79.0%; p < 0.001). Analog insulin users were less likely to discontinue basal insulin compared with NPH users (adjusted hazard ratio (95%CI): Poland: 0.73 (0.67 – 0.79); Germany: 0.27 (0.27 – 0.28)). Higher age (> 75 vs. ≤ 60 years: Poland: 1.24 (1.16 – 1.33), Germany: 1.09 (1.07 – 1.11)) and GLP-1 receptor agonist use (Poland: 2.76 (1.38 – 5.53), Germany: 1.21 (1.16 – 1.26)) were related to higher risk of discontinuation. Male sex, metformin, sulfonylurea, thiazolidinedione, and short-acting insulin prescriptions as well as antihypertensive, antiepileptic, and lipid-lowering drug use were associated with lower risk of discontinuation in both countries (all p < 0.05). Conclusions: This real-world study shows that both in Poland and Germany treatment persistence of newly-prescribed basal insulin is influenced by type of insulin (analog vs. NPH) and by glucose-lowering and other comedications.
Correspondence to:
Prof. Dr. rer. med.
Karel Kostev
Epidemiology IMS HEALTH GmbH & Co. OHG
Darmstädter Landstraße 108
60598 Frankfurt am Main
Email: [email protected]
Original Research
Warfarin dose requirement with different genotypes of polymorphisms on CYP2C9 and VKORC1 and indications in Han-Chinese patients
Weirong Chen, Luhua Wu, Xin Liu, Yue Shen3, Yan Liang, Jun Zhu, Huiqiong Tan, Yanmin Yang, Qun Liu, Mingsheng Wang, Lisheng Liu, and Xingyu Wang
Price
42.00 $
Page No. 126
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (126-132)
Warfarin dose requirement with different genotypes of polymorphisms on CYP2C9 and VKORC1 and indications in Han-Chinese patients
Weirong Chen1#2*, Luhua Wu1#2*, Xin Liu1#3, Yue Shen3, Yan Liang4, Jun Zhu4, Huiqiong Tan4, Yanmin Yang4, Qun Liu5, Mingsheng Wang5, Lisheng Liu1, and Xingyu Wang1#3
1Beijing Hypertension League Institute, Beijing, 2First Affiliated Hospital, Medical College of Shantou University, Shantou, 3National Research Institute for Family Planning, 4Fu Wai Hospital, and 5Beijing ShiJingShan Hospital, Beijing, China
Aims: To investigate whether genetic variants of CYP2C9 and VKORC1 have different effects on the dose of warfarin in 180 Han Chinese patients who were recruited from the Fu Wai Hospital. All were on maintenance treatment with stable daily warfarin doses for a period of at least 3 months. Methods: DNA was isolated and genotyped using a Warfarin dosage Prediction Kit for single nucleotide polymorphisms (SNPs) of CYP2C9 and VKORC1. Results: The VKORC1 and CYP2C9*3 polymorphisms are significantly associated with warfarin maintenance dosages. Patients with AG&GG genotype in VKORC1 needed higher doses than those with AA genotypes (4.55 ± 1.27 mg/ day vs. 2.90 ± 0.97 mg/day, p < 0.001). Patients with *1/*3 genotype in CYP2C9 need doses lower than those with *1/*1 genotypes (1.73 ± 0.95 mg/day vs. 3.23 ± 1.13 mg/day, p < 0.001). There were no significant differences between the warfarin maintenance dosages in patients with atrial fibrillation (3.09 ± 1.16 mg/day), patients with heart valve replacement (2.95 ± 1.21 mg/day) and those with both atrial fibrillation and heart valve replacement (3.36 ± 1.13 mg/day) (p > 0.05). The mean warfarin daily dose requirements in the genotypes of VKORC1 and CYP2C9 were not dependent on the medical indication(s) present. Conclusions: Genetic variants of CYP2C9, VKORC1, and age are significant determinants of the maintenance dose of warfarin. The medical indications atrial fibrillation, valve replacement, or a combination of both are not determinants of the warfarin dose requirements.
*These authors contributed equally to this work.Correspondence to:
Xingyu Wang, PhD
Beijing Hypertension League Institute
24 Shijingshan Road, Beijing, 100043 China
Email: [email protected]
Original Research
Post-authorization changes in the safety and efficacy assessment, recommended indications, and drug quality profile of adalimumab: a chronological overview
Gergely Iványi and Romána Zelkó
Price
42.00 $
Page No. 133
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (133-137)
Post-authorization changes in the safety and efficacy assessment, recommended indications, and drug quality profile of adalimumab: a chronological overview
Gergely Iványi and Romána Zelkó
Faculty of Pharmacy, University Pharmacy Department of Pharmacy Administration, Semmelweis University, Budapest, Hungary
Objective: The intention of the present study was to demonstrate the postauthorization changes of adalimumab (European trade name: Humira), evaluating the variations in its safety, efficacy, and quality profile. Methods: Type-II, major variations of the Summary of Product Characteristics (SmPC) from September 8, 2003 to November 19, 2015, were analyzed, which, according to Commission Regulation (EC) No. 1234/2008, have to reflect changes that may have a significant impact on the safety, efficacy, or quality profile of a medicinal product. A unique scoring system was developed to estimate the influence of post-authorization variations in the safety and efficacy assessment, recommended indications, and drug-quality profile of adalimumab. Results: In the past 13 years, adalimumab has been proven to be beneficial in 12 indications. In this time period, the safety-related subsections of the SmPC expanded the most. 27.12% of the total changes were found in subsection 4.8 (Undesirable effects), 19.77% in subsection 4.4 (Special warnings and precautions for use). Section 5 (Pharmacological properties) was also significantly modified (19.77%) thanks to the numerous clinical trials studying the effects of adalimumab. Concerning the total changes in the content of the SmPC, 58.4% was safety, 29.4% efficacy, and only 1.8% was quality-related alteration. The rest, 10.4%, was considered as administrational modification. Conclusion: The extensive postauthorization research (both surveillance and clinical trials) significantly have increased our knowledge about the efficient and safe use of the medicine and have made adalimumab one of the top-10 selling pharmaceuticals worldwide. Regarding ongoing clinical trials, more pediatric indications are expected.Correspondence to:
Prof. Romána Zelkó, PhD, DSc
7-9 Hogyes E. Street, 1092 Budapest, Hungary
Email: [email protected]
Original Research
Evaluation of area under the curve of enteric-coated mycophenolate sodium by limited sampling strategy in Chinese kidney transplant recipients
Hongfeng Huang, Xi Yao, Jianyong Wu, Wenhan Peng, Jianghua Chen
Price
42.00 $
Page No. 138
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (138-146)
Evaluation of area under the curve of enteric-coated mycophenolate sodium by limited sampling strategy in Chinese kidney transplant recipients
Hongfeng Huang*, Xi Yao*, Jianyong Wu, Wenhan Peng, Jianghua Chen
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Aims: To investigate the area under the curve (AUC) of mycophenolic acid (MPA) in adult Chinese renal allograft recipients receiving concomitant enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine (CsA) during the early post-transplant phase and to develop optimal model equations for estimation of the MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC0–12h) using a limited-sampling strategy (LSS). Methods: The present study enrolled 24 Chinese renal recipients treated with EC-MPS, CsA, and corticosteroid, from whom 24 serial blood samples were collected over 12 hours. MPA concentration was evaluated with enzyme multiplied immunoassay technique (EMIT). LSS was developed by multiple stepwise regression analysis using a two-group method (test group, n = 12; and validation group, n = 12). Results: The MPA predose concentration had a poor correlation with MPA AUC0–12h, and the best equations obtained from the test group were the following: 25.73 + 0.59 × C1.5 + 0.79 × C2 + 2.03 × C4 (for three time points, r2 = 0.761) and 22.13 + 1.7 × C0.5 + 0.61 × C1.5 + 0.78 × C2 + 1.83 × C4 (for four time points, r2 = 0.853). When these equations were tested in the validation group, there were no significant differences in prediction errors. Conclusion: An LSS using time points at 1.5, 2, and 4 hours or 0.5, 1.5, 2, and 4 hours provides the most accurate and reliable estimation of the MPA AUC0–12h in Chinese adult renal recipients treated concomitantly with EC-MPS and CsA during the early post-transplant phase.
*These two authors contributed equally to this work.Correspondence to:
Jianghua Chen, MD
Kidney Disease Center, The First Affiliated Hospital
College of Medicine, Zhejiang University
No.79 Qingchun Road, Hangzhou,
Zhejiang Province 310003, China
Email: [email protected]
Original Research
Pharmacokinetics and safety of indacaterol and glycopyrronium (IND/GLY) following repeated once daily inhalation from a fixed-dose combination in healthy Chinese subjects
Shuang Ren, Romain Sechaud, Zhenzhong Su, Hanns-Christian Tillmann, Hisanori Hara, Xuemei Tan, Jie Hou, Ralph Woessner, Rong Zhao
Price
42.00 $
Page No. 147
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (147-155)
Pharmacokinetics and safety of indacaterol and glycopyrronium (IND/GLY) following repeated once daily inhalation from a fixed-dose combination in healthy Chinese subjects
Shuang Ren1, Romain Sechaud2, Zhenzhong Su1, Hanns-Christian Tillmann2, Hisanori Hara2, Xuemei Tan3, Jie Hou4, Ralph Woessner2, Rong Zhao1
1Novartis Institutes for Biomedical Research, Shanghai, China, 2Novartis Institutes for Biomedical Research, Basel, Switzerland, 3Novartis Institutes for Biomedical Research, Beijing, and 4Tianjin Economic Department Area (TEDA) International Cardiovascular Hospital, Tianjin, China
Objective: Indacaterol/glycopyrronium (IND/GLY) is a once-daily fixed-dose combination of two long-acting bronchodilators: indacaterol 110 µg (long-acting β2-adrenergic agonist, LABA) and glycopyrronium 50 µg (long-acting muscarinic antagonist, LAMA). This study assessed the pharmacokinetics of IND/GLY 110/50 µg following multiple once-daily inhaled administrations in healthy Chinese subjects. Methods: This was a single-centre, open-label, multiple-dose study of inhaled IND/GLY delivered via the Breezhaler® device. Pharmacokinetic samples were collected on day 1 after first dose, on days 5, 7, 10, and 12 (predose (trough)) and on day 14 (steady state) after last dose for pharmacokinetic analysis using non-compartmental analysis. Results: Both IND and GLY were absorbed rapidly after inhalation of IND/GLY (tmax: IND, 15 minutes; GLY, 5 minutes). Accumulation through systemic exposure of both IND and GLY from day 1 to day 14 was observed (mean accumulation ratio (Racc) of AUC0–24h (day 14/day 1): IND, 3.02; GLY 2.94; estimated accumulation ratio of Cmax: IND 1.56; GLY 1.33). Mean effective half-life (t1/2,acc) was 41.3 h and 40.0 h for IND and GLY, respectively. Pharmacokinetic steady states were reached after 12 and 10 days of daily dosing for IND and GLY, respectively. There was one mild adverse event (AE) not related to the study drug. No discontinuations due to treatment related AEs/SAEs (adverse event/serious adverse event) were reported. Conclusions: In healthy Chinese subjects, multiple once-daily inhaled doses of IND/GLY 110/50 µg were rapidly absorbed and were safe and well tolerated. The comparison of systemic exposure data following inhalation of IND/GLY 110/50 µg in Chinese vs. the non-Chinese populations did not indicate any clinically relevant differences across ethnicities.
Correspondence to:
Rong Zhao, PhD
Novartis Institutes for Biomedical Research
4218 Jinke Road, Pudong New District, Shanghai, China
Email: rong.zhao@
novartis.com
Original Research
Blood lipid abnormality changes the rate of alveolar-capillary uptake of sevoflurane: a prospective, non-interventional, clinical study
YanQiu Liu, YiMin Ren, Hong Gao, Li Zeng, ShaoFeng Lin, KaiQiang Zhang
Price
42.00 $
Page No. 156
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (156-162)
Blood lipid abnormality changes the rate of alveolar-capillary uptake of sevoflurane: a prospective, non-interventional, clinical study
YanQiu Liu, YiMin Ren, Hong Gao, Li Zeng, ShaoFeng Lin, KaiQiang Zhang
Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, China
Objective: This research studied the influence of different blood lipid components on the rate of alveolar-capillary uptake of sevoflurane. Method: 104 patients aged 20 – 50 years undergoing elective operations under general anesthesia were mechanically ventilated through endotracheal intubation after intravenous injections of midazolam, vecuronium, fentanyl, and etomidate. They inhaled 2% sevoflurane at an oxygen flow of 2 L/min, then the inspired concentrations (FI) and expired concentrations (FA of sevoflurane were recorded at 1, 3, 5, 7, 10, 15, 20, and 30 minutes. These cases were divided into a normal group and an abnormal group according to the lipid levels. Then, based on the lipid criteria, those cases with abnormal lipid levels were classified into a high-triglyceride (TG) and total-cholesterol (TC) group (group TG+TC) and a group with decreased high-density lipoprotein cholesterol (group HDL-C).The values of FA/FI and the times required to reach the titration value FA/FI = 0.8 were calculated were calculated for each group. Results: Compared with the normal group, FA/FI decreased within 7 – 10 minutes (p < 0.05) and the time taken to reach the titration value was prolonged in the abnormal group (p < 0.05). The value of FA/FI decreased during 7 – 10 minutes (p < 0.05) and the time taken to reach the titration value was longer (p < 0.05) in the group TG+TC. Conclusions: The increased value of blood/gas partition coefficients (B/G) was caused by the increase in the concentrations of TG and TC in blood lipids.
Correspondence to:
Hong Gao, MD
Department of Anesthesiology
The Affiliated Hospital of Guizhou Medical University
Guizhou Medical University
Guiyang, Guizhou, 550004, China
Email: [email protected]
Original Research
A study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in Chinese gout patients: a retrospective cohort study
Qiao Zhou, Jiang Su, Ting Zhou, Juan Tian, Jing Chen
Price
42.00 $
Page No. 163
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (163-168)
A study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in Chinese gout patients: a retrospective cohort study
Qiao Zhou, Jiang Su, Ting Zhou, Juan Tian, Xixi Chen, and Jing Zhu
Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
Objective: To evaluate and compare the safety and efficacy of three urate lowering agents: febuxostat, allopurinol, and benzbromarone, when used to treat Chinese gout patients. Methods: A total of 120 patients treated in our department from November 2011 to December 2014 were randomly selected and divided into four groups: febuxostat (40 mg per day), febuxostat (80 mg per day), allopurinol (100 mg, 3 × per day) or benzbromarone (50 mg per day), (n = 30 patients/group). The serum uric acid (UA) concentrations of the patients in each group were recorded and compared from week 2 through week 24 after the treatments, and all adverse events were evaluated to determine the safety of the various treatment regimens. Results: Treatment with febuxostat (40 mg) significantly reduced serum UA levels to those achieved with allopurinol or benzbromarone treatment. The treatment with febuxostat (80 mg) produced the best therapeutic effect and achieved the targeted UA level as early as week 2. However, the total number of patients experiencing adverse events was significantly higher in the febuxostat 80-mg group. The incidences of abnormal liver function, hyperlipidemia, and gout flare were higher in both febuxostat treatment groups. The allopurinol group had a higher incidence of hypersensitivity, and the benzbromarone group had a higher incidence of renal dysfunction. Conclusion: Chinese patients treated with the 40-mg dose of febuxostat experienced a treatment effect and total rate of adverse events similar to those produced by allopurinol or benzbromarone. To achieve a better therapeutic effect, the dose of febuxostat can be elevated to 80 mg per day; however, patients receiving the higher dose must be closely monitored for signs of liver dysfunction. Febuxostat is an alternative treatment for Chinese gout patients who are at a much higher risk for severe cutaneous adverse reactions as well as for patients with a history of kidney stones.
Correspondence to:
Jing Zhu, MD
32# W. Sec 2, 1st Ring Road
Chengdu, Sichuan, 610072, China
Email: [email protected]
Letter to the Editor
Individualized dosing of enoxaparin in a morbidly obese patient by monitoring the anti-factor Xa
Faizan Mazhar and Yousif Ahmed
Page No. 169
Abstract
Individualized dosing of enoxaparin in a morbidly obese patient by monitoring the anti-factor Xa
Faizan Mazhar1#2 and Yousif Ahmed3
1Prince Sultan Military College of Health Sciences, 2Department of Clinical Pharmacy, and 3Department of Clinical Pharmacy, King Fahad University Hospital, Al-Khobar, Saudia Arabia
Correspondence to:
Faizan Mazhar, PhD, MPhil, BCPS
Prince Sultan Military College of Health Sciences
Department of pharmaceutical care
King Fahd Military Medical Complex, Dhahran, Saudia Arabia
Email: [email protected]
Bioavailability Section
Bioequivalence of two formulations of pregabalin 150-mg capsules under fasting conditions in healthy male subjects
Hyun Lee, SeungHwan Lee, Sung-Vin Yim, Bo-Hyung Kim
Price
42.00 $
Page No. 171
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (171-176)
Bioequivalence of two formulations of pregabalin 150-mg capsules under fasting conditions in healthy male subjects
Hyun Lee1,2, SeungHwan Lee2, Sung-Vin Yim3, Bo-Hyung Kim3,4
1Program in Biomedical Radiation Sciences, Program in Biomedical Radiation Sciences, Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 3Department of Clinical Pharmacology and Therapeutics, and 4East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Korea
Background: Pregabalin binds to the α2δ auxiliary subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems and modulate calcium-dependent neurotransmitter release. Pregabalin is indicated for the treatment of peripheral and central neuropathic pain, partial seizures with or without secondary generalization, and treatment of generalized anxiety disorder (GAD). Objective: The purpose of this study was to assess the bioequivalence of two different formulations of pregabalin 150-mg capsules in healthy Korean male subjects under fasting conditions. Methods: This bioequivalence study was based on an open-label, single-dose, randomized, 2-period, 2-sequence crossover design with a washout period of 7 days. Blood samples for pharmacokinetic (PK) evaluation were collected up to 24 hours postdose. Plasma concentrations of pregabalin were determined using a validated LC-MS/MS method. PK parameters were determined using noncompartmental analysis. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of log-transformed Cmax and AUClast values met the bioequivalence criteria specified by Korean regulatory guidelines (90% CI 0.8 – 1.25). Results: The extent of exposure in terms of AUClast amounted to 26,018.3 – 3,580.8 µg×h/L for the test formulation and 25,680.2 ± 3,083.6 µg×h/L for the reference formulation. Cmax reached values of 4,782.7 ± 1,124.2 µg/L and 4,654.0 ± 911.4 µg/L for the test product and reference product, respectively. The geometric mean ratio and 90% CIs of the test product to the reference product were 1.0132 (0.9862 – 1.0351) for AUClast and 1.0153 (0.9351 – 1.1044) for Cmax, which were well within the range necessary to establish bioequivalence (90% CI 0.8 – 1.25). Conclusions: The bioequivalence between test and reference formulations under fasting conditions was confirmed both in terms of the rate and extent of absorption.
Correspondence to:
Bo-Hyung Kim, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Kyung Hee University College of Medicine and Hospital
23 Kyungheedae-ro, Dongdaemun-gu,
Seoul 130-872, Korea
Email:
[email protected]
Bioavailability Section
Comparative pharmacodynamic effects of two clopidogrel formulations under steady-state conditions in healthy Thai volunteers
Nontaya Nakkam, Somsak Tiamkao, Sirimas Kanjanawart, Kutcharin Phunikhom, Siriporn Tiamkao, Suda Vannaprasaht, Wongwiwat Tassaneeyakul, and Wichittra Tassaneeyakul
Price
42.00 $
Page No. 177
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (177-185)
Comparative pharmacodynamic effects of two clopidogrel formulations under steady-state conditions in healthy Thai volunteers
Nontaya Nakkam1, Somsak Tiamkao2,3, Sirimas Kanjanawart1, Kutcharin Phunikhom1, Siriporn Tiamkao1,3, Suda Vannaprasaht1, Wongwiwat Tassaneeyakul4, and Wichittra Tassaneeyakul1
1Department of Pharmacology, 2Department of Medicine, 3North-Eastern Stroke Research Group, Faculty of Medicine, Khon Kaen University, Khon Kaen, and 4Faculty of Pharmacy, Mahasarakham University, Mahasarakham, Thailand
Objective: Clopidogrel is a commonly used antiplatelet aggregation agent. Compared with the reference clopidogrel product, most commercially available generic clopidogrel products contain different crystalline forms of clopidogrel. This study was aimed to compare the pharmacodynamics of a commonly used generic clopidogrel product in Thailand with the reference clopidogrel product under steady state conditions. Methods: A multiple-dose, randomized 2-way crossover study was conducted in 32 healthy male Thai volunteers. The subjects were assigned to receive 75 mg once daily of the test or the reference product for 7 days with a 2-week wash out period. Blood samples were collected on days 1, 5, 6, and 7 prior to drug administration and at 1, 2, 3, 4, 8, 12, and 24 hours after the last dose administered. The antiplatelet aggregation effects of clopidogrel were determined by using two different ex-vivo platelet aggregation tests including the whole blood impedance assay (WBA) and the VerifyNow® P2Y12 assay. Both pharmacodynamic parameters, the maximal antiplatelet effect (Emax) and the areas under the antiplatelet effect-time curve (AUEC0–24h), were calculated. Results: Neither the mean values of Emax (90.70 ± 15.15 vs. 89.50 ± 10.71% inhibition) nor of AUEC0–24h (1,892.84 ± 657.22 vs. 1,853.58 ± 673.95% inhibition × h) under steady-state conditions obtained using the WBA method of these two clopidogrel products were significantly different. The results obtained using the VerifyNow® P2Y12 assay were consistent with those of the WBA assay. Conclusion: This study clearly demonstrated that ex-vivo antiplatelet aggregation effect under steady-state conditions of the test product was not significantly different from the reference product.
Correspondence to:
Prof. Wichittra Tassaneeyakul, PhD
Department of Pharmacology, Faculty of Medicine
Khon Kaen University
Khon Kaen 40002, Thailand
Email: [email protected] or [email protected]
Bioavailability Section
A single dose, randomized, open-label, cross-over bioequivalence study of sildenafil citrate tablets in healthy Chinese volunteers
Dai Li, Yu-Lu Wang, Su-Mei Xu, Dan Li, Xiao-Min Li, Jing Pan, Ping-Sheng Xu
Price
42.00 $
Page No. 186
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (186-193)
A single dose, randomized, open-label, cross-over bioequivalence study of sildenafil citrate tablets in healthy Chinese volunteers
Dai Li1*, Yu-Lu Wang2*, Su-Mei Xu2, Dan Li1, Xiao-Min Li1, Jing Pan1, Ping-Sheng Xu1
1National Institution of Drug Clinical Trial, and 2Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
Objective: The present study was designed to evaluate the bioequivalence of a newly developed sildenafil citrate tablet 50 mg (Jinge®, Test) and a marketed counterpart (Viagra®, 100 mg, Reference) in healthy adult male Chinese volunteers. Methods: This single-dose, randomized, open-label, four-period, and two-treatment self-crossover study included two parts: fasting and postprandial studies. In each part of the study, the subjects were randomly assigned to receive test or reference products (100 mg sildenafil) in a 1 : 1 ratio, and then received the alternative products, following a 1-week washout period. Plasma sildenafil concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Tolerability was assessed during the entire study period. Results: 32 healthy volunteers (aged 19 – 30) were enrolled in the study; 31 volunteers completed the fasting study, while 32 volunteers completed the postprandial study. The test formulation was bioequivalent to the marketed formulation as the 90% CIs for the ratio of geometric means of Cmax (fasting: 98.79 – 119.61%; fed: 94.47 – 119.65%), AUClast (fasting: 98.70 – 109.71%; fed: 96.39 – 112.89%), and AUC∞ (fasting: 98.45 – 108.87%; fed: 96.36 – 112.74%) were within equivalence limits (80 – 125%) under both fasting and postprandial conditions. When sildenafil was given with high-fat meals, mean Cmax was reduced by 23%, and median tmax ranged from 0.75 to 1.50 hours (p ≤ 0.05). However, both AUClast and AUC∞ were comparable between fasting and postprandial conditions. No serious adverse events were found among the subjects. Conclusions: This study confirmed that test and reference sildenafil citrate tablets were bioequivalent under fasting and postprandial conditions.
*These authors contributed equally to this work.Correspondence to:
Ping-Sheng Xu, M.M.
National Institution of Drug Clinical Trial
Xiangya Hospital, Central South University
Changsha, 410008, China
Email: [email protected]
Bioavailability Section
The pharmacokinetic comparison and bioequivalence evaluation of two 10-mg baclofen formulations in healthy male subjects
Sumin Yoon, SeungHwan Lee, Kyung-Sang Yu, Sung-Vin Yim, Bo-Hyung Kim
Price
42.00 $
Page No. 194
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 2/2017 (194-200)
The pharmacokinetic comparison and bioequivalence evaluation of two 10-mg baclofen formulations in healthy male subjects
Sumin Yoon1, SeungHwan Lee1, Kyung-Sang Yu1, Sung-Vin Yim2, Bo-Hyung Kim2#3
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Department of Clinical Pharmacology and Therapeutics, and 3East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Korea
Backgrounds: Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients. It depresses the transmission of monosynaptic and polysynaptic reflex by stimulating GABAβ (gamma-aminobutyric acid) receptors. Objectives: The aim of this study was to compare the pharmacokinetic characteristics of two 10-mg baclofen formulations and to assess bioequivalence. Methods: A randomized, single-dose, two-period, two-sequence crossover study was conducted in healthy male subjects. Each subject received the test or reference formulations. After washout period, all subjects received the alternative formulation. Blood samples were collected for up to 24 hours after the dose in each period. Pharmacokinetic (PK) parameters, including tmax, Cmax, and AUClast were calculated by noncompartmental methods. The geometric mean ratio (GMR) of the test to the reference formulation and its 90% confidence interval (CI) for Cmax and AUClast were calculated for assessment of bioequivalence. Results: A total of 22 subjects completed the study. The median tmax of the test and the reference formulation were 1.50 and 1.25 hours, respectively. The mean (± SD) Cmax of the test and the reference formulation were 141.401 ± 29.447 ng/mL and 138.837 ± 31.392 ng/mL, respectively. The mean (± SD) AUClast of the two formulations were 702.404 ± 82.149 ng×h/mL and 726.803 ± 90.638 ng×h/mL, respectively. The GMR (90% CI) of the test to the reference formulation for the Cmax and AUClast were 1.0306 (0.9564 – 1.1106) and 0.9674 (0.9437 – 0.9916), respectively. Conclusions: The two different baclofen 10-mg formulations had similar PK profiles and were bioequivalent based on Cmax and AUClast.
Correspondence to:
Bo-Hyung Kim, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Kyung Hee University College of Medicine and Hospital
23 Kyungheedae-ro, Dongdaemun-gu,
Seoul 02447, Korea
Email: [email protected]
