Volume 52, No. 6/2014(June)
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Original
Pharmacokinetics of a new orally soluble film formulation of sildenafil administered without water
Eun-Young Kim, Sun Young Lee, Ji-Young Jeon, Yong-Jin Im, Yunjeong Kim, Hyun Il Kim, Kwan Seong Shin, Su Jun Park, Young-Hwan Seo, Jae-Yong Lee, Jong Kwan Park, Soo-Wan Chae, and Min-Gul Kim
Price
42.00 $
Page No. 437
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (437-445)
Pharmacokinetics of a new orally soluble film formulation of sildenafil administered without water
Eun-Young Kim1*, Sun Young Lee1,2*, Ji-Young Jeon1, Yong-Jin Im1, Yunjeong Kim1, Hyun Il Kim3, Seong Shin Kwak3, Su Jun Park3, Young-Hwan Seo4, Jae-Yong Lee4, Jong Kwan Park1,5, Soo-Wan Chae1, and Min-Gul Kim1
1Clinical Trial Center and Biomedical Research Institute, 2Department of Radiation Oncology, Chonbuk National University, Jeonju, 3CTCBIO Inc., Seoul, 4Biosuntek Inc., Gyeonggi-do, and 5Department of Urology, Chonbuk National University, Jeonju, Republic of Korea
Objective: To compare the pharmacokinetic profiles and to assess bioequivalence of a newly developed orally soluble film formulation of sildenafil, taken without water, with those of a conventional formulation of sildenafil. Methods: This study was conducted in a population of healthy subjects as an open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design. The subjects were randomly assigned to 1 of 2 sequences of the two formulations: an orally soluble film (OSF) of 50 mg sildenafil as the test drug and a film-coated tablet (FCT) of 50 mg sildenafil as the reference drug. Blood samples were collected at intervals from 0 to 24 hours after administration. Plasma concentrations of sildenafil and its active metabolite N-desmethyl sildenafil were analyzed using a liquid chromatography/tandem mass spectrometry method. Results: 48 healthy male subjects completed the study. The geometric mean (CV%) for Cmax in the OSF and FCT formulations were 267.21 (4.68%) ng/mL and 285.97 (5.32%) ng/mL, respectively. The geometric mean for AUClast in the OSF and FCT formulations were 664.48 (4.40%) ng×h/mL and 647.96 (4.63%) ng×h/mL, respectively. The geometric mean for AUC∞ in the OSF and FCT formulations were 685.65 (4.37%) ng×h/mL and 666.28 (4.60%) ng×h/ mL, respectively. The 90% confidence intervals of the ratios of the geometric means of the Cmax, AUClast, and AUC∞ were 0.844 – 1.030, 0.961 – 1.091, and 0.965 – 1.093, respectively. Conclusions: The OSF sildenafil formulation exhibited no significant differences in its pharmacokinetics compared with those of the FCT formulation. Therefore this convenient OSF sildenafil formulation, which can be taken without the need for water or chewing, offers physicians a novel and attractive treatment option for men with erectile dysfunction.
*These authors contributed equally to this work.Correspondence to:
Min-Gul Kim, MD, Clinical Assistan Professor
Clinical Trial Center an Biomedical Research Institute
Chonbuk National University ospital, Jeonju, Republic of Korea
Email: [email protected]
Original
Why did the FDA approve efavirenz 800 mg when co-administered with rifampin?
Jiang Liu, Kirk M. Chan-Tack, Pravin Jadhav, Shirley Seo, Sarah M. Robertson, Jeffrey Kraft, Mary E. Singer, Kimberly A. Struble, and Vikram Arya
Price
42.00 $
Page No. 446
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (446-453)
Why did the FDA approve efavirenz 800 mg when co-administered with rifampin?
Jiang Liu1, Kirk M. Chan-Tack2, Pravin Jadhav1‡, Shirley Seo3, Sarah M. Robertson3‡, Jeffrey Kraft3, Mary E. Singer2, Kimberly A. Struble2, and Vikram Arya3
1Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, 2Division of Antiviral Products, and 3Division of Clinical Pharmacology 4, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
Objectives: Literature reports regarding the efficacy of efavirenz (EFV) 600 mg with rifampin (RIF) are not consistent. Evaluation of a drug-drug interaction (DDI) study and supportive semi-mechanistic population pharmacokinetic (PK) analyses were undertaken to help delineate this issue. Design/Methods: DDI study and supportive semi-mechanistic population PK analyses were provided by BMS. Population PK analysis was based on six studies with intensive EFV PK sampling. An ACTG study with sparse PK sampling was used for model evaluation. Simulations compared EFV exposure at various doses in combination with RIF to EFV exposures at 600 mg once daily (QD). Effects of CYP2B6 genotypes on the magnitude of EFV-RIF interaction were also explored. Results: In DDI study, co-administering EFV 600 mg QD and RIF reduced mean EFV exposure by ~ 30%. Population PK model provided acceptable predictive performance of central tendency and variability for EFV C0, Cmax, and AUC. Simulations predicted that increasing EFV to 800 mg QD with RIF would result in EFV AUC and Cmax similar to EFV 600 mg QD alone. EFV AUC and Cmax were ~ 2 times higher in subjects with reduced function CYP2B6 genotypes. However, the RIF effect was consistent across all genotypes. EFV dose adjustment to 800 mg QD did not increase the risk of overexposure compared to 600 mg EFV QD within each genotype. Conclusion: Dose adjustment based on matching systemic exposure was recommended to mitigate the potential for sub-therapeutic EFV exposures. Our review did not reveal any safety concerns in subjects receiving EFV 800 mg QD with RIF.Correspondence to:
Kirk Chan Tack, MD
WO 22, Room 6337, 10903 New Hampshire Avenue
Silver Spring, MD 20993, USA
Email: [email protected]
Original
Warfarin compared with aspirin for older Chinese patients with stable coronary heart diseases and atrial fibrillation complications
Xinbing Liu, Hongman Huang, Jianhua Yu, Guoliang Cao, Liuliu Feng, Qitan Xu, Shufu Zhang, Mingcheng Zhou, and Yigang Li
Price
42.00 $
Page No. 454
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (454-459)
Warfarin compared with aspirin for older Chinese patients with stable coronary heart diseases and atrial fibrillation complications
Xinbing Liu1, Hongman Huang1, Jianhua Yu1, Guoliang Cao2, Liuliu Feng1, Qitan Xu1, Shufu Zhang1, Mingcheng Zhou3, and Yigang Li4
1Department of Cardiology, Shanghai Shi Dong Hospital, 2Department of Geriatrics, Shanghai No. 3 People’s Hospital, 3Department of Cardiology, An Tu Hospital, and 4Department of Cardiology, Xin Hua Hospital, Shanghai, China
Objective: To compare the therapeutic warfarin and aspirin efficacies for treatments of atrial fibrillation (AF) complicated with stable coronary heart disease particularly in older Chinese patients. Methods: In our prospective study 101 patients with AF and stable coronary heart disease older than 80 years were randomized into two groups. One group (n = 51) basically received 1.25 mg/day warfarin per os, followed by addition of 0.5 – 1.0 mg/day from day 3 – 5 if the international normalized ratio (INR) was initially < 1.5 and in order to achieve a maintained INR between 1.6 and 2.5 (warfarin group). The second group (n = 50) received 100 mg aspirin per day (control group). All patients were medicated and monitored for a period of 2 years. The primary endpoint was the occurrence of ischemic stroke or systemic embolism, and the composite secondary endpoint was non-fatal myocardial infarction and all causes of death. For safety evaluation, the hemorrhage rates were recorded. Results: The warfarin medication was superior regarding the overall occurrence of ischemic stroke or systemic embolism as well as non-fatal myocardial infarction and all causes of death outcomes compared to aspirin administration during the 2 years of medication (17.6% vs. 36.0%, p = 0.03), while there was no significant difference of mild (5 vs. 4), severe (2 vs. 1), and fatal (1 vs. 1) hemorrhage incidences between the warfarin and aspirin groups (p > 0.05). Conclusion: Warfarin was found to be more efficacious than aspirin for an anticoagulation therapy of older Chinese patients with AF and stable coronary heart disease.Correspondence to:
Mingcheng Zhou
Department of Cardiology, An Tu Hospital
No. 200 Yanji East Road, Shanghai, 200093, China
Email: [email protected]
Original
In-depth investigation for prescribing trends of benzodiazepines in South Korea
Sung-Hee Oh, Kang Seob Oh, Kyoung-Uk Lee, Jong-Min Woo, Boung-Chul Lee, Jin Seub Hwang, EunJeong Park, Su Jin Kwak, and Jin-Won Kwon
Price
42.00 $
Page No. 460
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (460-470)
In-depth investigation for prescribing trends of benzodiazepines in South Korea
Sung-Hee Oh1, Kang Seob Oh2, Kyoung-Uk Lee3, Jong-Min Woo4, Boung-Chul Lee5, Jin Seub Hwang1, EunJeong Park1, Su Jin Kwak1, and Jin-Won Kwon1,6
1National Evidence-based Healthcare Collaborating Agency, Seoul, 2Department of Psychiatry, School of Medicine, Sungkyunkwan University, Seoul, 3Department of Psychiatry, Uijeongbu St. Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, 4Department of Psychiatry and Stress Research Institute, Inje University Seoul Paik Hospital, Seoul, 5Department of Psychiatry, Hangang Sacred Heart Hospital, Hallym University, Seoul, and 6College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea
This study aimed to investigate national prescription trends of benzodiazepines (BZD) for adults between 2007 and 2011 using Health Insurance Review and Assessment Service (HIRA) database in South Korea. Data analysis was performed by claim unit or patient unit. For the analysis of patient unit, each claim was merged by the same patient. Defined daily dose (DDD) was used to analyze the data in terms of dose and periods of BZD prescription. We identified a total of 22,361,449 adult patients who had BZD prescription at least once in 1,989,263 claims during 5 years. The average national BZD prescription prevalence for 1 year was 23.7%, 7.9%, 4.7%, and 3.2% of ≥ 1 day supply, ≥ 30 days supply, ≥ 90 days supply, and ≥ 180 days supply, respectively. The trends for 5 years were very similar. Among study population, 87.7% visited only non-psychiatric departments and the most frequent indication was gastrointestinal related diseases. BZD consumption expressed as DDDs per 1,000 inhabitants per day was 109.2. BZD consumption tended to be ~ 4 × higher in elderly than that of non-elderly (268.6 vs. 60.0 in male and 367.7 vs. 90.9 in female). Our study indicated the possibilities for inappropriate prescription of BZD, and the limitation policy on continuous prescription over 30 days supply did not seem to be effective. The effective interventions including an educational program for appropriate prescription of BZD should be considered.Correspondence to:
Jin-Won Kwon, MPH, PhD
College of Pharmacy and Research Institute of Pharmaceutical Sciences
Kyungpook National University
80 Daehak-ro, Buk-gu, Daegu 702-701, South Korea
Email: [email protected]
Original
C5 variant is associated with decreased risk of coronary artery disease in outpatients with severe hypercholinesterasemia
Daiji Nagayama, Takeyoshi Murano, Atsuhito Saiki, Kohji Shirai, and Ichiro Tatsuno
Price
42.00 $
Page No. 471
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (471-477)
C5 variant is associated with decreased risk of coronary artery disease in outpatients with severe hypercholinesterasemia
Daiji Nagayama1, Takeyoshi Murano2, Atsuhito Saiki1, Kohji Shirai1, and Ichiro Tatsuno1
1Center of Diabetes, Endocrinology and Metabolism, and 2Department of Clinical Laboratory Medicine, Toho University, Sakura Medical Center, Sakura-City, Chiba, Japan
Objective: Although the C5 variant of cholinesterase is known to be a cause of hypercholinesterasemia, the pathophysiological significance of the C5 variant and the C5 variant-related hypercholinesterasemia in cardiovascular diseases remain unclear. The present study aimed to clarify the pathophysiological significance of the C5 variant as a risk or protective factor for coronary artery disease (CAD) in patients with severe hypercholinesterasemia. Methods: Severe hypercholinesterasemia was defined as serum cholinesterase (ChE) activity ≥ 450 IU/L (≥ 2.0 SD). We screened 11,648 consecutive outpatients between 2005 and 2011 at Toho University, Sakura Medical Center. In patients with severe hypercholinesterasemia, phenotyping of the C5 variant was conducted using polyacrylamide gel electrophoresis and α-naphthyl butyrate staining. Results: 157 subjects (1.4% of 11,648 outpatients screened) were diagnosed with severe hypercholinesterasemia (mean serum ChE activity 574 ± 109 IU/L), and the frequency of the C5 variant was 45.2%. Subjects with the C5 variant had higher age, lower body mass index, milder dyslipidemia and liver dysfunction, and lower rates of hypertension and CAD compared with subjects without the C5 variant. Multivariate logistic regression model demonstrated that the presence of C5 variant independently lowered the risk of CAD, with odds ratio 0.071 (95% confidence interval (CI) 0.007 – 0.763, p = 0.029). Conclusion: The prevalence of the C5 variant was relatively high, and the C5 variant is associated with decreased risk of CAD in outpatients with severe hypercholinesterasemia.Correspondence to:
Dr. Ichiro Tatsuno
Center of Diabetes Endocrinology and Metabolism
Toho University, Sakura Medical Center
564-1, Shimoshizu, Sakura- City, Chiba 285-8741, Japan
Email: [email protected]
Original
Pharmacokinetics, pharmacodynamics, and tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers
Renli Teng and Kathleen Butler
Price
42.00 $
Page No. 478
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (478-491)
Pharmacokinetics, pharmacodynamics, and tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers
Renli Teng and Kathleen Butler
AstraZeneca LP, D2C-253, Wilmington, DE, USA
Objectives: Two studies assessing ticagrelor pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and Caucasian volunteers. Materials and methods: Single-ascending dose (SAD) study: Japanese (n = 20) and Caucasians (n = 20) received single doses of ticagrelor (50, 100, 200, 300, 400, and 600 mg) or placebo. Multiple-ascending dose (MAD) study: Japanese (n = 36) and Caucasians (n = 36) received single doses of 100 mg or 300 mg ticagrelor (day 1), twice-daily 100 mg or 300 mg ticagrelor, or placebo (days 4 – 9), and single doses of 100 mg or 300 mg ticagrelor (day 10). Results: Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally higher in Japanese vs. Caucasians. In the SAD study, area under the plasma concentration-time curve (AUC) values were 33% (ticagrelor) and 55% (AR-C124910XX) greater in Japanese vs. Caucasians following 600 mg ticagrelor. In the MAD study, AUC values of ticagrelor and AR-C124910XX following multiple doses of ticagrelor 100 mg and 300 mg were statistically significantly greater (33 – 48%) in Japanese vs. Caucasians. In both groups, mean peak inhibition of platelet aggregation was > 86% after single doses (≥ 100 mg ticagrelor) and > 84% after multiple doses. Bleeding times were ≥ 60 minutes in more Japanese than Caucasians with multiple dosing of 100 mg and 300 mg ticagrelor Adverse events were similar between groups (mild-to-moderate intensity). Conclusions: The pharmacokinetics and tolerability of ticagrelor were broadly similar in Japanese and Caucasians, although exposure was slightly greater in Japanese volunteers. Ticagrelor was generally well tolerated.Correspondence to:
Dr. Renli Teng, PhD, Clinical Pharmacology
AstraZeneca LP, FOC W1-677
1800 Concord Pike, P.O. Box 15437
Wilmington, DE 19850-5437, USA
Email: [email protected]
Original
Filgrastim use in the emergency department of a Spanish general hospital
Francisco José Rodríguez-Lucena, Leticia Soriano-Irigaray, Carmen Matoses- Chirivella, Inmaculada P. Jiménez-Pulido, José M. del Moral-Sánchez, Maria Morante-Hernández, and Andrés Navarro-Ruiz
Price
42.00 $
Page No. 492
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (492-496)
Filgrastim use in the emergency department of a Spanish general hospital
Francisco José Rodríguez-Lucena, Leticia Soriano-Irigaray, Carmen Matoses- Chirivella, Inmaculada P. Jiménez-Pulido, José M. del Moral-Sánchez, Maria Morante-Hernández, and Andrés Navarro-Ruiz
Pharmacy Service, General Universitary Hospital of Elche, Elche, Spain
Background: Febrile neutropenia is a cause of dose reduction in hematological cancer treatments, with patient risk of infection proportional to duration and severity. In addition, colony-stimulating factors have been shown to be beneficial in a patient subgroup, although they are probably overused in the clinical setting. Objective: Evaluation of compliance with American Society of Clinical Oncology 2006 criteria when it comes to filgrastim use in the Emergency Department of a Spanish general hospital. Methods and materials: A prospective observational study from August 2011 to February 2012 in a tertiary Spanish General Hospital. We included all patients prescribed with filgrastim in the Emergency Department. Data was collected on demographics, the pharmacotherapy history, the administered chemoprophylaxis, and the destination after discharge from a clinical department, the complete blood count, and the presence of fever ≥ 38 °C. Results: 51 patients were recorded over the period of the study. 27.45% of prescriptions complied with the clinical practice guideline criteria given the risk of febrile neutropenia, whereas 72.34% of prescriptions did not comply with the criteria, 17.65% of which did not fulfil any requirements. Conclusions: A high percentage of colony-stimulating factors use in the Emergency Department does not comply with the medical practice guideline.Correspondence to:
Francisco José Rodríguez-Lucena, MD
Pharmacy Service of the Hospital
General Universitario de Elche
Camino de la Almazara 11, 03203, Elche, Spain
Email: [email protected]
Original
Association of CYP3A4*18B and CYP3A5*3 polymorphism with cyclosporine-related liver injury in Chinese renal transplant recipients
Hua-wen Xin, Hui-ming Liu, Yuan-qi Li, Hui Huang, Li Zhang, Ai-rong Yu, and Xiao-chun Wu
Price
42.00 $
Page No. 497
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (497-503)
Association of CYP3A4*18B and CYP3A5*3 polymorphism with cyclosporine-related liver injury in Chinese renal transplant recipients
Hua-wen Xin1, Hui-ming Liu1, Yuan-qi Li2, Hui Huang2, Li Zhang2, Ai-rong Yu1, and Xiao-chun Wu1
1Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, and 2Monitoring Center for Adverse Reaction of Drugs and Medical Instruments of Hubei Province, Wuhan, China
Objective: The purpose of this study was to investigate the associations between CYP3A4*18B and CYP3A5*3 polymorphism and cyclosporine-related liver injuries in Chinese renal transplant recipients. Methods: We genotyped 339 renal transplant recipients treated with a triple immunosuppressive regimen including cyclosporine for CYP3A4*18B and CYP3A5*3 polymorphism using the polymerase chain reaction restriction fragment length polymorphism assay. Results: The incidence of liver injury in the study population was 36.9% (125/339). At 1 month after transplantation, the trough concentration of cyclosporine (C0) in the group with CYP3A4*1/*1(GG alleles) was significantly higher than in the group with CYP3A4*18B/*1 8B(AA alleles) (p < 0.05). At 3 months after transplantation, the C0 in the group with CYP3A4*1/*1 and group with CYP3A4*1/*18B was markedly higher than in the group with CYP3A4*18B/*18B (p < 0.05). The GG genotypes of CYP3A4*18B were more common in the liver injury group compared with the control group (p < 0.05). Univariate logistic regression analysis showed that subjects carrying the GG genotypes had a 5.136- and 2.528-fold higher risk of developing cyclosporine-related liver injury than those with the AA and GA genotypes. When adjusted for sex, the risk of the CYP3A4*18B genotypes was OR = 4.969 for GG compared to AA (p = 0.030), and OR = 2.634 for GG compared to GA (p = 0.025). However, no association was observed between CYP3A5*3 polymorphisms with cyclosporine-related liver injury. Conclusions: These results suggested that the wild type of CYP3A4*18B is a risk factor for the development of cyclosporine- related liver injuries in Chinese renal transplant recipients.Correspondence to:
Hua-Wen Xin, MD, PhD
Department of Clinical Pharmacology
Wuhan General Hospital of Guangzhou Command
627 Wuluo Road, Wuhan, 430070, China
Email: [email protected]
Original
Lower-dose warfarin delays renal progression and prolongs patient survival in patients with stage 3 – 5 chronic kidney disease and nonvalvular atrial fibrillation: a 12-year follow-up study
Ping-Fang Chiu, Ching-Hui Huang, Hung-Hsiang Liou, Chia-Lin Wu, Chirn-Bin Chang, Chia-Chu Chang, and Horng-Rong Chang
Price
42.00 $
Page No. 504
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (504-508)
Lower-dose warfarin delays renal progression and prolongs patient survival in patients with stage 3 – 5 chronic kidney disease and nonvalvular atrial fibrillation: a 12-year follow-up study
Ping-Fang Chiu1,2,3, Ching-Hui Huang4, Hung-Hsiang Liou3, Chia-Lin Wu3, Chirn- Bin Chang3, Chia-Chu Chang2,3*, and Horng-Rong Chang1,2*
1Institute of Medicine, 2School of Medicine, Chung Shan Medical University, Taichung, 3Nephrology Division, and 4Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
Background: Anticoagulants are used to reduce the risk of stroke in patients with atrial fibrillation (Af) and chronic kidney disease (CKD). Warfarin is one of the commonly used anticoagulants; however, its effect on renal function remains unclear. Methods: In a retrospective cohort study (January 2001 – July 2013), we surveyed data charts from 2,450 patients with stage 3 – 5 CKD, and enrolled 159 patients with Af. In total, 104 patients had a CHADS2 score of ≥ 2 (congestive heart failure, hypertension, ≥ 75 years old, diabetes, 1 point; prior stroke or transient ischemic attack or thromboembolism, 2 points). These patients were categorized into groups A and B based on warfarin treatment. Group A included 73 patients and was not undergoing warfarin treatment and group B included 31 patients undergoing warfarin treatment. The baseline demographic and biochemical data as well as changes in estimated glomerular filtration rate (eGFR) after 6, 12, and 18 months of warfarin treatment were analyzed. We also studied censored patient survival over 12 years using Kaplan-Meier model. Results: The mean international normalization ratio (INR) of warfarin treatment in group B was 1.92 ± 1.04. Moreover, group B showed a significant increase in eGFR. The maximum improvement was at 6 months (mean eGFR increased from 25.97 to 31.12 mL/min; p = 0.01) and lasted for up to 18 months (eGFR 28.65 mL/min). Despite higher initial CHADS2 scores, group B showed a superior survival rate compared with group A (p = 0.02). Conclusion: Lower doses of warfarin may protect against renal dysfunction and could be beneficial for treatment of stage 3 – 5 CKD with Af.Correspondence to:
Chia-Chu Chang, MD
Division of Nephrology, Department of Internal Medicine
Changhua Christian Hospital, 135 Nanhsiao St., Changhua 500, Taiwan
Email: [email protected]
Original
A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development
Rajesh Sachdeo, Arnaud Partiot, Victor Biton, William E. Rosenfeld, Virinder Nohria, Debra Tompson6, Sarah DeRossett, and Roger J. Porter
Price
42.00 $
Page No. 509
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (509-518)
A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development
Rajesh Sachdeo1, Arnaud Partiot2*, Victor Biton3, William E. Rosenfeld4, Virinder Nohria5, Debra Tompson6, Sarah DeRossett7, and Roger J. Porter2**
1NJ Comp Epilepsy Center, Capital Health Neuroscience Department, Hopewell, NJ, 2Wyeth Research, Clinical Research and Development, Collegeville, PA, 3Arkansas Epilepsy Program, Little Rock, AR, 4The Comprehensive Epilepsy Care Center For Children and Adults, St. Louis, MO, 5111 Skyline View Road, Franklin, NC, USA, 6GlaxoSmithKline, Stevenage, Hertfordshire, UK, and 7GlaxoSmithKline, Research and Development, Research Triangle Park, NC, USA
Objective: To obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy. Materials: Study 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 – 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 × daily). The RTG dose was increased every 1 – 2 weeks by 50 – 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient’s background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients’ seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (≥ 50% reduction in seizure rate from baseline) were evaluated. Results: 60 patients (mean age 37.2, range 16 – 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling “drunk”, confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance. Conclusions: Studies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately.
*Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA
**Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USACorrespondence to:
Roger J. Porter, MD
University of Pennsylvania
461 Timber Lane, Devon, PA 19333-1232, USA
Email: [email protected]
Original
The effect of experimentally induced sleep disturbance on the pharmacokinetics of lorazepam in healthy volunteers
Tsutomu Kotegawa, Kimiko Tsutsumi, Hiromitsu Imai, Kyoichi Ohashi, and Shigeyuki Nakano
Price
42.00 $
Page No. 519
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (519-524)
The effect of experimentally induced sleep disturbance on the pharmacokinetics of lorazepam in healthy volunteers
Tsutomu Kotegawa1, Kimiko Tsutsumi2, Hiromitsu Imai1, Kyoichi Ohashi1, and Shigeyuki Nakano2
1Department of Clinical Pharmacology and Therapeutics, and 2Department of Pharmaceutical Medicine and Communication, Oita University Faculty of Medicine, Oita, Japan
The aim of this study was to evaluate the effect of sleep disturbance on the pharmacokinetics, especially on the absorption, of lorazepam in humans. Eight healthy male volunteers received a single oral dose of lorazepam 1 mg before sleep on two occasions in a cross-over design. In either of the two doses, subjects were intermittently exposed to noise for 1.5 hours after oral lorazepam administration. Plasma lorazepam concentrations were measured by HPLC. The exposure to noise significantly prolonged tmax (control vs. noise: 2.0 vs. 3.0 hours) and significantly decreased AUC of lorazepam in the absorption phase. The reduction was 54% (95% CI, 15 – 75%) and 24% (3 – 40%) for AUC (0 – 1 hours) and AUC (0 – 3 hours), respectively. No significant changes were observed in other pharmacokinetic parameters. The results of this study suggest that the onset of drug action after oral lorazepam administration can be altered by sleep disturbance.Correspondence to:
Tsutomu Kotegawa, Associate professor, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Oita University Faculty of Medicine
Idaigaoka, Hasama-machi, Yufu-shi 879-5593, Japan
Email: [email protected]
Case Report
Teicoplanin-induced hepatocellular liver injury: a case report and literature review of 17 cases in mainland China
Jian-Xiang Xie, Ji-Fu Wei, and Ling Meng
Price
42.00 $
Page No. 525
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (525-529)
Teicoplanin-induced hepatocellular liver injury: a case report and literature review of 17 cases in mainland China
Jian-Xiang Xie, Ji-Fu Wei, and Ling Meng
Research Division of Clinical Pharmacology, The First Affiliate Hospital of Nanjing Medical University, Nanjing, Jiangsu, The People’s Republic of China
We report a rare case of teicoplanin- induced hepatocellular liver injury in a 49-year-old male patient with pulmonary infection. Liver function returned to normal after drug withdrawal. We reviewed 17 case reports of adverse reactions associated with teicoplanin in mainland China and found that (1) among all patients 15 were male and 53% of patients were elderly, (2) red man syndrome, anaphylactic shock and symptom of hematological system were common, (3) red man syndrome, excitement and anaphylactic shock related to teicoplanin reported in mainland China were very rare abroad. The clinician should be vigilant about the adverse reaction of teicoplanin and further studies are needed to explore the pathogenesis.Correspondence to:
Ji-Fu Wei and Ling Meng, MD
Research Division of Clinical Pharmacology
The First Affiliate Hospital of Nanjing Medical University
Nanjing, Jiangsu 210029, China
Email: [email protected] and [email protected]
Bioavailability Section
Pharmacokinetics and bioequivalence of sildenafil granules and sildenafil tablets in Korean healthy volunteers
Renhua Zheng and Bo-Hyung Kim
Price
42.00 $
Page No. 530
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 6/2014 (530-536)
Pharmacokinetics and bioequivalence of sildenafil granules and sildenafil tablets in Korean healthy volunteers
Renhua Zheng1 and Bo-Hyung Kim1,2
1Department of Clinical Pharmacology and Therapeutics, and 2East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Republic of Korea
Background: A sildenafil tablet formulation as a PDE-5 inhibitor is widely used for the treatment of erectile dysfunction. Recently, a fine granular formulation of sildenafil was developed by a domestic Korean pharmaceutical company. Objectives: This study was performed to compare the bioavailability of sildenafil fine granules with that of sildenafil tablets for assessing bioequivalence in 40 healthy male volunteers. Methods: This was an open-label, randomized sequence, single-dose, two-period, and two-treatment crossover study. Half of the volunteers received a single dose of sildenafil fine granule 50 mg and then sildenafil tablet 50 mg after a 7-day washout period. The remaining half of volunteers received the tablet first and the the granule with the same washout period. 10- mL blood samples were serially sampled to measure the concentrations of sildenafil and the N-desmethyl metabolite. Tolerability was assessed during the study. Results: The pharmacokinetic parameters of sildenafil were similar between granular and tablet formulations. The 90% CI of geometric mean ratios (sildenafil granule/tablet) for the pharmacokinetic parameters of sildenafil were within 0.8 – 1.25, as a bioequivalent acceptable range; 1.111 (90% CI, 1.002 – 1.231) for maximum plasma concentration (Cmax) and 1.092 (1.019 – 1.117) for area under the concentration- time curve from time zero to time of last measurable concentration (AUClast). Also, the 90% CI of geometric mean ratios for Cmax and AUClast of the metabolite were within 0.8 – 1.25. Both formulations were well tolerated by volunteers. Conclusion: This study confirmed that sildenafil granules and sildenafil tablet are bioequivalent with regards to pharmacokinetics of sildenafil and N-desmethyl sildenafil.Correspondence to:
Bo-Hyung Kim, MD, PhD
Department of Clinical Pharmacology and Therapeutics
East-West Medical Research Institute
Kyung Hee University College of Medicine
and Hospital Seoul, Republic of Korea
23 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-872, Korea
Email: [email protected]
