Volume 53, No. 9/2015(September)
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Original Research
QT-prolonging effects of monoclonal antibody drugs in humans: a systematic review of two literature and a public adverse event database
Torquil Jackson, Jelena Kondic, and Joerg Seebeck
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42.00 $
Page No. 705
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (705-711)
QT-prolonging effects of monoclonal antibody drugs in humans: a systematic review of two literature and a public adverse event database
Torquil Jackson, Jelena Kondic, and Joerg Seebeck
Prime Vigilance Ltd., Guildford, UK
Drug-induced prolongation of the electrocardiogram QT interval, a risk factor for ventricular arrhythmia and death, has been observed for some small drugs with masses < 1 kDa. Over the last two decades, patient exposure to large molecule monoclonal antibody drugs with masses > 40 kDa has increased dramatically; hence, the aim of this study was to systematically review the scientific literature for evidence of QT prolongation induced by these drugs. Methods: The PubMed and Embase databases were searched for cases indicative of druginduced QT prolongation for 28 preidentified monoclonal antibody drugs authorized in Europe. Cases were identified by applying a standardized search string and a subsequent text search and manual review. In parallel, the public European Medicines Agency (EMA) database was searched for reported frequencies of adverse events indicative of QT prolongation. Results: A valid case of drug-induced QT prolongation, caused indirectly by hypocalcaemia, could be identified for only 1 out of 28 monoclonal antibody drugs (denosumab) from the PubMed and Embase search. The EMA database showed no hits for denosumab. Considering that hypocalcaemia-mediated QT prolongation is an already-identified and labelled risk for denosumab, the current study did not identify any additional evidence of QT prolongation caused by monoclonal antibody drugs. Correspondence to:
Joerg Seebeck, MD
26-28 Frederick Sanger Road
Guildford GU2 7YD, UK
Email: [email protected]
Original Research
Physicians’ and pharmacists’ acceptance of online, real-time “drug combinations to avoid” messages
Dong-Sook Kim, Ha-Lim Jeon, Sukhyang Lee, and Nam Kyung Je
Price
42.00 $
Page No. 712
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (712-721)
Physicians’ and pharmacists’ acceptance of online, real-time “drug combinations to avoid” messages
Dong-Sook Kim1, Ha-Lim Jeon1, Sukhyang Lee2, and Nam Kyung Je3
1Research Team, Health Insurance Review & Assessment Service, Seoul, 2College of Pharmacy, Ajou University, Suwon, and 3College of Pharmacy, Pusan National University, Busan, Korea
Background: Computerized physician order entry (CPOE) systems combined with a clinical decision-support system (CDSS) can prevent potential drug-therapy problems; however, medication-related decision- support alerts with low specificity often generate alert fatigues and are ignored by health-care providers. The computerized prospective drug utilization review (DUR) program supported by the Korean government has been providing “drug combinations to avoid (DCA)” alerts to physicians and pharmacists since December 2010. Objectives: The aim of this study is to explore providers’ responses to DCA alerts and identify the characteristics of institutions, providers, and drug components associated with providers’ acceptance of online, real-time DCA messages. Methods: A retrospective analysis was conducted on the DUR prescription-transfer data from April 1, 2011 to March 31, 2012 in South Korea. The frequency of DCA alerts and provider acceptance was observed in two ways: “within-prescription review” and “between-prescriptions review”. Multivariate regression was used to determine the predictors of acceptance. Results: The overall acceptance rate was 37.9%, which was relatively high compared with the results from the previous studies with regular drug-drug interaction (DDI) alerts. The acceptance rates varied depending on the origin and types of DCA. The types and location of institutions and severity of DCA were positive predictors of alert acceptance. Conclusions: To improve providers’ adaptation to DCA alerts, various strategies, including tiering, applying human factors, and eliminating inappropriate alerts should be considered.Correspondence to:
Nam Kyung Je, PharmD
Pusan National University
College of Pharmacy, Research Bldg
#532, Busandaehakro 63 Bungil 2,
Geumjeong-Gu, Busan 609-735, Korea
Email: [email protected]
Original Research
Prescription patterns of psychotropic medications and use of electroconvulsive therapy in Chinese patients with dementia
Lu Li, Zhi-Min Wang, Helen F.K. Chiu, Gabor S. Ungvari, Chee H. Ng, Ada W.Y. Tse, Grace K.I. Lok, Jian-Song Zhou, and Yu-Tao Xiang
Price
42.00 $
Page No. 722
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (722-727)
Prescription patterns of psychotropic medications and use of electroconvulsive therapy in Chinese patients with dementia
Lu Li1, Zhi-Min Wang2, Helen F.K. Chiu3, Gabor S. Ungvari4,5, Chee H. Ng6, Ada W.Y. Tse3, Grace K.I. Lok7, Jian-Song Zhou8, and Yu-Tao Xiang1,2
1Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao SAR, 2Mood Disorders Center, Beijing Anding Hospital, Capital Medical University, 3Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China, 4The University of Notre Dame Australia / Marian Center, 5School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, 6Department of Psychiatry, University of Melbourne, Melbourne, Australia, 7Kiang Wu Nursing College of Macau, Macao SRA, and 8Mental Health Institute of the Second Xiangya Hospital, Central South University, Hunan and Key Laboratory of Psychiatry and Mental Health of Hunan Province, China
Background: Little is known about psychiatric pharmacotherapy and somatic treatments in dementia in China. This study examined the prescription patterns of psychotropic medications and use of electroconvulsive therapy (ECT) in dementia patients hospitalized in a psychiatric institution in Beijing, China. Methods: This was a retrospective chart review of 401 patients with dementia treated over a period of 7 years (2007 – 2013) in a university-affiliated psychiatric institution in Beijing. Socio-demographic and clinical data were collected from the electronic chart management system (ECMS) for discharged patients. Results: Nearly all patients (96.8%) received psychotropic medications in order of frequency: second-generation antipsychotics (83.0%), benzodiazepines (77.8%), first generation antipsychotics (39.7%), antidepressants (29.7%), and mood stabilizers (24.7%). The rate of polypharmacy and ECT use was 82.0% and 3.7%, respectively. Prescription of mood stabilizers was associated with longer length of hospitalization. Conclusions: In a major psychiatric hospital in China, ECT was sporadically used in patients with dementia, while the vast majority of patients received at least one type of psychotropic medication. Factors contributing to the high use of psychopharmacological interventions in this population warrant further investigations.Correspondence to:
Dr. Zhi-Min Wang
Mood Disorders Center, Beijing Anding Hospital, China
or
Dr. Yu-Tao Xiang
3/F, Building E12, Faculty of Health Sciences
University of Macau, Avenida da Universidade
Taipa, Macau SAR, China
Email: [email protected] or [email protected]
Original Research
The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients
Jing-Jing Zhang, Shuai-Bing Liu, Ling Xue, Xiao-Liang Ding, Hua Zhang, and Li-Yan Miao
Price
42.00 $
Page No. 728
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (728-736)
The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients
Jing-Jing Zhang1, Shuai-Bing Liu1,2, Ling Xue1, Xiao-Liang Ding1, Hua Zhang1, and Li-Yan Miao1,2
1Department of Clinical Pharmacology Research Lab, The First Affiliated Hospital of Soochow University, and 2College of Pharmaceutical sciences, Soochow University, Suzhou, China
Purposes: The aims of this study were to assess the influence of the polymorphism of cytochrome P450 oxidoreductase (POR) as well as other relevant genes (CYP3A4, CYP3A5, ABCB1) on individual variability of tacrolimus pharmacokinetics and perform population pharmacokinetic analysis of tacrolimus in Chinese renal transplant recipients. Methods: Tacrolimus trough whole blood concentrations and clinical details were retrospectively collected from 83 renal recipients. CYP3A4*1G, CYP3A5*3, and ABCB1 C3435T were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), POR*28 and CYP3A4*22 were genotyped by sequencing method. Population pharmacokinetic analysis was performed using NONMEM program. Results: The significant influences of CYP3A5*3, CYP3A4*1G, and POR*28 polymorphisms on tacrolimus dose-adjusted trough concentrations (C0/D) were observed in 83 renal recipients. Subgroup analysis showed that POR*28 polymorphisms significantly decreased tacrolimus C0/D by 1.50 – 1.84-fold (p < 0.05) in patients who were CYP3A5 expressers (CYP3A5*1 carriers, n = 46), while similar results could not be obtained from CYP3A5 non-expressers (CYP3A5*3/*3 carriers, n = 37). Additionally, population pharmacokinetic analysis identified that the combined genotype of CYP3A5-POR was the only covariant for the apparent clearance of tacrolimus (CL/F). Conclusions: The study demonstrated that the POR*28 C>T mutation could decrease the C0/D of tacrolimus in renal recipients who were CYP3A5 expressers. The population pharmacokinetic model showed that the combined genotype of CYP3A5-POR was associated with the CL/F of tacrolimus which might provide references for personalized use of tacrolimus in clinic.Correspondence to:
Prof. Dr. Li-yan Miao
Department of Clinical Pharmacology Research Lab
The First Affiliated Hospital of Soochow University
Soochow, China
Email: [email protected]
Original Research
Effect of CYP3A4*1G, CYP3A5*3, POR*28, and ABCB1 C3435T on the pharmacokinetics of nifedipine in healthy Chinese volunteers
Xiao-Fei Wang, Liang Yan, Hui-Min Cao, Lu-Man Wei, Wei-Hong Yang, Sheng-Jun Zhang, and Li-Rong Zhang
Price
42.00 $
Page No. 737
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (737-745)
Effect of CYP3A4*1G, CYP3A5*3, POR*28, and ABCB1 C3435T on the pharmacokinetics of nifedipine in healthy Chinese volunteers
Xiao-Fei Wang1,2*, Liang Yan2*, Hui-Min Cao2, Lu-Man Wei2, Wei-Hong Yang2, Sheng-Jun Zhang3, and Li-Rong Zhang2
1Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 2Department of Pharmacology, School of Basic Medical Sciences, and 3Clinical Research Center, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
Objective: Nifedipine is a calcium channel blocker that is widely used in the treatment of cardiovascular disease. However, significant individual variances in the disposition of nifedipine have been reported, and genetic factors are considered to play an important role. The aim of the present study was to investigate the effect of CYP3A4*1G, CYP3A5*3, ABCB1-C3435T, and POR*28 genetic polymorphisms on nifedipine pharmacokinetics in healthy Chinese volunteers. Methods: 45 healthy Chinese volunteers enrolled in this study received a single oral dose of 90 mg nifedipine after providing written informed consent. Volunteers were genotyped for CYP3A4*1G, CYP3A5*3, POR*28, and ABCB1-C3435T. The blood concentrations of nifedipine were determined by high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Results and discussion: There were significant differences of AUC0–∞ and AUC0–48h in the different CYP3A5*3 genotype groups (p = 0.043 and p = 0.048, respectively). The CYP3A5*3 GG group and POR*28 CT/TT group were found to have lower AUC0–∞ and Cmax compared with the POR*28 CC group (p = 0.046 and p = 0.002, respectively). In addition, the POR*28 CT/TT group was found to have longer t1/2 but lower Cmax than the CYP3A4*1G GG group (p = 0.032 and p = 0.002, respectively) as well as the CYP3A4*1G GG and the CYP3A5*3 GG group (p = 0.038 and p = 0.036, respectively) compared with the POR*28 CC group. No significant associations were found between CYP3A4*1G/ABCB1-C3435T polymorphism and pharmacokinetics of nifedipine. Conclusion: Both CYP3A5*3 and POR*28 polymorphisms are found to be associated with the difference in disposition of nifedipine; POR*28 is considered to have an impact on CYP3A4 activity.Correspondence to:
Prof. Li-Rong Zhang, PhD
Department of Pharmacology, School of Medicine
Zhengzhou University
100 Science Road, Zhengzhou 450001, China
Email: [email protected] and [email protected]
Original Research
Pioglitazone inhibits the secretion of proinflammatory cytokines and chemokines in astrocytes stimulated with lipopolysaccharide
Dong Qiu and Xiang-Nan Li
Price
42.00 $
Page No. 746
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (746-752)
Pioglitazone inhibits the secretion of proinflammatory cytokines and chemokines in astrocytes stimulated with lipopolysaccharide
Dong Qiu1 and Xiang-Nan Li2
1Department of Clinical Laboratory, Henan Medical College and 2Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
Neuroinflammation caused by the secretion of cytokines and chemokines by glial cells can promote the development of neurodegenerative disorders. The aim of this study was to explore the effects of pioglitazone (Pio), a drug that induces release of inflammatory mediators, on cytokine and chemokine secretion in astrocytes stimulated with lipopolysaccharide (LPS) to induce inflammation. Astrocytes obtained from the cerebral cortex of newborn C57BL/6 mice and grown in culture were stimulated with LPS and treated with Pio. Treatment of astrocytes with LPS significantly increased the levels of pro-inflammatory factors nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8, but decreased the level of anti-inflammatory factors IL-4 and IL-10 (p < 0.05) compared to untreated control astrocytes. Pio treatment in LPS-stimulated astrocytes had the opposite effect, inhibiting secretion of NO, TNF-α, IL-1β, IL-6, and IL-8 and enhancing IL-4 and IL-10 secretion (p < 0.05). In addition, Pio treatment suppressed the expression of pro-inflammatory chemokines Ccl20, Mcp-1, and Mip-1α mRNA in astrocytes stimulated with LPS (p < 0.05). These results showed that Pio can inhibit the neuroinflammatory response in LPS-activated astrocytes and this response may result from the regulation of cytokine and chemokine secretion from astrocytes.Correspondence to:
Dong Qiu, MS
Department of Clinical Laboratory
Henan Medical College
No. 8 Xinzhenglonghu Zhenshuanghudadao,
Zhengzhou 451191, Henan Province, China
Email: [email protected]
Original Research
Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers
Noushin Brealey, Ashutosh Gupta, Jessica Renaux, Rashmi Mehta, Ann Allen, and Alex Henderson
Page No. 753
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (753-764)
Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers
Noushin Brealey1, Ashutosh Gupta2, Jessica Renaux3, Rashmi Mehta4, Ann Allen5, and Alex Henderson6
1Respiratory Medicines Development Centre, GSK, Uxbridge, UK, 2Quantitative Sciences India, GSK, Bangalore, India, 3Respiratory Clinical Pharmacology Science and Study Operations, GSK, Uxbridge, UK, 4Research Triangle Park, NC, USA, 5Clinical Pharmacology Modelling and Simulation Department, GSK, Stevenage, and 6Clinical Pharmacology Science and Study Operations, GSK, Stevenage, UK
Objective: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/ umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. Methods: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPTA® dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 μg, FF/UMEC 400/500 μg, UMEC/VI 500/100 μg, or FF/VI 400/100 μg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 μg or 400/250/100 μg, FF/VI 400/100 μg, or UMEC/VI 250/100 μg. PK and PD parameters and safety were assessed. Results: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. Conclusions: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies.
This article was corrected in:
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 1/2016, pp 76-80Correspondence to:
Noushin Brealey, MSc MRCGP
Clinical Development Director
MDC Global Clinical, RD Respiratory R&D, GSK
Stockley Park West, 1 – 3 Ironbridge Road
Uxbridge, Middlesex, UB11 1BT, UK
Email: [email protected]
Original Research
Pharmacokinetic/pharmacodynamic research on three different infusion time regimens of linezolid in healthy Chinese volunteers
Yun Cai, Nan Bai, Xu Liu, Beibei Liang, Jin Wang, and Rui Wang
Price
42.00 $
Page No. 765
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (765-771)
Pharmacokinetic/pharmacodynamic research on three different infusion time regimens of linezolid in healthy Chinese volunteers
Yun Cai, Nan Bai, Xu Liu, Beibei Liang, Jin Wang, and Rui Wang
Center of Medicine Clinical Research, Translational Medical Center, PLA General Hospital, Beijing, China
Objective: To evaluate the pharmacokinetic and pharmacodynamic (PK/PD) results of three different infusion time regimens of single doses of 600 mg linezolid in healthy Han Chinese volunteers. Methods: We conducted a clinical trial involving 6 male and 6 female healthy Chinese volunteers. They were randomized to receive intravenous linezolid infusion (600 mg/0.5 hours, 600 mg/2 hours, or 600 mg/4 hours) in three periods with washout periods of 7 days between each dosage. Serum linezolid concentration was measured in each subject at pre-dose (at 0 hours) until 24 hours after each dose. The ratio of the area under the serum concentration-time curve (AUC) to the minimum inhibitory concentration (MIC), AUC/MIC, was adopted as the major relevant parameter. Monte Carlo simulation was used to evaluate the probability of target attainment (PTA) of these three linezolid regimens. Results: One subject in 600 mg/0.5 hours regimen complained of mild pain at the injection site. No significant difference was found in pharmacokinetic parameters among the three different infusion regimens. When AUC/MIC was applied as parameter, PTA of 4 hours infusion regimen was much lower than that of the 0.5 hours and 2 hours infusion regimens (55.65% vs. 74.91% and 72.03%, respectively). Especially at higher MIC (2 μg/mL), the PTAs of the 0.5 hours and 2 hours infusion regimens decreased to 57.2% and 50.1%, respectively, while that of the 4 hours infusion regimen dropped sharply to only 25.95%. When T>MIC was applied as a parameter, PTA of the 0.5 hours regimen was higher than 90%, while the 2 hours and 4 hours regimens remained 100%. Conclusion: Our findings suggest that 2 hours infusion of linezolid at a fixed dose (600 mg) regimen is appropriate to achieve the safety and efficacy against MRSA-caused infections in Chinese adults.Correspondence to:
Rui Wang, MD
Center of Medicine, Clinical Research
The PLA General Hospital
28 Fu Xing Road, Beijing 100853, China
Email: [email protected]
Original Research
Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers
Pieter-Jan de Kam, Jacqueline H.M. van Kuijk, Anthe . Zandvliet, and Torben Thomsen
Price
42.00 $
Page No. 772
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (772-782)
Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers
Pieter-Jan de Kam1, Jacqueline H.M. van Kuijk2, Anthe S. Zandvliet2, and Torben Thomsen3
1MSD Singapore, Singapore, 2MSD BV, Oss, The Netherlands, and 3CRS Clinical Research Services Andernach GmbH, Mönchengladbach, Germany
Objective: Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/or proarrhythmic potential as compared to placebo in healthy post-menopausal women. Materials: Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 μg, corifollitropin alfa 240 μg, and moxifloxacin 400 mg with placebo. Methods: This randomized, doubleblind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 μg (therapeutic dose), corifollitropin alfa 240 μg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. Results: The largest time-matched mean QTcF difference versus placebo for the therapeutic dose of cConclusions: For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all timepoints, the UL 95% CI for the timematched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women.Correspondence to:
Pieter-Jan de Kam, PhD
MSD Singapore, Clinical Research, MSD Pharma
8 Biomedical Grove, #04-01/05, Neuros Building, Biopolis
138665 Singapore, Singapore
Email: [email protected]
Case Report
Posterior reversible encephalopathy syndrome and graft-versus-host disease after liver transplantation: a case report and review of the literature
Li-Qin Zhu, Sha-Sha Liao, Wen-Tao Jiang, and Yi-He Liu
Price
42.00 $
Page No. 783
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (783-787)
Posterior reversible encephalopathy syndrome and graft-versus-host disease after liver transplantation: a case report and review of the literature
Li-Qin Zhu1, Sha-Sha Liao1,3, Wen-Tao Jiang2, and Yi-He Liu2
1Department of Pharmacy, Tianjin First Central Hospital, Tianjin, 2Department of Transplantation, Tianjin First Central Hospital, Tianjin, and 3Department of Basic Medicine, Tianjin Medical University, Tianjin, China
Case (description): A 52-yearold male patient presented with seizures on the 16th day post liver transplantation suggesting tacrolimus-associated posterior reversible encephalopathy syndrome (PRES). On the 18th day, the patient was diagnosed with graft-versus-host disease (GVHD). Calcineurin inhibitor (CNI) was stopped and the patient received 1 g methylprednisolone and 25 g immunoglobulin. However, on the 21st day, the patient’s clinical condition progressively worsened and he died of multi-organ failure. GVHD could have occurred with PRES because the CNI dose was reduced. The best treatment for patients with PRES and GVHD is using immunosuppressants other than CNI. Antibody preparations and steroids could be a standard treatment.Correspondence to:
Yi-He Liu, BD
Department of Transplantion
Tianjin First Center Hospital
No.24 Fukang Road, Nankai District, Tianjin, 300192, China
Email: [email protected]
Bioavailability Section
Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study
Daniela Baldoni, Shirin Bruderer, Naguib Muhsen, and Jasper Dingemanse
Price
42.00 $
Page No. 788
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 9/2015 (788-798)
Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study
Daniela Baldoni1, Shirin Bruderer1, Naguib Muhsen2, and Jasper Dingemanse1
1Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland and 2QPS, Groningen, The Netherlands
Objective: Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. Film-coated tablets with strength between 200 and 1,600 μg were used. Bioequivalence between 8 × 200 μg and a new 1,600 μg tablet was evaluated at steady state in healthy male subjects. Materials and methods: This was an open-label, 2-treatment, 2-period, crossover, up-titration, phase 1 study. The treatments were selexipag at 1,600 μg b.i.d. for 4.5 days either as 8 × 200 μg tablets (reference: A) or 1 × 1,600 μg tablet (test: B), both preceded by an up-titration phase starting from 400 μg b.i.d. doses, in 200-μg steps every 4th day. Subjects were randomized 1 : 1 to the A-B or B-A sequence. The pharmacokinetics and tolerability of selexipag and its active metabolite, ACT-333679, were investigated. Results: 80 subjects were enrolled in the study: 65 subjects completed the study according to protocol, and 15 subjects withdrew from the study. The most frequent adverse events (AEs) were headache (86%), myalgia (73%), and jaw pain (73%). There was no difference in nature and overall frequency of AEs between the two treatments. Steady state was attained within 3 days of the selexipag 1,600 μg b.i.d. treatments. The 90% confidence intervals (CIs) of the geometric mean ratio (B/A) at steady state for AUCτ and Cmax,ss were within (0.80, 1.25) bioequivalence interval: (0.92, 1.06) and (0.95, 1.14), respectively, for selexipag and (0.95, 1.06) and (0.94, 1.07), respectively, for the active metabolite, ACT-333679. Conclusions: Bioequivalence was demonstrated between 8 × 200 μg and 1 × 1,600 μg selexipag at steady state.Correspondence to:
Shirin Bruderer, PhD
Actelion Pharmaceuticals Ltd
Gewerbestrasse 16, 4123 Allschwil, Switzerland
Email: [email protected]
