Volume 55 (2017), No. 3/2017(March)
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Peer review in Clinical Pharmacology using the 8-D Assessment
Barry G. Woodcock
Page No. 201
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (201-202)
Peer review in Clinical Pharmacology using the 8-D Assessment
Barry G. Woodcock
Dustri Medical Science Publications, Munich-Oberhaching, Germany
The requirement for editors of clinical pharmacology journals to maintain an overview of the peer review process for manuscripts submitted can be facilitated by use of the 8-D Assessment. The 8-D Assessment comprises peer review criteria to determine if the:1. Design of the study, 2. Diagnoses employed, 3. Drug molecules involved, 4. Dosages applied, 5. Data collected, 6. Discussion of the findings, 7. Deductions made, and 8. Documentation are in accord with the objectives of the study and meet the requirements of evidence-based medicine. This tool, although easy to apply, requires a high level of clinical pharmacology expertise, especially in the fields of drug disposition, pharmacokinetics, and drug action.
Original Research
Evaluating the association of multiple single nucleotide polymorphisms with response to gemcitabine and platinum combination chemotherapy in urothelial carcinoma of the bladder
Shaheen Alanee, Sohela Shah, Emily Zabor, Joseph Vijai, Irina Ostrovnaya, Ilana Garcia-Grossman, Deepa Pendse, Jason Littman, Ashley Regazzi, Kenneth Offit, Dean Bajorin
Price
42.00 $
Page No. 203
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (203-209)
Evaluating the association of multiple single nucleotide polymorphisms with response to gemcitabine and platinum combination chemotherapy in urothelial carcinoma of the bladder
Shaheen Alanee1, Sohela Shah2, Emily Zabor3, Joseph Vijai2, Irina Ostrovnaya3, Ilana Garcia-Grossman4, Deepa Pendse4, Jason Littman2, Ashley Regazzi4, Kenneth Offit2#5, Dean Bajorin4#5
1Department of Urology, Henry Ford Health System, Detroit, MI,
2Clinical Genetics Service, Department of Medicine, 3Department of
Epidemiology & Biostatistics, 4Genitourinary Oncology Service,
Department of Medicine, Memorial Sloan-Kettering Cancer Center, and 5Department of Medicine, Weill Cornell Medical College, New York, NY, USA
Objective: To examine germline single nucleotide polymorphisms (SNPs) as markers of response to gemcitabine platinum (GP) combination chemotherapy in urothelial carcinoma (UC). Methods: Saliva or blood was prospectively collected from 216 patients treated with GP for UC of the bladder between 1991 and 2011. Based on reported associations with gemcitabine and cisplatin response or putative mechanisms of gemcitabine or cisplatin/carboplatin activity, we selected SNPs of interest and were able to genotype 59 SNPs (using the SequenomMass ARRAYiPLEX platform) in 261 patients randomly split 2/3 into a training set (n = 174) and 1/3 into a test set (n = 87). Logistic regression was used to test the association between response to GP and SNPs. Results: The median age at diagnosis was 64 years (range: 28 – 85) for the discovery set and 67 years (range: 30 – 84) for the validation set. Males composed 76% and 69%, and white non-Hispanics composed 88% and 91% of the training and test validation sets, respectively. Three SNPs on GALNTL4 (rs7937567, rs12278731, and rs9988868) and one intergenic SNP (rs1321391) were significantly associated with response to GP in the training set and were used to build a SNP score. However, when assessed in the test set, the SNP score was not significantly associated with response. Conclusion: Multiple SNPs selected from previous studies failed to predict response to GP in this cohort. Larger studies capable of accounting for population-based allele frequency heterogeneity may be required for replication of genetic alterations important to pharmacogenomics.
Correspondence to:
Shaheen Alanee, MD, MPH, MBA
Senior Staff Physician, Urologic Oncology
Department of Urology, Henry Ford Health System
2799 West Grand Ave., Detroit, MI 48202, USA
Email: [email protected]
Original Research
Association between pioglitazone use and the risk of bladder cancer among subjects with diabetes mellitus: a dose-response meta-analysis
Zhuyue Li, Min Sun, Feng Wang, Jia Shi, and Kang Wang
Price
42.00 $
Page No. 210
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (210-219)
Association between pioglitazone use and the risk of bladder cancer among subjects with diabetes mellitus: a dose-response meta-analysis
Zhuyue Li1, Min Sun2, Feng Wang3, Jia Shi4, and Kang Wang5
1Department of Nursing, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 2Department of General Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, 3Department of Endocrine, The Second Affiliated Hospital of Chongqing Medical University, 4Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, and 5Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
Purpose: Previous epidemiological studies reported inconsistent results regarding the association between pioglitazone use and the risk of bladder cancer (BC). We conducted a dose-response meta-analysis to assess this association. Methods: PUBMED and EMBASE databases were searched through August 2015. Pooled results derived from a random-effects model, and the dose-response analyses were conducted for the association between cumulative dose or duration of pioglitazone use and BC risk. Results:14 studies were included. After comparing “ever use” with “never use” of pioglitazone, an increased risk of BC (HR = 1.16, 95% CI = 1.06 to 1.25) was present, and there was no significant heterogeneity between studies (P for heterogeneity = 0.54, I2 = 0.0%). Every 12 months increase (HR = 1.16, 95% CI = 1.03 – 1.30) or 10 g increase (HR = 1.05, 95% CI = 1.02 – 1.09) in pioglitazone use was marginally associated with elevated BC risk. The evidence of linear relationships was found for the cumulative dose of pioglitazone and BC risk, and a nonlinear curve for association between the duration of pioglitazone use and the risk of BC was revealed. Subgroup analyses revealed that an increased risk of BC for pioglitazone use was observed in European male subjects with more than 12 months of pioglitazone use and in the “multivariate adjusted” group. Conclusions: Pioglitazone use among subjects with diabetes mellitus increases BC risk mildly. More studies are needed to investigate the association between the cumulative dose of pioglitazone use and BC risk.
Correspondence to:
Dr. Kang Wang
Department of Endocrine and Breast Surgery
The First Affiliated Hospital of Chongqing Medical University
Chongqing Medical University
Chongqing, 400016, China
Email: [email protected]
Original Research
The cost savings of newer oral anticoagulants in atrial fibrillation-related stroke prevention
Norliana Masbah and Mary Macleod
Price
42.00 $
Page No. 220
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (220-230)
The cost savings of newer oral anticoagulants in atrial fibrillation-related stroke prevention
Norliana Masbah1 and Mary Macleod2
1Department of Pharmacology, Faculty of Medicine, University Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia, and
2Department of Medicine and Therapeutics, Division of Applied Medicine,
Polwarth Building, Foresterhill, University of Aberdeen, UK
Background: Newer oral anticoagulants (NOACs) are considered as better alternatives compared to warfarin for stroke prevention in atrial fibrillation (AF) in terms of clinical effectiveness although the drug acquisition cost is more substantial. Aim: This study determined the direct stroke costs based on inpatient hospitalization in a subgroup of the National Health Service (NHS) Grampian, Scotland, stroke patients, to evaluate the differences in costs related to AF stroke, and to ascertain whether the use of NOACs within this study population would produce greater cost savings. Methods: Hospitalization records over 5 years involving 3,601 stroke patients were analyzed. Direct costs were based on the costs of inpatient length of stay per day. The potential cost savings if AF patients had been on NOACs were estimated using efficacy data from a landmark clinical trial involving rivaroxaban. Results: Out of the total stroke cases, 29.5% of total stroke cases were secondary to AF, and these cases were more severe with longer hospitalizations. Only 254 patients (39.4%) with confirmed AF were anticoagulated with warfarin prior to admission. AF patients incurred higher median costs (£4,719 (interquartile range (IQR) £1,815 – £12,452) compared to non-AF patients (£3,267 (IQR £1,175 – £11,368)), although the association was statistically insignificant. The use of NOACs in AF-related patients with ischemic strokes would potentially prevent more strokes (leading to 58 fewer cases in comparison to warfarin), resulting in 17.1% in total cost reduction. Conclusion: AF stroke patients incurred higher total direct costs compared to non-AF cases. However, more cost savings were evident with NOACs, due to more strokes being prevented through the use of NOACs compared to warfarin.
Correspondence to:
Dr. Norliana Masbah
Department of Pharmacology, Faculty of Medicine
Universiti Kebangsaan Malaysia Medical Centre
Jalan Yaacob Latif, Bandar Tun Razak
56000 Cheras, Kuala Lumpur, Malaysia
Email: [email protected]
Original Research
Single- and multiple-dose pharmacokinetics and tolerability of paroxetine controlled-release tablet in healthy Chinese subjects
Rui Chen, Kai Shen, and Pei Hu
Price
42.00 $
Page No. 231
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (231-236)
Single- and multiple-dose pharmacokinetics and tolerability of paroxetine controlled-release tablet in healthy Chinese subjects
Rui Chen
, Kai Shen, and Pei Hu
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China
Objectives: To evaluate the pharmacokinetics of paroxetine controlled-release (CR) tablets after single and multiple oral administrations and to evaluate its safety profile in healthy Chinese subjects. Methods: This was a phase 1, open-label, single- and multiple-dose combined study. All 12 healthy subjects received a single oral dose of 25-mg paroxetine CR, followed by a washout period of 5 days. Then, the subjects received multiple oral doses of 25-mg paroxetine CR for 14 consecutive days. Serial venous blood samples were collected 96 hours after single dosing and 24 hours after the last dose in multiple-dosing. Blood samples were analyzed using LC-MS/MS. Pharmacokinetic parameters of paroxetine were calculated via noncompartmental analysis using the WinNonlin software (Pharsight Corp., Mountain View, CA, USA). Results: For both single- and multiple-dose regimens, a lag time of ~ 4 hours was observed before the absorption of paroxetine CR tablet with a tmax of ~ 7 – 9 hours. From single- to multiple-dose regimens, the mean Cmax increased from 7.08 to 36.95 ng/mL, the mean AUC0–24h increased from 100.91 to 706.75 h×ng/mL, and the mean t1/2 increased from 12.3 to 83.6 hours (all p < 0.05). The point estimate and 90% confidence intervals of the Ctrough ratio indicated that the concentration of paroxetine reached steady state after 14 days of repeated dosing. The point estimate of the accumulation factor indicated that the extent of drug exposure at steady state was ~ 9 times that of single dosing. All reported adverse events were considered to be mild. Conclusions: Paroxetine CR tablet is absorbed with a delay of ~ 4 hours after oral administration, and the accumulation factor is ~ 9 at steady state. Paroxetine CR tablet is well tolerated by healthy Chinese subjects.
Correspondence to:
Prof. Pei Hu
Phase I Unit, Clinical Pharmacology Research Center
Peking Union Medical College Hospital
Damucang Hutong 41, Beijing, 100032, China
Email: [email protected]
Original Research
Drug utilization and blood pressure control in ambulatory hypertensive patients: focus on those with compelling indications
Aduragbeno D.A. Adedapo, Onyinye O. Akunne, Olulola O. Oladapo, and Babatunde L. Salako
Price
42.00 $
Page No. 237
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (237-245)
Drug utilization and blood pressure control in ambulatory hypertensive patients: focus on those with compelling indications
Aduragbeno D.A. Adedapo1, Onyinye O. Akunne1, Olulola O. Oladapo2, and Babatunde L. Salako2
1Department of Pharmacology and Therapeutics, and 2Department of Medicine, University of Ibadan, Ibadan, Nigeria
Objective: Compelling indications require the use of specific antihypertensive drug classes and often two or more antihypertensive medications for blood pressure (BP) control. This study assessed drug utilization patterns among hypertensive patients with compelling indications, conformity with recommended guidelines, and the effect on BP control. Materials and methods: A prospective, cross-sectional study of hypertensive patients attending three subspecialty hospital clinics. Data on demographics, prescriptions, and BP were collected. BP control was defined as BP less than 140/90 mmHg in nondiabetic subjects and less than 130/80 for those with diabetes. Analysis was done with SPSS version 17. Results: Of the 1,926 patients with hypertension, 877 (45.5%) had compelling indications. Patients were aged 59.3 ± 11.5 years. The most frequently-encountered compelling indications were hypertensive heart disease (35.8%), diabetic mellitus (31.9%), and renal diseases (11.5%). The most prescribed drug was angiotensin-converting enzyme inhibitor (ACEIs), which was present in 22.6% of all prescriptions. Only 23.1% of patients had fully controlled BP. Poor BP control significantly correlated with the number of antihypertensive drugs r = 0.205, p < 0.001, but negatively correlated with age and duration of hypertension, r = –0.071, p = 0.038 and r = –0.448, p = 0.042, respectively. Conclusion: BP control was very poor in this study, and there was a high prevalence of compelling indications. Poor control was negatively correlated with increasing age and duration of hypertension. The most common compelling indications were hypertensive heart disease, diabetes mellitus, and renal disease.Correspondence to:
Dr. Aduragbenro Adedapo
Department of Pharmacology and Therapeutics
University of Ibadan, and
Department of Clinical Pharmacology
University College Hospital, Ibadan, Nigeria
Email: [email protected]
Original Research
Pharmacokinetics and safety of nifedipine GITS/candesartan fixed-dose combination in subjects with hepatic impairment
Yuwang Liu, Michael-Friedrich Boettcher, Anja Schmidt, Sigrun Unger, Atef Halabi, Erich Brendel, and Hartmut Blode
Price
42.00 $
Page No. 246
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (246-255)
Pharmacokinetics and safety of nifedipine GITS/candesartan fixed-dose combination in subjects with hepatic impairment
Yuwang Liu1, Michael-Friedrich Boettcher2, Anja Schmidt2, Sigrun Unger3, Atef Halabi4, Erich Brendel5, and Hartmut Blode6
1Bayer Healthcare Co. Ltd., Clinical Sciences China, Beijing, China, 2Bayer Pharma AG, Clinical Sciences, Wuppertal, 3Bayer Pharma AG, Research & Clinical Sciences Statistics, Building 0431, Wuppertal, 4CRS Clinical Research Services Kiel GmbH, Kiel, 5EB Pharmacokinetics Consulting, Solingen, and 6Bayer Pharma AG, Clinical Sciences, Berlin, Germany
Objective: To investigate the pharmacokinetic (PK) profiles and safety of nifedipine and candesartan after a single oral dose of nifedipine gastrointestinal therapeutic system (GITS) 30 mg/candesartan cilexetil 8 mg (N30/C8 mg) fixed-dose combination (FDC) in adults with mild to moderate hepatic impairment. Methods: A phase I, single-center, non-randomized, non-controlled, non-blinded, observational study (N = 32). PK profiles for nifedipine and candesartan were assessed in patients with mild (Child-Pugh A; group 1) or moderate (Child-Pugh B; group 2) hepatic impairment and compared with age- and gender-matched healthy controls (groups 3 and 4) following a single dose of N30/C8 FDC. Safety and tolerability were assessed throughout the study. Results: On average, area under the plasma concentration vs. time curves (AUC) for nifedipine increased 93% and 253% in mild and moderate hepatic impairment, while maximum plasma concentrations (Cmax) increased 64% and 171%, respectively. AUC values for candesartan increased 19% and 92%, while Cmax values increased 3% and 11%, respectively. In subjects with or without liver impairment, adverse event rates were similar and consistent with the known side-effect profiles of nifedipine GITS and candesartan as monotherapies. Conclusions: Careful monitoring, and, if necessary, dose adjustment according to response and tolerability may be required for nifedipine GITS/candesartan FDC in patients with mild and moderate hepatic impairment.
Correspondence to:
Hartmut Blode, PhD
Bayer Pharma AG, Clinical Sciences
Building P300, 13342 Berlin, Germany
Email: hartmut.blode@
bayer.com
Original Research
A single and multiple postprandial dose study investigating the pharmacokinetics and pharmacodynamics of edoxaban in healthy Chinese volunteers
Xia Chen, Dongyang Liu, Yiwen Wu, Yang Liu, Hanlin Song, Ji Jiang, and Pei Hu
Price
42.00 $
Page No. 256
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (256-263)
A single and multiple postprandial dose study investigating the pharmacokinetics and pharmacodynamics of edoxaban in healthy Chinese volunteers
Xia Chen, Dongyang Liu, Yiwen Wu, Yang Liu, Hanlin Song, Ji Jiang, and Pei Hu
Phase I Unit, Clinical Pharmacological Research Center, Peking Union Medical College Hospital, Beijing City Key Laboratory, Beijing, China
Aims: This study investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of once-daily postprandial doses of edoxaban 60 mg in healthy Chinese subjects. Methods: 6 male and 6 female healthy Chinese volunteers, aged 18 – 45 years, were enrolled into this open-label, phase-I trial. Subjects received single oral doses of edoxaban 60 mg after a meal, followed by successive once-daily doses for 7 days. Serial blood samples were taken pre- and postdose to measure plasma concentrations of edoxaban and its major active metabolite D21-2393 as well as prothrombin time (PT) and activated partialprothrombin time (aPTT). Safety was assessed throughout the study. Results: Eoxaban was quickly absorbed after dosing. The resultant maximum and total exposure of edoxaban after single postprandial dose were similar to those after the same dose in fasting condition, but tmax was about half an hour longer. Meanwhile, the exposure of D21-2393 and the metabolite-over-parent ratio were both lower vs. the fasting condition, suggesting involvement of food on D21-2393 formation. Steady state was attained after two successive daily doses. The PK parameters of edoxaban with multiple postprandial doses were comparable to those observed in Caucasian and Japanese volunteers. Similarly, the PD profiles and the concentration-response relationship of edoxaban were not changed with repeated doses. Minor bleeding was the most commonly reported adverse event during the study. Conclusion: Once daily postprandial doses of edoxaban 60 mg was safe and well tolerated in healthy Chinese volunteers. The PK and PD characteristics of edoxaban were comparable among Chinese, Caucasian, and Japanese subjects.
Correspondence to:
Prof. Pei Hu, MD
41#, Damucang Hutong, Xicheng District, Beijing 100032, China
Email: [email protected]
Case
Report
A case of multiple vertebral compression fractures due to glucocorticoid-induced osteoporosis in a pediatric patient with nephrotic syndrome
Akira Ashida, Yuko Fujii, Hideki Matsumura, and Hiroshi Tamai
Price
42.00 $
Page No. 264
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (264-269)
A case of multiple vertebral compression fractures due to glucocorticoid-induced osteoporosis in a pediatric patient with nephrotic syndrome
Akira Ashida, Yuko Fujii, Hideki Matsumura, and Hiroshi Tamai
Department of Pediatrics, Osaka Medical College, Osaka, Japan
Introduction: Glucocorticoid therapy has a number of adverse effects, among which osteoporosis and bone fracture can be major complications. Immunosuppressive therapy for nephrotic syndrome is effective and can help to reduce the cumulative dose of glucocorticoids. Therefore, for this reason, the number of patients with nephrotic syndrome who develop glucocorticoid-related osteoporotic compression fracture is decreasing. Here we describe a pediatric case of multiple vertebral compression fractures due to glucocorticoid-induced osteoporosis during treatment for nephrotic syndrome. Case presentation: A 12-year-old boy with nephrotic syndrome was treated with the standard corticosteroid regimen stipulated by the International Study of Kidney Disease in Children (ISKDC). Although he achieved complete remission, he suffered two episodes of relapse, and after the second such episode, the disease became resistant to the steroid therapy. Therefore, the patient received steroid pulse therapy followed by steroid tapering concomitant with cyclosporine administration. However, ~ 9 months after the start of steroid therapy, the patient developed multiple vertebral compression fractures with severe back pain. Conclusion: It is necessary to evaluate the state of bone at an early stage of treatment for nephrotic syndrome in children, even if the cumulative dose of glucocorticoid is not particularly high.
Correspondence to:
Akira Ashida MD, PhD
Department of Pediatrics, Osaka Medical College
2-7 Daigakumachi, Takatsuki-shi,
Osaka, 569-8686, Japan
Email: ped006@
osaka-med.ac.jp
Case Report
Treatment with everolimus for a patient with systemic metastatic breast cancer results in severe pulmonary injury: a case report
Meng Xiangying, Wang Tao, Wu Shikai, Song Santai, and Jiang Zefei
Price
42.00 $
Page No. 270
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (270-274)
Treatment with everolimus for a patient with systemic metastatic breast cancer results in severe pulmonary injury: a case report
Meng Xiangying*, Wang Tao*, Wu Shikai, Song Santai, and Jiang Zefei
Breast Cancer Department, Affiliated Hospital of Academy of Military Medical Sciences, Fengtai District, Beijing, China
Everolimus has been used in patients with hormone receptor-positive breast cancer. This study reports that treatment with everolimus alone induced severe pulmonary injury in a patient with systemic metastatic breast cancer. A 58-yearold woman with systemic metastatic breast cancer was treated with everolimus alone for 4 weeks and developed severe cough and dyspnea. Computed tomography (CT) scan of the chest showed a progressive lung tumor accompanied by bilateral pulmonary homogeneous ground-glass opacity, especially in the inferior lobe of the left lung. Laboratory examinations revealed a high frequency of monocytes, higher levels of serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and C-reactive protein as well as mild hypoxemia and hypocarbia. However, she had no evidence of infection with mycoplasma pneumoniae, chlamydia, pneumocystis, tuberculosis, influenza A virus, and was negative for serum galactomannan (GM) antigen assay. She was suspected to have drug-induced interstitial pneumonia. Everolimus treatment was stopped, and treated with methylprednisolone and empiric antibiotic therapy for 7 days. She received further corticosteroid treatment and felt much better, accompanied by clearance of lung inflammation; she was discharged from hospital. Our experience suggests that treatment with everolimus alone may cause severe pulmonary injury and should be considered carefully in cases of patients with systemic metastatic breast cancer.
*Meng Xiangying and Wang Tao contributed to the work equally and should be regarded as co-first authors.Correspondence to:
Jiang Zefei, MD
Breast Cancer Department
Affiliated Hospital of Academy of Military Medical Sciences
#8 Dongda Street, Fengtai District
Beijing, 100071, China
Email: [email protected]
Facies dolorosa
Meperidine-induced QTc-interval prolongation: prevalence, risk factors, and correlation to plasma drug and metabolite concentrations
Guillermo Alberto Keller, María Cedilia Villa Etchegoyen, Nicolás Fernández, Nancy Mónica Olivera, Patricia Noemi Quiroga, Roberto Alejandro Diez, and Guillermo Di Girolamo
Price
42.00 $
Page No. 275
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (275-285)
Meperidine-induced QTc-interval prolongation: prevalence, risk factors, and correlation to plasma drug and metabolite concentrations
Guillermo Alberto Keller1,2, María Cecilia Villa Etchegoyen1, Nicolás Fernández3, Nancy Mónica Olivera3, Patricia Noemi Quiroga3, Roberto Alejandro Diez1, and Guillermo Di Girolamo1
1Drug Surveillance & Safety Center, Department of Pharmacology, School of Medicine, University of Buenos Aires, 2Emergency Department, Hospital General de Agudos Donación Francisco J. Santojanni, and 3Analytical Toxicology Advisory Centre (CENATOXA), Chair of Toxicology and Legal Chemistry, School of Pharmacy & Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
A prolongation of the QTc-interval has been described for several opioids, including pethidine (meperidine). Objective: To evaluate in the clinical setting the frequency and risk factors associated with the QT-interval prolongation induced by meperidine. Research design and methods: We recruited patients requiring meperidine administration and recorded their medical history and comorbidities predisposing to QT-interval prolongation. Ionograms and electrocardiograms (ECGs) were performed at baseline and during treatment; QT was corrected using the Bazzet, Fridericia, Framinghan, and Hogdes formulas. We measured meperidine and normeperidine by gas chromatography. Values are expressed as mean ± SD (range). Results: 58 patients were studied (43.1% males). All patients received meperidine at a dose of 304 ± 133 (120 – 480) mg/day. Meperidine and normeperidine concentrations were 369 ± 60 (265 – 519) and 49 ± 17 (15 – 78) ng/mL, respectively. Intratreatment control found QTcB 370 ± 30 (305 – 433), QTcFri 353 ± 35 (281 – 429), QTcFra 360 ± 30 (299 – 429), QTcH 359 ± 27 (304 – 427), ΔQTcB +9 ± 42 (–90 to +136), ΔQTcFri +4 ± 45 (–86 to +137), ΔQTcFra +5 ± 40 (–77 to +129), and ΔQTcH +7 ± 40 (–76 to +129) ms. Meperidine concentration correlated with QTc-interval (R > 0.36) and ΔQTc (R > 0.69) but the correlation was even better for normeperidine concentration, QTc (R > 0.52) and ΔQTc (R > 0.81). Depending on the QTc correction formula used, 13 – 15 patients (22.41 – 25.86%) presented ΔQTc values > 30 ms, and 7 – 8 patients (12.07– 13.79%) showed ΔQTc values > 60 ms. Renal failure was associated with risk for ΔQTc > 30 ms of 3.74 (IC95% 1.73 – 8.10) and for ΔQTc > 60 ms of 4.27 (IC 95% 1.26 – 14.48). No patient developed arrhythmias during the study. Conclusions: Meperidine treatment causes ECG changes (QTc-interval prolongation) in high correlation with normeperidine plasma concentration. Renal failure increases the risk.
Correspondence to:
Guillermo Alberto Keller, MD,
Second Chair of Pharmacology
Department of Pharmacology
School of Medicine, University of Buenos Aires
Paraguay 2155 – Piso 16, C1121ABG
Ciudad Autónoma de Buenos Aires, Argentina
Email: [email protected]
Bioavailability Section
Pharmacokinetic and bioequivalence study comparing a candesartan cilexetil/rosuvastatin calcium fixed-dose combination with the concomitant administration of candesartan cilexetil and rosuvastatin calcium in healthy Korean subjects
Dan-Bee Park, Kyungho Jang, Jae-Won Lee, Cheol-Won Park, Back-Hwan Lee, Min-Gul Kim, and Ji-Young Jeon
Price
42.00 $
Page No. 286
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 3/2017 (286-294)
Pharmacokinetic and bioequivalence study comparing a candesartan cilexetil/rosuvastatin calcium fixed-dose combination with the concomitant administration of candesartan cilexetil and rosuvastatin calcium in healthy Korean subjects
Dan-Bee Park1*, Kyungho Jang1,2*, Jae-Won Lee3, Cheol-Won Park3, Back-Hwan Lee3, Min-Gul Kim1,4, and Ji-Young Jeon1
1Center for Clinical Pharmacology and Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Jeonju, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 3Research & Development Division, Alvogen Korea CO., Ltd., and 4Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju, Republic of Korea
Context: A fixed-dose combination (FDC) of candesartan and rosuvastatin was recently developed for the treatment of cardiovascular disease and expected to enhance patient compliance. Objective: This study was performed to compare the single-dose pharmacokinetic properties and tolerability of DP-R208 (candesartan and rosuvastatin FDC) to those of each component administered alone in healthy Korean male volunteers. Materials and Methods: A total of 40 healthy Korean volunteers were enrolled in this randomized, open-label, single-dose, two-treatment, two-way crossover study. During each treatment period, subjects received the test formulation (FDC tablet containing candesartan and rosuvastatin) or reference formulation (co-administration of candesartan and rosuvastatin). Plasma samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, and 48 hours post-dose. Safety and tolerability were assessed by the evaluation of adverse events (AEs), physical examinations, laboratory assessments, 12-lead electrocardiograms (ECGs), and vital sign measurements. Results: The 90% confidence intervals (CIs) of the geometric least-square mean ratios of Cmax, AUClast, and AUCinf were 0.86 – 1.00, 0.92 – 1.04, and 0.92 – 1.03 for candesartan, and 0.88 – 1.06, 0.91 – 1.08, and 0.91 – 1.03 for rosuvastatin, respectively. All of the AEs were mild, and there was no significant difference in the incidence of AEs between the formulations. Furthermore, the pharmacokinetic properties of the test and reference formulations met the regulatory criteria for bioequivalence. Discussion and conclusion: Both formulations were safe and well tolerated, and no significant difference was observed in the safety assessments of the treatments.
Correspondence to:
Ji-Young Jeon, PhD
Center for Clinical Pharmacology and Biomedical Research Institute
Chonbuk National University Hospital
20, Genji-ro, Deokjin-gu, Jeonju-si,
Jeollabuk-do 54907, Korea
Email: [email protected]
