International journal of clinical pharmacology and therapeutics (INT J CLIN PHARM TH )

Journal description

The International Journal of Clinical Pharmacology and Therapeutics appears monthly and publishes manuscripts containing original material with emphasis on the following topics: Clinical trials, Pharmacoepidemiology - Pharmacovigilance, Pharmacodynamics, Drug disposition and Pharmacokinetics, Quality assurance, Pharmacogenetics, Biotechnological drugs such as cytokines and recombinant antibiotics. Case reports on adverse reactions are also of interest.

Current impact factor: 1.04

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 1.044
2012 Impact Factor 1.2
2011 Impact Factor 1.183
2010 Impact Factor 1.189
2009 Impact Factor 1.381
2008 Impact Factor 1.299
2007 Impact Factor 1.281
2006 Impact Factor 1.361
2005 Impact Factor 1.755
2004 Impact Factor 1.414
2003 Impact Factor 0.923
2002 Impact Factor 1.471
2001 Impact Factor 1.351
2000 Impact Factor 1.222
1999 Impact Factor 0.871
1998 Impact Factor 0.77
1997 Impact Factor 0.519
1996 Impact Factor 0.828
1995 Impact Factor 0.607
1994 Impact Factor 0.424
1993 Impact Factor 0.37
1992 Impact Factor 0.756

Impact factor over time

Impact factor
Year

Additional details

5-year impact 1.36
Cited half-life 8.10
Immediacy index 0.33
Eigenfactor 0.00
Article influence 0.35
Website International Journal of Clinical Pharmacology & Therapeutics website
Other titles International journal of clinical pharmacology and therapeutics, Clinical pharmacology and therapeutics
ISSN 0946-1965
OCLC 29934177
Material type Periodical
Document type Journal / Magazine / Newspaper

Publications in this journal

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    ABSTRACT: Objective: Our aim was to determinate the acenocoumarol dose requirement in highly sensitive geriatric patients, based on a minimum of genotype (VKORC1 and CYP2C9) data. Methods: We used a Gaussian kernel density estimation test to identify patients highly sensitive to the drug and PHARMACHIP®-Cuma test (Progenika Biopharma, SA, Grifols, Spain) to determine the CYP2C9 and VKORC1 genotype. Results: All highly sensitive geriatric patients were taking ≤ 5.6 mg/week of acenocoumarol (AC), and 86% of these patients presented the following genotypes: CYP2C9*1/*3 or CYP2C9*1/*2 plus VKORC1 A/G, CYP2C9* 3/*3, or VKORC1 A/A. Conclusion: VKORC1 A and CYP2C9 *2 and/or *3 allelic variants extremely influence on AC dose requirement of highly sensitive geriatric patients. These patients display acenocoumarol dose requirement of ≤ 5.6 mg/week.
    International journal of clinical pharmacology and therapeutics 02/2015;
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    ABSTRACT: Purpose: Despite the fact that the most recently articulated theory of migraine is the central sensitization hypothesis, few basic and clinical research studies on central sensitization have been conducted in patients with migraine. Here, we aim to reveal the risk factors of migraine with allodynia and to illustrate the effects of pregabalin on alleviating allodynia. Methods: 63 migraine patients meeting the International Headache Society criteria were prospectively included. The cutaneous allodynia (CA) symptoms that occurred during headache attacks were examined with the Allodynia Symptom Checklist (ASC). The risk factors of allodynia were determined using logistic regression analysis. 41 patients with allodynia were treated with pregabalin (150 - 600 mg/d) for 12 weeks. The improvements in allodynia and headache severity as well as the side effects of the drug were recorded at 1 and 3 months following drug administration. Results: Among the 63 patients, there were 41 cases (65.1%) of allodynia, including 35 cases (85.4%) of thermal allodynia, 12 cases (29.4%) of static mechanical allodynia, and 9 cases (22.0%) of dynamic mechanical allodynia. The allodynia appeared to be associated with gender (female), disease duration, and medication overuse. Compared with baseline, both the ASC scores in the three types of CA and the number of patients with allodynia were significantly decreased (p < 0.05) in patients treated with pregabalin. The frequency, severity, and duration of headache as well as the migraine disability assessment (MIDAS) and headache impact test (HIT-6) scores were significantly decreased (p < 0.05) when compared with baseline. The overall efficiency of drug therapy was 85.4% among all patients who received pregabalin. There were few side effects detected, and the patients showed good tolerability to drug therapy. Conclusions: Our results showed that 65.1% of patients with migraine had allodynia and that migraine with allodynia was related to the patient gender (female), disease duration, and medication overuse. Pregabalin was effective at relieving allodynia in migraine.
    International journal of clinical pharmacology and therapeutics 02/2015;
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    ABSTRACT: Objectives: The purpose of the study was to compare the efficacy and adverse events of dezocine with that of fentanyl or placebo for the control of emergence agitation. Methods: 114 children scheduled for adenotonsillectomy under sevoflurane anesthesia were allocated randomly into 1 of the 3 groups to receive dezocine 0.1 mg x kg-1 (group D, n = 38), fentanyl 1 μg x kg-1 (group F, n = 38), or saline (group S, n = 38) just before the end of anesthesia. Emergence agitation scores were assessed. Postoperative pain scores, awakening and extubation times, and the incidence of adverse effects were recorded. Results: Emergence agitation scores, the incidence of emergence agitation and severe emergence agitation were significantly lower in groups D and F than in group S (p = 0.021, p = 0.018, and p = 0.028, respectively). The postoperative pain scores were lower in groups D and F as compared to group S (p = 0.01). Awakening and extubation times in groups D and F were longer than that of group S (p = 0.001 and p = 0.000, respectively). The overall incidence of postoperative complications was higher in group F compared to that in groups D and S (p = 0.01). Conclusions: In children undergoing adenotonsillectomy under sevoflurane anesthesia, a single IV injection of dezocine 0.1 mg x kg-1 and fentanyl 1 μg x kg-1 were comparable in decreasing the incidence and severity of emergence agitation. However, the use of dezocine was associated with a lower incidence of postoperative side effects.
    International journal of clinical pharmacology and therapeutics 02/2015;
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    ABSTRACT: Objectives: To establish the relative bioavailability (rBA) between two p.o. 5-mg levomethadone hydrochloride formulations, i.e., L-Polamidon® 5 mg tablets (test) vs. L-Polamidon® solution for substitution (reference). To assess the safety and tolerability of both formulations. Subject and methods: A total of 33 healthy male subjects, aged 29 ± 6 years (BMI: 23.9 ± 2.5 kg/m2) completed this single center, open-label, randomized, 2-period cross-over study with single dose administrations under fasting conditions and coadministration with naltrexone for safety reasons. Administrations of both investigational products were separated by a washout period of at least 2 weeks, i.e., 13 treatmentfree days. The total dose for each subject was 2 — 5 mg resulting in 10 mg levomethadone hydrochloride. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours postdose. A validated non-stereoselective liquid chromatography-tandem mass spectroscopy method (LC-MS/MS) was applied for the determination of levomethadone in plasma. The lower limit of quantitation was 0.100 ng/mL. Adverse events were descriptively analyzed in the study population. Results: The geometric means of the parameters related with the extent of total exposure of levomethadone, i.e., AUC0-tlast and AUC0-∞, were 244.422 ng x h/mL and 332.999 ng x h/mL for test and 246.837 ng x h/mL and 329.467 ng x h/mL for reference, respectively. The geometric means of the peak exposure for levomethadone, i.e., Cmax, were 8.923 ng/mL for test and 8.635 ng/mL for reference. The point estimates (PEs) of the Test/Reference (T/R) adjusted geometric mean ratios of AUC0-tlast, AUC0-∞, and Cmax were 99.20%, 101.42%, and 104.11%, respectively, and all of them showed 90%-confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment In total, 21 subjects experienced 55 AEs during the study, the most frequently reported AE, i.e., headache, accounted for 13 out of the total 55 AEs (23.6%) and no AEs of severe intensity were reported. Conclusions: Bioequivalence could be demonstrated in terms of rate and extent of absorption after administration of test and reference products under naltrexone protection. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined.
    International journal of clinical pharmacology and therapeutics 02/2015;
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    ABSTRACT: This study assessed the impact of varying lenvatinib crystalline forms in 10-mg lenvatinib capsules on drug bioavailability in healthy volunteers. Lenvatinib 10-mg capsules (low C and high C forms). This randomized, three-period- crossover study compared the pharmacokinetics and safety of two crystalline forms of capsules (low C-form, < 4% crystalline; high C-form, 38% crystalline) to a standard (ref Cform, 15% crystalline). 59 subjects were evaluable for pharmacokinetics. Test/reference ratios of the geometric least squares means (LSM) and 90% confidence intervals (CI) for AUC0-t (t up to 120 hours), AUC0-∞, and Cmax for low C-form vs. ref C-form were 101 (94.8, 107), 101 (95.3, 107), and 98.7 (88.6, 110), respectively; and for high C-form vs. ref C-form were 96.0 (92.1, 100), 96.5 (92.5, 101), and 90.6 (83.5, 98.4), respectively. The incidence of treatment-emergent adverse events (TEAE) and treatment-related adverse events (TRAE) were comparable between all formulations (TEAE range 20 - 24%; TRAE range 15 - 19%). One serious TRAE (spontaneous abortion) occurred in the low C-form group. For both comparisons, the 90% CIs of the test/reference ratios were within the regulatory acceptance range (80 - 125%), suggesting that both test formulations (low Cform and high C-form) were bioequivalent to the reference formulation for Cmax, AUC0-t, and AUC0-∞.
    International journal of clinical pharmacology and therapeutics 02/2015; 53(2):190-8.
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    ABSTRACT: Objective: Health-related quality of life (HRQOL) in hypertensive patients may be influenced by the presence and the knowledge of disease, beliefs associated with the disease, blood pressure (BP) control, and drug utilization. The impact of hypertension on HRQOL in hypertensive patients compared to the normal population has not been assessed in Nigeria, the most populous country in sub-Saharan Africa. This study compares HRQOL in hypertensive patients and the normal population; the effect of BP control and medication on HRQOL of hypertensive patients is also assessed. Materials and methods: A prospective cross-sectional study of 713 individuals, 606 were hypertensive patients attending the University College Hospital in Oyo State, Nigeria, while 107 were normal persons residing in Ibadan. Data on sociodemographic status, clinical variables, and drug utilization were collected. World health organization-quality of life short version (WHO-QOL-BREF) questionnaires were used to assess HRQOL of participants. Results: Hypertensive patients had poorer HRQOL compared with normal individuals in the physical health (p < 0.05), psychological (p < 0.01), and total quality of life domains. Blood pressure control had no effect on HRQOL in domain (p > 0.05). Drug use significantly worsened HRQOL of hypertensive patients in the psychological (p < 0.01), social relationship (p < 0.01), and the total quality of life domains (p < 0.01). Multiple regression analysis showed that while income per month was positively predictive of physical, psychological, and total quality of life domains (r2 = 1.988, p = 0.001; r2 = 3.710, p < 0.001; r2 = 2.748, p < 0.001), symptom count was negatively predictive of the same (r2 = -0.746, p = 0.005; r2 = 1.869, p < 0.001; and r2 = -1.094; p < 0.001), respectively. Reduced symptoms and higher income improved quality of life in hypertensive patients. Conclusion: The presence of hypertension and antihypertensive medication reduced HRQOL of hypertensive patients, although BP control surprisingly did not impact HRQOL. However, lower symptom count and higher income improved quality of life.
    International journal of clinical pharmacology and therapeutics 01/2015;
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    ABSTRACT: Background: Flupirtine is a nonopioid, central analgesic without antipyretic or antiphlogistic properties. Flupirtine-MR is an oral modified-release formulation with a 100 mg fast-input and a 300 mg portion with slow protracted release. Methods: Single- (D01) and repeated-dose (D03 - D09) pharmacokinetics of 400 mg flupirtine-MR were investigated in patients with severe renal dysfunction (REN: N: 12; 21 - 50 years of age; creatinine clearance (CLCr) ≤ 30 mL/min per 1.73 m2 body surface area (BSA)) and healthy older subjects (EN1: N: 8; 60 - 69 years; CLCr ≥ 80 mL/min and EN2: N: 8; ≥ 70 years, CLCr ≥ 60 mL/min) vs. young healthy control subjects (YN: N: 12; 21 - 40 years; CLCr ≥ 90 mL/min). Results: Renal dysfunction led to a relatively small average increase in systemic exposure to flupirtine: on D09, the REN : YN-ratios were 1.37 (95% confidence interval (CI): 1.03 - 1.82), 1.21 (CI: 1.01 - 1.45), and 1.34 (CI: 1.09 - 1.64) for Css,0, Css,max, and Css,av, respectively. A similar increase in exposure was observed in older subjects: the respective EN1 : YN-ratios were 1.30 (CI: 0.95 - 1.79), 1.23 (CI: 1.01 - 1.49), and 1.23 (CI: 0.98 - 1.54); the EN2 : YN-ratios were 1.50 (CI: 1.10 - 2.04), 1.16 (CI: 0.85 - 1.41), and 1.41 (CI: 1.12 - 1.79), respectively. Neither age nor renal function was a predominant factor of pharmacokinetic variability. Single and repeated doses of flupirtine-MR were very well tolerated. Conclusions: The average renal and age effects were small, but the use of a lower starting dose (1/2 tablet) is recommended since some of these subjects might have relatively high exposure levels.
    International journal of clinical pharmacology and therapeutics 01/2015;
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    ABSTRACT: Background: Meta-analyses have suggested that pharmacist-led medication reviews have no discernable effect on patient mortality. These analyses may not have found a statistically significant effect because they did not adequately control for the wide variation in the delivery of care and patient selection parameters. Therefore, a more precise approach to evaluating the effect of clinical pharmacist interventions on the mortality rates of hospitalized cardiac patients is required. Objective: To evaluate the impact of the clinical pharmacist as a direct patient-care team member on the mortality of all patients admitted to cardiology units. Methods: A prospective, nonrandomized observational study compared patients who received standard care with patients admitted to a service that included clinical pharmacists. Propensity score matching was applied to enhance the comparability. The primary endpoint of the study was the composite of all-cause mortality in the study group and the control group. Results: Pharmacists were consulted by physicians to correct any drugrelated issues that they suspected may cause or contribute to a fatal outcome in the cardiology ward. A total of 428 interventions were suggested by the clinical pharmacist in the study group; 375 (87.6%) of them were accepted by the cardiology team. All-cause mortality was 1.8% during phase 1 treatment (preintervention) and was reduced to 1.1% during phase 2 treatment (postintervention); the difference was statistically significant. There was no statistical difference in allcause mortality in the control unit between phase 1 and phase 2. Results were similar in the propensity score-matched subcohort. Conclusions: Drug-related problems that were suspected to cause or contribute to a possibly fatal outcome were determined by the clinical pharmacist service in patients hospitalized in a cardiology ward. Correction of these drug-related problems by physicians after the pharmacist's advice caused a significant decrease in mortality as analyzed by propensity score matching. The significant reduction in the mortality rate in this patient population observed in this study is "hypothesis generating" for future randomized studies.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objectives: To determine the initial distribution of medication in patients with de novo Parkinson's disease (PD), to estimate the share of patients who not receive a recommended initial therapy according to current German guidelines, and to compare the time-to-levodopa. Methods: We used the Disease Analyzer database (IMS HEALTH), containing basic medical data from ~ 20 million patients in Germany. The primary outcome was the therapy change rate from initial treatment to levodopa estimated by Kaplan-Meier analyses. A Cox proportional hazards model was used to estimate the relationship between time-to-levodopa and confounders for a maximum follow-up of 10 years (between January 2002 and December 2011). Adjusted hazard ratios (HR) and 95% confidence intervals (CI) are presented for change-to-levodopa rate. Results: A representative sample of de-novo patients diagnosed with PD was drawn (n = 108,885). 71.8% of patients received levodopa as a first line treatment. 29,708 patients started with other anti-PD substances: 13.3% with dopamine agonists (DA), 3.6% with amantadine, 5.9% with anticholinergics, and 0.8% with monoamine oxidase B (MAO-B) inhibitors. Therefore, the proportion of patients who not receive a recommended initial therapy according to current German guidelines was ~ 10%. 29.0% of patients not starting with levodopa switched to levodopa within 5 years. After 5 years, more than 80% of PD patients using anticholinergics as their initial treatment remained levodopa-free. MAOB- inhibitors and DAs showed significantly lower proportions of levodopa-free patients after 5 years (35% and 55%, respectively). Compared to MAO-B inhibitors, the HR for switching to levodopa was 0.38 (CI 0.34 - 0.43; p < 0.001) for anticholinergics and 0.85 (CI 0.75 - 0.97; p = 0.017) for nonergot DA. Conclusions: Surprisingly, initial treatment with anticholinergics is correlated with the longest delay of levodopa treatment among all monotherapies. Our results suggest re-evaluating the comparative effectiveness of all initial PD treatments in head-tohead comparisons.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objective: The objective of this study was to evaluate the pharmacokinetic parameters of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), following a single oral dose of 900 mg in healthy subjects under fed and fasting conditions. Methods: The study participants (n = 12) were randomized to receive one 900 mg triflusal capsule in a fasting condition (no food for 12 hours) or a fed condition (after a high-fat meal); after a 2-week washout period, participants received the same dose of triflusal capsule under the converse condition. Pharmacokinetic parameters were calculated using WinNonlin 6.2 software. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography. Results: The mean Cmax of triflusal and HTB were 13.96, 110.2 ug/mL for the fasting state and 9.546, 97.15 ug/mL for the fed state, respectively. The AUC0-144 of triflusal and HTB were 19.66, 5,572 h×μg/mL for the fasting state and 22.20, 5,038 h×μg/mL for the fed state, the AUC0-∞ of triflusal and HTB were 19.79, 6,333 h×μg/mL for the fasting state and 22.44, 5,632 h×μg/mL for the fed state, respectively. The results showed that Cmax and AUCs for triflusal were outside the bioequivalency (BE) interval after food intake, but there was no statistically significant change for HTB. Conclusion: High-fat food intake may affect the pharmacokinetics of triflusal capsule in healthy subjects.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5 - 111.0) and 107.1 (100.1 - 114.7), respectively. In total, 7 adverse drug reactions occurred in 4 subjects during the study; of these, 3 cases were from 3 subjects in the test treatment group, and 4 cases were from 3 subjects in the reference treatment group. All adverse drug reactions had been reported previously, and all subjects recovered fully without any sequelae. In conclusion, the pharmacokinetic profiles of metformin in two different study treatments, a voglibose/metformin FDC vs. the coadministration of the individual formulations, met the regulatory criteria for bioequivalence in healthy Korean subjects under fasting conditions. There was no significant difference in safety profiles between the two treatments.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objective: To assess the effect of food on the pharmacokinetics (PK) of canagliflozin and metformin following administration of a canagliflozin/metformin (150/1,000 mg) immediate-release (IR) fixed-dose combination (FDC) tablet. Methods: A randomized, open-label, singlecenter, single-dose, 2-period, 2-sequence crossover study was conducted in healthy participants. Participants were randomized to 2 sequences of fasted and fed (or vice versa) administration of one 150/1,000 mg canagliflozin/metformin IR FDC, with 10 - 14 day washout between treatments PK parameters (AUC, Cmax, tmax, t1/2) were assessed for canagliflozin and metformin. Safety was evaluated. Results: When comparing the IR FDC tablet administered with and without food, PK parameters of canagliflozin were bioequivalent as the 90% confidence intervals (CIs) for log-transformed AUClast, AUC∞, and Cmax were within the bioequivalence limits of 80 - 125%. For metformin, overall exposure was similar under fed and fasted conditions as geometric mean ratios for AUC and associated 90% CI were contained within the bioequivalence limits, but geometric mean Cmax decreased by 16% in the fed compared to fasted state. Both treatments were well tolerated with similar adverse events and most common were gastrointestinal events, generally attributed to metformin. Conclusions: Food did not affect canagliflozin bioavailability parameters (Cmax and AUCs) or AUCs of metformin. The Cmax of metformin was decreased by 16%, which is not considered clinically meaningful. The canagliflozin/ metformin FDC tablet is recommended to be taken with meals to reduce the symptoms of gastrointestinal intolerability associated with metformin.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objective: Changes in the cortisol diurnal rhythm have been found in neuropsychiatric diseases, including anxiety and depression. The aim of this study was to investigate the reliability and reproducibility of cortisol diurnal rhythm in healthy males, through determination of the inter- and intrasubject variability, to facilitate evaluation of this biomarker for drug target engagement. Materials and methods: This openlabel, 2-period study design evaluated serum cortisol release over a 24-hour period in 18 healthy males. A cosinor model was used to model the cortisol diurnal rhythm, and the inter- and intrasubject coefficients of variation (CVs) were calculated across the 2 periods. Results: Three significant cortisol concentration peaks were observed at ~ 7 AM, 1 PM, and 7 PM. The intersubject CVs (%) for the amplitude, acrophase, and midline estimating statistic of rhythm (MESOR) were 18.2, 19.3, and 16.8, respectively. The intrasubject CVs (%) were 11.2, 7.6, and 6.9, respectively. The inter- and intrasubject CVs (%) for the lunch-induced 1 PM peak and the> dinner-induced 7 PM peak were 22.1, 17.3, 44.7, and 22.1 respectively. Conclusions: Assessment of serum cortisol diurnal rhythm suggests that the amplitude, acrophase, and MESOR, but not the meal-induced peaks, have the potential to be a reliable biomarker in drug development targeting the hypothalamic- pituitary-adrenocortical (HPA) axis.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objective: To evaluate the effect of ethnicity on the pharmacokinetics (PK) of tildrakizumab, a novel anti-IL-23 monoclonal antibody for the treatment of psoriasis. Materials and methods: This was an open-label, 2-part study in healthy adult subjects. In part 1, Japanese subjects and matched Caucasian and Chinese subjects (to Japanese) were assigned to 1 of 3 cohorts and administered tildrakizumab 50, 200, or 400 mg subcutaneously (SC). In part 2, Japanese subjects received tildrakizumab 10 mg/kg IV. Pre- and post-treatment antidrug antibodies were assessed. Safety and tolerability were assessed throughout the study. Results: 59 subjects were enrolled; 53 in part 1 and 6 in part 2. Overall geometric mean AUC∞ was 6.15, 6.05, and 6.32 day×μg/mL/mg in Japanese, Caucasian, and Chinese subjects, respectively, after administration of a single SC dose. Bioavailability was ~ 92%. Six out of 58 evaluable subjects were positive for post-treatment ADA; 2 of these positive subjects had reduced tildrakizumab exposure. Most AEs were mild in intensity and the most frequent treatment-related AEs were injection site hematoma (15%), injection site pain (10%), and injection site erythema (8%). Conclusions: The pharmacokinetics of tildrakizumab were similar in Japanese, Caucasian, and Chinese subjects. Tildrakizumab exposure increased proportionally with dose in the range of 50 - 400 mg. A single SC dose of 50, 200, and 400 mg or a single IV dose of 10 mg/kg was generally well tolerated.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Introduction: Experimental studies have shown that liposomal curcumin can exert a reduction in tumor growth in pancreatic and colorectal cancer. In this phase I clinical trial we investigated the pharmacokinetics, safety, and tolerability of intravenously administered liposomal curcumin in healthy subjects. Material and methods: 50 male and female participants were included in this randomized, placebo-controlled double-blind phase I dose escalation study. Subjects received a single dose of liposomal curcumin (10 - 400 mg/m2; n = 2 - 6 per group) or placebo over 2 hours intravenously. Results: Dose-dependent increases in the plasma concentrations of curcumin and its metabolite tetrahydrocurcumin (THC) were detected. After the end of drug infusion, curcumin and THC plasma concentrations decreased within 6 - 60 minutes below the limit of quantification. Mean urinary excretion was ~ 0.1% of total systemic clearance. Liposomal curcumin was tolerated well, but a transient red blood cell echinocyte formation with concomitant increase in mean cellular volume was observed at dosages ≥ 120 mg/m2. Conclusion: Short-term intravenous dosing of liposomal curcumin appears to be safe up to a dose of 120 mg/m2. Changes in red blood cell morphology may represent a dose limiting sign of toxicity.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objective: To evaluate the pharmacokinetics of oral canagliflozin and its Oglucuronide metabolites (M7 and M5) after single and multiple doses in healthy adult participants. The pharmacodynamics, safety, and tolerability of canagliflozin were also evaluated. Methods: In this open-label, single- (day 1) and multiple-dose (days 4 – 9), parallelgroup, phase 1 study, 27 healthy participants were randomized into three groups (1 : 1 : 1) to receive 50, 100, or 300 mg canagliflozin. Pharmacokinetics and pharmacodynamics were assessed at pre-pecified timepoints on days 1, 9, and 10. Results: Mean area under the plasma concentration-time curve, and the maximum observed plasma concentration of canagliflozin, M7, and M5 increased in a dose-dependent manner, across all the 3 doses, following single- and multiple-dose administration. The mean apparent elimination halflives of canagliflozin, M7, and M5 were independent of the dose. Canagliflozin decreased the renal threshold for glucose (RTG) and increased the urinary glucose excretion (UGE) in a concentration- and dose-dependent manner. The relationship between drug concentrations and RTG was described by a sigmoidal relationship with RTGmin (minimum value of RTG) of 37.5 ng/mL (95% confidence interval (CI): 34.3, 40.8) and half-maximal effective concentration (EC50) of 21 ng/mL (95% CI: 18.3, 23.8). No deaths, serious adverse events, hypoglycemic events, or discontinuations due to adverse events were observed. Conclusion: Pharmacokinetics of canagliflozin and its metabolites (M7 and M5) were linear, and no time-dependent changes were observed after single- and multiple-dose administration. Similarly, pharmacodynamic effects of canagliflozin on RTG and UGE were found to be dose- and concentration-dependent. Overall, canagliflozin was well-tolerated in healthy participants.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Background: Hemodynamic stability is one of the most critical concerns during induction of anesthesia. Whether the pharmacokinetic model by Marsh or the one by Schnider will produce better hemodynamic stability remains unclear. This study compared hemodynamic changes during induction between the two models. Methods: 60 patients who underwent elective surgery were randomly assigned to plasma target-controlled infusion by Marsh's (n = 30) or Schnider's (n = 30) model with an initial target concentration of 4 μg×mL-1. The target was then reset and gradually titrated to a sedation level with a narcotrend index (NI) below 64. Stroke volume, cardiac output, systemic vascular resistance, arterial pressure, target, and effect site concentration, and dose of propofol infused were recorded every minute during the first 25 minutes of infusion. Results: Throughout the first 25 minutes, stroke volume index and cardiac index were decreased significantly in both Marsh and Schnider groups, but no statistical difference was detected between the groups (p > 0.05). Central venous pressure (CVP), systemic vascular resistance index (SVRI), and heart rate (HR) did not significantly change during induction (p > 0.05). Time to loss of responsiveness (LOR), and time for NI to decrease to 64 was faster in Marsh than in Schnider (1.51 ± 0.8 minutes vs. 2.8 ± 1.2 min, p < 0.001; 3.3 ± 2.0 minutes vs. 5.2 ± 2.3 minutes, p < 0.01, respectively). Conclusions: When target concentrations are titrated according to NI during induction of anesthesia, Marsh's model could induce sedation faster than Schnider's. Meanwhile, hemodynamic changes were not observed to be statistically different between the two models. Hypotension induced by plasma target-controlled infusion of propofol could mainly be attributed to decreased stroke volume instead of vascular dilation.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objective: A new twice daily sustained-release (SR) paracetamol formulation was developed to improve convenience and enhance patient compliance for treatment of pain from chronic diseases. This research aimed to evaluate bioavailability and compare pharmacokinetic (PK) properties of the new SR paracetamol formulation (2 — 1,000 mg) with those of immediaterelease (IR) paracetamol (2 — 500 mg) and existing extended-release (ER) paracetamol (2 — 665 mg). Methods: Two randomized, single-dose, 4-way crossover studies were conducted. A total of 28 healthy male and female volunteers participated in each study. The relative bioavailability, partial extent of absorption, overall elimination, food effect, and safety were evaluated. Results: The estimates of relative bioavailability of new SR with IR formulation based on dose-adjusted AUC0-inf were 91% (0.86 - 0.96) for the fasted state and 99% (0.95 - 1.02) for the fed state, while these estimates comparing new SR with ER formulation were 99% (0.96 - 1.03) in the fasted state and 98% (0.95 - 1.02) in the fed state. The accumulated mean time period at or above the minimal therapeutic plasma paracetamol concentration for the new SR was from 90% to 112% longer than that of the IR formulation, in fasted and fed state, respectively. Food significantly increased Cmax of SR formulation, with ratios fast vs. fed 0.79 (p < 0.0001) and 0.77 (p < 0.0001) in study I and II, respectively. Conclusions: The new SR formulation was well absorbed, with more than 90% relative bioavailability as compared to the currently marketed IR and ER products and better sustained-release PK characteristics, which make it suitable for twice-daily paracetamol treatment.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objective: To compare the bioavailability and safety profile of crushed ticagrelor tablets suspended in water and administered orally or via nasogastric tube, with that of whole tablets administered orally. Methods: In this single-center, open-label, randomized, three-treatment crossover study, 36 healthy volunteers were randomized to receive a single 90-mg dose of ticagrelor administered orally as a whole tablet or as crushed tablets suspended in water and given orally or via a nasogastric tube into the stomach, with a minimum 7-day wash-out between treatments. Plasma concentrations of ticagrelor and AR-C124910XX were assessed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post-ticagrelor dose for pharmacokinetic analyses. Safety and tolerability was assessed throughout the study. Results: At 0.5 hours postdose, plasma concentrations of ticagrelor and AR-C124910XX were higher with crushed tablets administered orally (148.6 ng/mL and 13.0 ng/mL, respectively) or via nasogastric tube (264.6 ng/mL and 28.6 ng/mL, respectively) compared with whole-tablet administration (33.3 ng/mL and 5.2 ng/mL, respectively). A similar trend was observed at 1 hour postdose. Ticagrelor tmax was shorter following crushed vs. whole-tablet administration (1 vs. 2 hours, respectively). Geometric mean ratios between treatments for AUC and Cmax were contained within the bioequivalence limits of 80 - 125% for ticagrelor and AR-C124910XX. All treatments were generally well tolerated. Conclusions: Ticagrelor administered as a crushed tablet is bioequivalent to whole-tablet administration, independent of mode of administration (oral or via nasogastric tube), and resulted in increased plasma concentrations of ticagrelor and ARC124910XX at early timepoints.
    International journal of clinical pharmacology and therapeutics 12/2014;
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    ABSTRACT: Objective: This study was performed to compare the pharmacokinetic properties and relative bioavailability of two isosorbide-5-mononitrate (5-ISMN) sustained-release drugs in healthy Korean subjects under fasting and fed conditions. Methods: A total of 60 healthy volunteers (30 each in the fasting and fed arms of the study) were enrolled in the study and were randomized to treatment. After the administration of a single dose of one of the investigational products, blood samples were collected at specific time intervals from 0 to 36 hours. The plasma concentrations of 5-ISMN were measured by LC-MS/MS. The pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of the parameters were obtained by analysis of variance on logarithmically transformed data. Results: The corresponding 90% CIs of AUClast and Cmax for the test/reference geometric mean ratio were 90.75 – 98.44% and 92.28 - 98.33%, respectively, under fasting conditions. In the fed state study, the 90% CIs for the geometric mean ratio of test to reference drugs were 94.79 - 103.33% for AUClast and 99.86 - 108.02% for Cmax. Conclusion: The test product is equivalent to the reference product in subjects under fasting and fed conditions within the Korean regulatory bioequivalence criteria. Both formulations were safe and well tolerated, and there were no noteworthy differences in the safety profiles between the test and reference drugs.
    International journal of clinical pharmacology and therapeutics 12/2014;