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

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.

  • Impact factor
    1.20
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    Impact factor
  • 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: We assessed the effect of 1 x 300 mL/d and 3 x300 mL/d grapefruit juice (GFJ) on ambrisentan and bosentan pharmacokinetics in healthy volunteers. Methods: In the ambrisentan study, 12 healthy extensive metabolizers (EM) of CYP2C19 received therapeutic doses of ambrisentan (5 mg q.d. on study days 1 - 11) and GFJ (1 x 300 mL/d on study days 6 - 8 and 3 x 300 mL/d on study days 9 - 11). Ambrisentan pharmacokinetics was assessed on study days 5, 8, and 11. In the bosentan study, 16 healthy EM of CYP2C9, who were stratified into two groups (CYP3A5 expressors (n = 8) and CYP3A5 non-expressors (n = 8)), received bosentan (125 mg b.i.d. on study days 1 - 13) and GFJ (1 x 300 mL/d on study days 8 - 10 and 3 x 300 mL/d on study days 11 - 13). Bosentan pharmacokinetics was assessed on study days 7, 10, and 13. Results: Whereas 1 x 300 mL/d GFJ had no effect on the pharmacokinetics of ambrisentan and its metabolite, 3 x 300 mL/d GFJ increased the exposure with ambrisentan by 8% and the molar plasma metabolic ratio by 22% (both p < 0.05). Correspondingly, the apparent oral clearance of ambrisentan decreased to 92% (p < 0.05). GFJ slightly prolonged tmax of bosentan and increased the metabolic ratio of bosentan/hydroxy-bosentan by 19% (p < 0.05). Conclusion: GFJ had no clinically relevant effect on the pharmacokinetics or safety profile of ambrisentan and bosentan. Therefore, no dose adjustments are needed, and GFJ can be safely co-administered even at very high doses.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Background: The aim of our study was to analyze the persistence with tamoxifen (TAM) and aromatase inhibitors (AIs) in postmenopausal women with hormone-receptor-positive breast cancer (BC) in early and late stage disease. Methods: This study based on data from The IMS Oncology Analyzer (OA) including retrospective longitudinal patient treatment histories from diagnosis for all cancer types. 4,626 patients with a diagnosis of breast cancer with current or terminated treatment with TAM or AIs between January 2003 and March 2012 in Germany were included. Results: Our results indicate a significantly increased risk for treatment discontinuation for patients in the age groups of 41 - 50 and 51 - 60 years compared to older patients as well as in patients with a stage IV tumor compared to patients with lower stage tumors. If treatment was initiated by a gynecologist, patients are less likely to discontinue their therapy compared to treatment initiated by an oncologist. Furthermore, the risk of therapy break up was significantly lower in patients treated in an office-based setting compared to the reference group of patients treated in general hospitals. Conclusion: In conclusion, persistence with endocrine treatment in woman with hormone-receptor-positive breast cancer is low, especially in later stage disease, and needs to be significantly increased to improve outcome in clinical practice. Further research is required to understand this complex, but important aspect.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objective: To compare the pharmacokinetic properties of two newly developed generic ambroxol formulations with a branded innovator product in healthy Chinese male volunteers. Methods: This was a single-dose, randomized, open-label, threeperiod crossover study in healthy volunteers aged 18 - 45 years under fasting conditions. Subjects were assigned to receive 1 of 2 test formulations or a reference tablet of ambroxol 30 mg. Each study period was separated by a 1-week washout phase. Blood samples were collected at pre-specified times. A non-compartmental mmethod was employed to determine pharmacokinetic properties (Cmax, tmax, AUC0-tlast, AUC0-inf) to test for bioequivalence. The predetermined regulatory range of 90% CI for bioequivalence was 80 - 125%. Results: 24 subjects were enrolled in and completed the study. The geometric mean Cmax values for the test tablet, test capsule, and reference product were 82.73, 85.36, 84.56 ng/mL, and their geometric mean AUC0-tlast (AUC0-inf) were 660.87 (753.49), 678.98 (756.79), and 639.41 (712.14) ng x h/mL, respectively. For test tablet vs. reference, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0-tlast, and AUC0-infž were 91.2% to 104.9%, 96.5% to 110.7%, and 98.8% to 113.4%, respectively. For test capsule, the corresponding values were 94.1% to 108.3%, 99.2% to 113.7%, and 99.2% to 113.9%, respectively. No adverse events occurred during the study. Conclusions: The ambroxol 30 mg tablets and capsules were considered bioequivalent to the reference formulation in accordance with predetermined regulatory criteria.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objectives: The purpose of the study was to identify the most sensitive analyte (i.e., encapsulated, free, and total forms) for assessing the bioequivalence (BE) of liposome drug products using Monte Carlo simulation. Methods: We proposed a liposome classification system that divided liposome drug products into four classes according to the extent of reticuloendothelial system uptake and in vivo release rate: class I: low reticuloendothelial system uptakerapid release rate; class II: low reticuloendothelial system uptake-slow release rate; class III: high reticuloendothelial system uptakerapid release rate; Class IV: high reticuloendothelial system uptake-slow release rate. In conjunction with the proposed classification scheme, a variety of drug classes were simulated to determine which analyte provides the most sensitive measure of BE. All drug classes were investigated in single and multiple dose studies. The sensitivity of analytes for measuring BE was evaluated using the power curve. Results and conclusions Our simulations indicated the encapsulated form provides the most accurate assessment BE for liposome drug products with low reticuloendothelial system uptake (i.e., class I and II). For liposome drug products with high reticuloendothelial system uptake (i.e., class III and IV), the free form provides the best indication BE. Measurement of total drug form to assess BE was preferred only for liposome drug products with low reticuloendothelial system uptake and slow release rates (i.e., class II liposomal drug product). In general, a single dose form is sufficient for demonstrating the BE of liposome drug products.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Objective: The purpose of this study was to describe the population pharmacokinetics (PK) of tacrolimus (TAC) in 52 Chinese pediatric patients early after liver transplantation. Methods: Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data from the first day after surgery. A total of 488 concentration data were obtained and analyzed by a nonlinear mixed-effect modeling (NONMEM) method. A number of demographic and clinical variables were tested for their influence on TAC PK parameters. Results: The PK of TAC were best described by a one-compartment model with first-order absorption and elimination. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 5.72 L/h and 131 L, respectively. The absorption rate constant (Ka) was fixed in 4.48 h-1. The inter-individual variabilities in CL/F and V/F were 13.5% and 78.1%. In the final analysis performed in all 52 patients, the post-operation day (POD) and alanine aminotransferase (ALT) influenced TAC CL/F and V/F, and total protein (TP) was the only covariate retained on V/F. Conclusion: A population PK model of TAC was developed in Chinese pediatric patients early afte liver transplantation. It identified significant relationships between the PK of TAC and the characteristics of the patients. POD, ALT, and TP were identified as the main factors influencing the PK of TAC. The developed model could be useful to optimize individual pediatric TAC dosing regimen in routine clinical practice.
    International journal of clinical pharmacology and therapeutics 09/2014;
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    ABSTRACT: Once-daily darunavir/ritonavir (800/100 mg), plus other antiretrovirals, is recommended for HIV-1-infected patients. Low therapy adherence is linked with poor outcomes. Pill burden can impact adherence. An 800-mg darunavir tablet would reduce pill burden.
    International journal of clinical pharmacology and therapeutics 09/2014; 52(9):805-16.
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    ABSTRACT: Tianeptine is widely used for controlling depressive symptoms.
    International journal of clinical pharmacology and therapeutics 09/2014; 52(9):817-23.
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    ABSTRACT: Objectives: This study evaluates the effect of adherence to stain on hospitalization for cardiovascular disease and all-cause mortality in South Korea. Methods: We performed a national cohort study on 423,786 individuals using the Korean National Health Insurance Claims Database. The cohort was composed of individuals who were aged between 18 and 84 years, were newly treated with statin, and were followed from 2005 to 2009. Adherence to statin was calculated using medication possession ratio (MPR) and associations between adherence to statin and health outcomes were evaluated using Cox's proportional hazards regression analysis. Results: Of the study subjects, 41.9% were male, 7.4% were beneficiaries of a tax-financed medical aid program (MAP), 1.5% had prior cardiovascular disease (CVD), 13.0% had diabetes, and 27.5% had hypertension. Non-adherence to statin was found to be associated with an increased risk of cardiovascular hospitalization (HR 2.18, 95% CI: 2.02 - 2.35) and all-cause mortality (HR = 1.75, CI: 1.66 - 1.84). As the age of the study group increased, non-adherence was more strongly associated with the risk of hospitalization for CVD. In addition, the risk of hospitalization for CVD was relatively high in patients who were male, older or MAP beneficiaries, and who had hypertension, diabetes, and high Charlson's comorbidity index. Conclusions: This study supports that non-adherence to statin is associated with an elevated risk of hospitalization for cardiovascular disease and all-cause mortality.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Interferon alpha (IFNalpha)-based treatment of chronic hepatitis C viral (HCV) infection may induce pulmonary and extrapulmonary sarcoidosis. We report a case of a 50-year-old male patient who suffered from hepatitis C-induced liver cirrhosis with respiratory insufficiency due to severe hepatopulmonary syndrome. After 9 months of treatment with IFNalpha and ribavirin, he developed an asymptomatic, clinically occult pulmonary granulomatosis, which was not detectable in CT. The diagnosis was made by bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy. The condition did not progress to clinically apparent disease despite continuation of IFNalpha treatment.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objective. The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of metformin. Methods. A randomized, open-label, two-way crossover study with a 7-day washout period was conducted. All subjects were given an oral dose of metformin with or without voglibose 3 x daily for 7 days. Plasma concentrations of metformin on day 7 were measured using high performance liquid chromatography (HPLC) with UV detection for pharmacokinetic assessment Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. Results. 22 subjects completed the study. The geometric mean ratios for Css,max of metformin (metformin plus voglibose vs. metformin only) were 0.98 (90% CI, 0.92 - 1.05; p > 0.05) and for AUCtau, the ratio was 0.99 (90% CI, 0.92 - 1.06; p > 0.05). There were no significant differences in adverse drug reactions between metformin with and without voglibose. However, the incidence of adverse events was higher in period 1 than in period 2 (16 cases vs. 1 case, p < 0.001). Conclusions. Co-administration of metformin and voglibose had no statistically or clinically significant effects on the pharmacokinetics of metformin in healthy subjects. The pharmacodynamic interaction study to evaluate the effect of metformin on the pharmacodynamics of voglibose is in progress.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objective: To evaluate the effects of siponimod (BAF312) on the pharmacokinetics (PK) and pharmacodynamics (PD) of a monophasic oral contraceptive (OC). Materials and methods: This was a phase 1, single-center, open-label, multipledose, single-sequence study in healthy females. Eligible subjects (n = 23) were exposed sequentially to two treatment periods: period 1 (OC alone) and period 2 (OC + siponimod) in two consecutive menstrual periods. PK parameters were assessed on day 21 of both treatment periods. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone concentrations were measured at baseline and days 3, 6, 8, 11, 14, 16, 19, 21, and 23 of each period. Largest ovarian follicle size and sex hormone-binding globulin (SHBG) concentration were measured and Hoogland score was calculated at baseline and day 21 of each period. Safety and tolerability of siponimod was also assessed. Results: Co-administration (OC + siponimod) increased the AUCt,ss and Cmax,ss of levonorgestrel by 28% and 18%, respectively, but had no effect on the PK of ethinylestradiol. No significant changes in estradiol, FSH, and LH were noted with co-administration vs. OC alone. Progesterone levels < 5 nmol/L, largest follicle size < 10 mm, and Hoogland score of 1 on day 21 indicated lack of ovulation in all subjects during co-administration. Co-administration was well tolerated. Conclusion: In conclusion, PK and PD of the OC were not altered to a clinically significant extent and contraceptive efficacy was maintained with co-administration. Hence, OC as a contraceptive measure can be safely co-administered with siponimod.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objective: This study was undertaken to investigate potential drugdrug interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and simvastatin. Materials and methods: In this open-label, randomized crossover trial, healthy volunteers (median (range) age 36.5 (20 - 50) years) received 3 single-dose treatments: 25 mg empagliflozin (n = 18), 40 mg simvastatin (n = 17), and 25 mg empagliflozin with 40 mg simvastatin (n = 18). Results: Based on standard criteria, simvastatin had no effect on empagliflozin area under the plasma concentration-time curve (AUC0-inf, adjusted geometric mean ratio (GMR): 102.05; 90% CI: 98.90 - 105.29) or maximum plasma concentration (Cmax, GMR: 109.49; 90% CI: 96.91 - 123.69). There were only minor deviations in simvastatin AUC0-inf (GMR: 101.26; 90% CI: 80.06 - 128.07) and Cmax (GMR: 97.18; 90% CI: 76.30 - 123.77) when co-administered with empagliflozin. Empagliflozin had no effect on AUC0-inf (GMR: 104.87; 90% CI: 90.09 - 122.07) or Cmax (GMR: 97.27; 90% CI: 84.90 - 111.44) of simvastatin acid, the active metabolite of simvastatin. Adverse events (AEs) were reported for 6 subjects on empagliflozin, 4 on simvastatin, and 5 on co-administered treatment. No serious AEs or investigator-defined drug-related AEs were reported. Conclusion: No relevant drug-drug interaction was observed, and pharmacokinetic results suggest that no dose adjustments for either drug are necessary when empagliflozin and simvastatin are co-administered. Empagliflozin was well tolerated when administered alone or in combination with simvastatin.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objectives: Granulocyte macrophage colony-stimulating factor (GM-CSF) has been proved to be among the most important chemokines, playing a key role in rheumatoid arthritis (RA). However, the mechanism underlying the regulation of GM-CSF has not been established clearly yet. The aim of this study was to investigate the influence of paeonol in the expression of GM-CSF in fibroblast-like synoviocytes (FLS). Methods: The expression of GM-CSF was detected both at protein and mRNA levels in FLS after the stimulation of TNF-alpha at diverse concentrations and times. And then GM-CSF was detected again after pre-treatment with paeonol. Phosphorylation of PI3K/Akt and expression of NF-kappaB and p-IkappaBalpha were detected with western blot. Meanwhile, inhibitors of the pathways were used to investigate the mechanism of regulation of GM-CSF. Results: Recombinant TNF-alpha up-regulated GM-CSF in a concentration- and time-dependent manner in FLS, which was significantly suppressed by paeonol. Paeonol also exerted its ability to suppress the promoting effects of TNF-alpha on the phosphorylation of PI3K/Akt and activation of NF-kappaB pathway. Administration of the inhibitors LY294002, perifosine, BAY11-7082, and SC-514 confirmed the roles of PI3K/Akt and NF-kappaB on the production of GM-CSF. Furthermore, TNF-alpha induced proliferation, while paeonol suppressed proliferation of FLS. Conclusion: These results demonstrate that paeonol suppressed TNF-alpha-induced GM-CSF production via the PI3K/Akt/NF-kappaB pathway.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objective: Numerous studies have shown that the tolerance of children to fluoroquinolones (FQs) is satisfactory, and some indications have been recently agreed upon. However, vigilance is required when prescribing FQ to children. The aim of our study was to describe the prescription of FQs to children hospitalized in our hospital. Materials and methods: This is a chart retrospective observational study at the Robert-Debré teaching Hospital between January 2009 and December 2010. Data was collected about patients (name, sex, weight, age) and prescribed treatments (indication, international nonproprietary names, dose, number of doses per day, administration route). Quality of collected data was assessed by analyzing the clinical files of 32 randomly selected patients. Results: We analyzed data for 397 patients (3 days - 18 years old and 640 g - 115 kg). Ciprofloxacin was prescribed for 382 patients (96%), ofloxacin for 10 patients (3%), and levofloxacin for 5 patients (1%). Febrile neutropenia was the most common indication (108 patients, i.e., 27%), followed by inflammatory bowel disease (50 patients, 13%). Doses conformed to recommendations for 88% of the patients. Analysis of the 32 cases indicated an overall compliance percentage of 94.4%. Conclusion: This is the first study to collect so much data on FQ prescriptions for hospitalized children. Use in practice went beyond the licensed indication. Doses were consistent with those for recommended indications.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: A simple, rapid and sensitive high-power liquid chromatographic (HPLC) method for analysis of 5-fluorouracil (5-FU) in patient plasma was developed and validated to study clinical pharmacokinetics (PK). Plasma sample preparation was processed with ammonium acetate buffer (pH 3.5; 0.01M) followed by liquid-liquid extraction with isopropanol/ethyl acetate (15 : 85, v/v). Extraction recovery ranged from 87.55 to 95.26%. Separation was performed using a C18 column at 25 °C with UV detection at 265 nm. The isocratic mobile phase composed of acetonitrile-ammonium acetate buffer (pH 3.5; 0.01M) (2.5 : 97.5 v/v) at a flow rate of 0.8 mL/min. Retention time was less than 7 minutes. Standard curve was linear between 0.01 - 10 µg/mL and 10 - 100 µg/mL for plasma sample. The limit of quantification was 10 ng/mL. The intra- and interday precision was below 10% (RSD). The accuracy ranged from 85.24 to 104.14%. The analysis method is rapid because it needs neither time-consuming extraction procedures nor complex chromatographic condition. The method was successfully applied to access pharmacokinetics and plasma concentration at steady state (SSC) of 5-FU. The results showed the PK and SSC of 5-FU characterized by a large interpatient variability. To increase therapeutic response and reduce toxicity, we should optimize 5-FU dose by investigating PK behavior to obtain ideal SSC.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Background: Potential drugdrug interactions are a concern for patients taking tamoxifen. Objective: This study was designed to determine the effect of coadministering desvenlafaxine on tamoxifen pharmacokinetics. Materials and methods:This open-label, 2-period inpatient and outpatient study enrolled healthy, postmenopausal women. Period 1, day 1, subjects were administered tamoxifen 40 mg followed by 23 days of blood sampling for pharmacokinetic analyses. During period 2, subjects received desvenlafaxine 100 mg/d for 28 days; a single dose of tamoxifen 40 mg was administered with desvenlafaxine 100 mg on day 7, followed by 23 days of blood sampling. Pharmacokinetics of tamoxifen and its metabolites (AUC over infinite time (AUCinf), AUC to the last measurable concentration (AUClast), peak plasma concentration (Cmax)) were compared for monotherapy vs. combination therapy using the ratio of adjusted mean differences. A superposition method was used in the statistical analysis of N-desmethyl-tamoxifen and endoxifen to address the carry-over observed for those metabolites. The test for interaction was considered negative if the 90% confidence intervals (CIs) for the ratios were within 80 – 125%. Results: Coadministration of tamoxifen with steady-state desvenlafaxine did not alter tamoxifen AUCinf, AUClast, and Cmax, as reflected by the ratio of adjusted geometric means (90% CIs) of 100.7% (96.7%, 104.9%), 103.5% (100.2%, 106.9%), and 99.4% (94.0%, 105.2%), respectively. Similarly, coadministration did not alter 4-hydroxy- tamoxifen and N-desmethyl-amoxifen pharmacokinetics. The 11.8% (88.2% (82.6%, 94.2%)) and 8.0% (92.0% (84.7%, 100.0%)) decreases in endoxifen AUClast and Cmax, respectively, were not significant (90% CIs fell wholly within the prespecified acceptance range). Conclusions: Steady-state desvenlafaxine 100 mg did not affect tamoxifen pharmacokinetics. For women treated with tamoxifen, desvenlafaxine may represent a safe and effective treatment unlikely to alter tamoxifen efficacy.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objectives: A novel once-aweek contraceptive patch delivers the same systemic exposure seen with a combined oral contraceptive pill containing 0.02 mg ethinyl estradiol (EE) and 0.06 mg gestodene (GSD). This study evaluated the relative bioavailability of EE and GSD after application of this patch to three different sites. Methods: In this phase I, open-label, randomized, intra-individual comparison, crossover study, 43 women (aged 18 - 45 years) were randomized to one of six treatment sequences. Patches were applied to two test sites (buttocks and outer, upper arm) and one comparator site (lower abdomen). In each treatment period, four patches were worn for 7 days each, followed by a 7-day, patch-free interval. The primary objective was to investigate the relative bioavailability of transdermally administered EE and GSD between test and comparator sites using the primary variable area under the concentration- time curve (AUC(0-168)) during week 4 of each period. Results: Of the 43 women who were randomized, 43 were included in the set for safety evaluation and 40 were included in the set for pharmacokinetic (PK) analysis. Three subjects were excluded from the PK analysis as they failed to complete the study. AUC(0-168) for EE and GSD were equal when the patch was applied to buttocks or abdomen (AUC(0-168) ratios: EE, 1.07 (94% confidence interval, CI: 0.994 - 1.16); GSD, 1.02 (94% CI: 0.946 - 1.10)). Relative bioavailabilities for EE and GSD were 31% and 24% higher, respectively, for arm vs. abdomen. AUC(0-168) 94% CI for the arm/abdomen ratio exceeded the pre-defined bioequivalence range of 80 - 125% (EE: 1.21 - 1.42; GSD: 1.15 - 1.34). Other PK parameters were correspondingly higher for arm vs. buttocks or abdomen. Patch adhesion and tolerability were good, with no relevant differences between sites. Conclusion: Differences in systemic EE/GSD exposure following patch application to the outer, upper arm vs. lower abdomen and buttocks are unlikely to be clinically relevant, and there were no relevant safety concerns.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Aim: Vorapaxar is a proteaseactivated receptor (PAR)-1 antagonist being developed for the prevention and treatment of thrombotic vascular events. To evaluate race/ethnic differences between Caucasians and Chinese in the pharmacokinetics of vorapaxar and its active metabolite SCH 2046273 (M20) or in the metabolite/parent ratio, we conducted a cross-study comparison on pharmacokinetic data of vorapaxar and M20 obtained from two similarly designed studies: one in healthy Chinese subjects and the other in a healthy Western (United States, [U.S.]) population. Methods: The pharmacokinetic profiles of vorapaxar and M20 were characterized using open label, two treatment parallel group designs in men and women aged 18 - 45 years. Vorapaxar was administered orally as a single dose of 40 mg in Chinese subjects (n = 14) or 120 mg in U.S. subjects (n = 14), or 2.5 mg QD for 6 weeks in both studies (Chinese, n = 14; U.S., n = 23). Results: Vorapaxar was rapidly absorbed in both Chinese and U.S. subjects. Vorapaxar and M20 had similar elimination half-lives. The range of metabolite/parent ratios after single dose or daily administration was largely overlapped in Chinese and U.S. subjects. Steady state was attained by day 21 for vorapaxar and M20 in both race/ethnic groups. The accumulation ratios for vorapaxar and M20 during daily administration were similar in Chinese and U.S. subjects. Vorapaxar was well-tolerated in Chinese and U.S. subjects. Conclusion: The pharmacokinetic profiles of vorapaxar and M20 and the metabolite/parent ratios in healthy Chinese were generally comparable to those in a healthy Western population.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objective: Pitavastatin, a highly potent inhibitor of 3-hydroxy-methylglutarylcoenzyme A reductase, is a known substrate of OATP1B1. Ursodeoxycholic acid (UDCA) inhibits OATP1B1 expression by repressing hepatocyte nuclear factor 1alpha (HNF1alpha). Thus, the effects of UDCA on the pharmacokinetics of pitavastatin were investigated in healthy subjects. Methods: An open-label, 2-phase, parallel study was conducted with 13 healthy volunteers. In the control phase, after an overnight fast, each subject received a single dose of 2 mg pitavastatin. After a 1-week washout period, in the UDCA phase, subjects received a daily oral dose of 600 mg of UDCA (300 mg b.i.d.) for 14 days. On day 15, 2 mg of pitavastatin was administered as described previously for the control phase. Results: In the UDCA phase, the maximum plasma concentration (Cmax) of pitavastatin was slightly higher than in the control phase (48.6 ± 22.9 ng/mL vs. 42.4 ± 16.1 ng/mL). However, the overall pharmacokinetic parameters of pitavastatin and pitavastatin lactone during the two study phases were not significantly different. Conclusions: UDCA had no significant effect on the pharmacokinetics of pitavastatin. These results do not support the notion that UDCA increases the systemic exposure of OATP1B1 substrate by inhibiting HNF1alpha and decreasing OATP1B1 transporter expression.
    International journal of clinical pharmacology and therapeutics 08/2014;
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    ABSTRACT: Objective: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK1070806, a novel IgG1 mAb that neutralizes human interleukin (IL)-18. Methods: In this first-timein-human (FTIH) study, cohorts of healthy and obese subjects were randomly allocated to receive single doses of GSK1070806 (0.008 - 10 mg/kg) or placebo. Blood was sampled ≤ 274 days post-dosing, and safety monitored. Results: GSK1070806 was generally well tolerated. The most common AEs were nasopharyngitis and headache, arising as frequently in the placebo as in the active drug groups; most AEs were mild to moderate and unrelated to dose level. There were no allergic, delayed-type hypersensitivity, or infusion-related reactions and the incidence of immunogenicity was low. GSK1070806 plasma pharmacokinetic profiles were comparable in healthy and obese subjects; there was no major deviation from dose proportionality for AUCinfž and Cmax although a trend for dose-dependent increase in t1/2 was observed. Serum drug-bound IL-18 levels increased post-dosing and were sustained for a long time-period following GSK1070806 administration. Ex-vivo whole blood assay demonstrated prolonged pharmacological activity of GSK1070806 as determined by its primary immunological mechanism of action, inhibition of IL-18-induced IFN-gamma production.Conclusion: GSK1070806 warrants clinical investigation in patients.
    International journal of clinical pharmacology and therapeutics 08/2014;

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