Journal of Clinical Pharmacology最新文献_第10页

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-08-01 Epub Date: 2013-05-30 DOI: 10.1002/jcph.100

Farzaneh Salem, Trevor N Johnson, Zoe E Barter, J Steven Leeder, Amin Rostami-Hodjegan

{"title":"Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.","authors":"Farzaneh Salem, Trevor N Johnson, Zoe E Barter, J Steven Leeder, Amin Rostami-Hodjegan","doi":"10.1002/jcph.100","DOIUrl":"https://doi.org/10.1002/jcph.100","url":null,"abstract":"The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"857-65"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31559161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 49

Which patient is most likely to benefit from dronedarone? Analysis from the Magdeburg Dronedarone Registry (MADRE study). 哪些患者最有可能从无人机龙获益?马格德堡无人机登记(MADRE研究)分析。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-08-01 Epub Date: 2013-05-29 DOI: 10.1002/jcph.103

Samir M Said, Hans D Esperer, Kathrin Kluba, Conrad Genz, Thomas Rauwolf, Alexander Schmeisser, Ruediger C Braun-Dullaeus

{"title":"Which patient is most likely to benefit from dronedarone? Analysis from the Magdeburg Dronedarone Registry (MADRE study).","authors":"Samir M Said, Hans D Esperer, Kathrin Kluba, Conrad Genz, Thomas Rauwolf, Alexander Schmeisser, Ruediger C Braun-Dullaeus","doi":"10.1002/jcph.103","DOIUrl":"https://doi.org/10.1002/jcph.103","url":null,"abstract":"Based on an analysis of the Magdeburg Dronedarone Registry data we sought to determine which patients could benefit from dronedarone therapy regarding rhythm control. The study included 191 patients (85 women) aged 63 ± 10 years with a history of paroxysmal or persistent AF and a follow-up of 14 ± 5 months. The total AF recurrence rate was 67% and lone AF was significantly more often associated with AF recurrences than non-lone AF (84% vs. 62%, P = .01). Arterial hypertension, treated coronary artery disease, and diabetes mellitus were not significantly related to AF recurrences (64%, 67%, 58% resp. P = .3). Response rate to dronedarone in patients with slightly increased left atrial size was significantly greater than in patients with normal or markedly increased left atrial size (47%, 16%, 27% resp., P = .001). The rate of adverse effects was 32% in the study sample, and was significantly lower in patients with lone AF as compared to those with non-lone AF (11% vs. 37%, P = .002). The body mass index was a predictor neither of response rate nor adverse effects. The results suggest that dronedarone is more effective in patients with non-lone AF and slightly increased left atrial size. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"841-5"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31468554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Placebo- and amitriptyline-controlled evaluation of central nervous system effects of the NK1 receptor antagonist aprepitant and intravenous alcohol infusion at pseudo-steady state. 在伪稳态下，安慰剂和阿米替林对照评价NK1受体拮抗剂阿瑞吡坦和静脉滴注酒精对中枢神经系统的影响。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-08-01 Epub Date: 2013-06-18 DOI: 10.1002/jcph.120

Erik T te Beek, Daniel Tatosian, Anup Majumdar, Diana Selverian, Erica S Klaassen, Kevin J Petty, Cynthia Gargano, Kristien van Dyck, Jacqueline McCrea, Gail Murphy, Joop M A van Gerven

{"title":"Placebo- and amitriptyline-controlled evaluation of central nervous system effects of the NK1 receptor antagonist aprepitant and intravenous alcohol infusion at pseudo-steady state.","authors":"Erik T te Beek, Daniel Tatosian, Anup Majumdar, Diana Selverian, Erica S Klaassen, Kevin J Petty, Cynthia Gargano, Kristien van Dyck, Jacqueline McCrea, Gail Murphy, Joop M A van Gerven","doi":"10.1002/jcph.120","DOIUrl":"https://doi.org/10.1002/jcph.120","url":null,"abstract":"Recent interest in NK1 receptor antagonists has focused on a potential role in the treatment of drug addiction and substance abuse. In the present study, the potential for interactions between the NK1 receptor antagonist aprepitant and alcohol, given as an infusion at a target level of 0.65 g/L, was evaluated. Amitriptyline was included as positive control to provide an impression of the profile of central nervous system (CNS) effects. In a double-blind, randomized, placebo- and amitriptyline-controlled study, the pharmacokinetics and CNS effects of aprepitant and alcohol were investigated in 16 healthy volunteers. Cognitive and psychomotor function tests included the visual verbal learning test (VVLT), Bond and Lader visual analogue scales (VAS), digit symbol substitution test (DSST), visual pattern recognition, binary choice reaction time, critical flicker fusion (CFF), body sway, finger tapping, and adaptive tracking. Alcohol impaired finger tapping and body sway. Amitriptyline impaired DSST performance, VAS alertness, CFF, body sway, finger tapping, and adaptive tracking. No impairments were found after administration of aprepitant. Co-administration of aprepitant with alcohol was generally well tolerated and did not cause significant additive CNS effects, compared with alcohol alone. Therefore, our study found no indications for clinically relevant interactions between aprepitant and alcohol.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"846-56"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31607711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Comparison of Subcutaneous and Intravenous Administration of Trastuzumab: A Phase I/Ib Trial in Healthy Male Volunteers and Patients With HER2-Positive Breast Cancer. 曲妥珠单抗皮下注射与静脉注射的比较：健康男性志愿者和 HER2 阳性乳腺癌患者的 I/Ib 期试验。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-01-24 DOI: 10.1177/0091270011436560

Chris Wynne, Vernon Harvey, Christian Schwabe, Devonie Waaka, Christine McIntyre, Beate Bittner

{"title":"Comparison of Subcutaneous and Intravenous Administration of Trastuzumab: A Phase I/Ib Trial in Healthy Male Volunteers and Patients With HER2-Positive Breast Cancer.","authors":"Chris Wynne, Vernon Harvey, Christian Schwabe, Devonie Waaka, Christine McIntyre, Beate Bittner","doi":"10.1177/0091270011436560","DOIUrl":"10.1177/0091270011436560","url":null,"abstract":"Trastuzumab is a key component of treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in both the early and metastatic settings. It is administered intravenously, with between 17 and 52 infusions in standard regimens over 1 year. Intravenous administration of trastuzumab requires substantial time commitments for patients and health care professionals and can result in patient discomfort. A subcutaneous formulation of trastuzumab, containing recombinant human hyaluronidase to overcome subcutaneous absorption barriers, would reduce the administration duration and remove the need to establish intravenous access, thus improving the overall convenience of trastuzumab administration. This open-label, 2-part, phase I/Ib study (NCT00800436) was undertaken in healthy male volunteers and female patients with HER2-positive early breast cancer to identify the dose of subcutaneous trastuzumab that resulted in exposure comparable with the approved intravenous trastuzumab dose. A subcutaneous trastuzumab dose of 8 mg/kg was found to result in exposure comparable with the intravenous trastuzumab dose of 6 mg/kg. The subcutaneous formulation was well tolerated, with a trend toward fewer adverse events versus intravenous administration; most adverse events were mild in intensity. These results support an ongoing phase III efficacy and safety study comparing a fixed subcutaneous trastuzumab dose with intravenous trastuzumab administration.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2013-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31316109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exposure-Exposure Relationship of Tocilizumab, an Anti-IL-6 Receptor Monoclonal Antibody, in a Large Population of Patients With Rheumatoid Arthritis. 抗 IL-6 受体单克隆抗体 Tocilizumab 在大量类风湿性关节炎患者中的暴露-暴露关系。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-01-24 DOI: 10.1177/0091270011437585

Micha Levi, Susan Grange, Nicolas Frey

{"title":"Exposure-Exposure Relationship of Tocilizumab, an Anti-IL-6 Receptor Monoclonal Antibody, in a Large Population of Patients With Rheumatoid Arthritis.","authors":"Micha Levi, Susan Grange, Nicolas Frey","doi":"10.1177/0091270011437585","DOIUrl":"10.1177/0091270011437585","url":null,"abstract":"Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies. Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers. A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies. An indirect-response model with a sigmoid Emax (maximal drug effect) inhibitory drug effect on DAS28 \"production\" rate adequately described the relationship between tocilizumab concentration and DAS28. Mean minimum serum tocilizumab concentration at steady state was greater than the EC50 (concentration at which 50% of Emax on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose. Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg. Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant. Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships. These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2013-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31316611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differences between Japan and the United States in dosages of drugs recently approved in Japan. 日本和美国最近批准的药物剂量的差异。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2011-04-01 Epub Date: 2010-07-13 DOI: 10.1177/0091270010375958

Kae Nakashima, Mamoru Narukawa, Yoshiko Kanazu, Masahiro Takeuchi

{"title":"Differences between Japan and the United States in dosages of drugs recently approved in Japan.","authors":"Kae Nakashima, Mamoru Narukawa, Yoshiko Kanazu, Masahiro Takeuchi","doi":"10.1177/0091270010375958","DOIUrl":"https://doi.org/10.1177/0091270010375958","url":null,"abstract":"The internationalization of clinical and regulatory guidelines and disease treatment and the globalization of the pharmaceutical industry have led drug development strategies in Japan to shift from bridging studies to multinational trials. However, the current standard for adequate dose-finding processes may sometimes complicate the timely participation of Japan in these multinational trials. The objective of this study is to investigate different factors that might influence dosage selection in Japan. Approved drug dosages in Japan and the United States during the period 2003-2008 were compared and assessed across different therapeutic areas and approval timings. Factors such as company type and daily dosage indication were demonstrated to have a statistically significant relationship with different dosages in Japan and the United States. Anticancer, antiviral, and enzyme drugs showed similar dosages in the 2 regions, whereas neurological drugs were observed to undergo more careful dosage-finding processes, resulting in the approval of generally lower doses in Japan. A broader analysis is needed for detailed assessment. The findings in this study serve as an initial review to identify important factors that should be considered before planning global drug development.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"51 4","pages":"549-60"},"PeriodicalIF":2.9,"publicationDate":"2011-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270010375958","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29121163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Population pharmacokinetics and pharmacodynamics of brief etomidate infusion in healthy volunteers. 健康志愿者短暂输注依托咪酯的人群药代动力学和药效学。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2011-04-01 Epub Date: 2010-05-24 DOI: 10.1177/0091270010369242

Kotaro Kaneda, Susumu Yamashita, Sukyung Woo, Tae-Hyung Han

{"title":"Population pharmacokinetics and pharmacodynamics of brief etomidate infusion in healthy volunteers.","authors":"Kotaro Kaneda, Susumu Yamashita, Sukyung Woo, Tae-Hyung Han","doi":"10.1177/0091270010369242","DOIUrl":"https://doi.org/10.1177/0091270010369242","url":null,"abstract":"This study established the pharmacokinetic and pharmacodynamic relationships of the bispectral index (BIS) and Observer's Assessment of Alertness/Sedation (OAA/S) scale with effect site drug concentrations during and after brief etomidate infusion. Eighteen American Society of Anesthesiologists status I or II volunteers received etomidate (0.2%) infusion at 5 mg/min until the loss of eyelash reflexes, and spontaneous recovery was allowed. Data for plasma etomidate concentrations, BIS, and OAA/S were collected every minute and analyzed by NONMEM. A 2-compartment pharmacokinetic model and a pharmacodynamic sigmoid E(max) model fit the data best, with volumes of distribution at central and peripheral compartments of 4.45 and 74.90 L, respectively, and systemic and intercompartmental clearances of 0.63 and 3.16 L/min, respectively. t(1/2)k(e0) was 1.550 min. EC(50) values were 0.526 and 0.554 µg/mL, and gamma values were 2.25 and 6.24 for BIS and OAA/S, respectively. The prediction probability between OAA/S and BIS was 0.8. The slopes of the curves suggest that BIS is a better monitor of depth of sedation and hypnosis, whereas OAA/S may be more useful for monitoring sleep versus wakefulness. These results should be interpreted within the context of short-term etomidate infusion of less than 10 minutes.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"51 4","pages":"482-91"},"PeriodicalIF":2.9,"publicationDate":"2011-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270010369242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29011200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 23

Effects of commonly administered agents and genetics on nebivolol pharmacokinetics: drug-drug interaction studies. 常用药物和遗传对奈比洛尔药代动力学的影响:药物-药物相互作用研究。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2011-04-01 Epub Date: 2010-05-20 DOI: 10.1177/0091270010370846

Charles Lindamood, Stephan Ortiz, Andrew Shaw, Russ Rackley, J Christopher Gorski

{"title":"Effects of commonly administered agents and genetics on nebivolol pharmacokinetics: drug-drug interaction studies.","authors":"Charles Lindamood, Stephan Ortiz, Andrew Shaw, Russ Rackley, J Christopher Gorski","doi":"10.1177/0091270010370846","DOIUrl":"https://doi.org/10.1177/0091270010370846","url":null,"abstract":"Drug interactions are a significant clinical concern, particularly in patients with conditions such as heart disease and hypertension, in whom coadministration of multiple drugs is common. Nebivolol is a selective β(1)-blocker with vasodilatory properties approved for the treatment of hypertension. Drug-drug interactions were investigated when nebivolol was coadministered to subjects classified as poor CYP2D6 metabolizers and extensive CYP2D6 metabolizers who were receiving other drugs commonly administered to patients with hypertension or compounds metabolized by cytochrome P450 (CYP) 2D6. There were no drug-drug interactions when nebivolol was coadministered with hydrochlorothiazide, furosemide, ramipril, losartan, digoxin, or warfarin. Coadministration with fluoxetine (also metabolized by CYP2D6) in extensive CYP2D6 metabolizers impeded the apparent clearance of nebivolol. The authors conclude that nebivolol is safe and well tolerated regardless of genotype and type of medication coadministered.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"51 4","pages":"575-85"},"PeriodicalIF":2.9,"publicationDate":"2011-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270010370846","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29003737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 30

Pharmacokinetics, safety, and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers. 老年非吸烟者在不同滴定方案下多次口服伐尼克兰的药代动力学、安全性和耐受性。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2011-04-01 Epub Date: 2010-05-13 DOI: 10.1177/0091270010370461

Qinying Zhao, Elias Schwam, Terence Fullerton, Melissa O'Gorman, Aaron H Burstein

{"title":"Pharmacokinetics, safety, and tolerability following multiple oral doses of varenicline under various titration schedules in elderly nonsmokers.","authors":"Qinying Zhao, Elias Schwam, Terence Fullerton, Melissa O'Gorman, Aaron H Burstein","doi":"10.1177/0091270010370461","DOIUrl":"https://doi.org/10.1177/0091270010370461","url":null,"abstract":"This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerability of the selective α4β2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65-85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator- and subject-blinded parallel-group design. Treatment regimens included weekly titration (n = 14; days 1-7, 0.5 mg once daily; days 8-14, 0.5 mg twice daily; days 15-21, 1 mg twice daily); 2-week twice-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 0.5 mg twice daily); 2-week once-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 1 mg once daily); and placebo (n = 10). Approximate dose-proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration-time curve over the 24-hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half-life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"51 4","pages":"492-501"},"PeriodicalIF":2.9,"publicationDate":"2011-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270010370461","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28985909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 10

Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants. 替卡法林是一种新型的维生素K还原酶拮抗剂，在健康受试者同时服用氟康唑后，不受CYP2C9和CYP3A4抑制的影响。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2011-04-01 Epub Date: 2010-07-09 DOI: 10.1177/0091270010370588

Linda M Bavisotto, David J Ellis, Peter G Milner, Daniel L Combs, Ian Irwin, Daniel M Canafax

{"title":"Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants.","authors":"Linda M Bavisotto, David J Ellis, Peter G Milner, Daniel L Combs, Ian Irwin, Daniel M Canafax","doi":"10.1177/0091270010370588","DOIUrl":"https://doi.org/10.1177/0091270010370588","url":null,"abstract":"Comparative pharmacokinetics of vitamin K epoxide reductase antagonists tecarfarin and warfarin were assessed before and after coadministration for 21 days of the CYP450 inhibitor fluconazole in a randomized, open-label, single-center drug interaction study. Twenty healthy adult participants were randomized 1:1 to receive approximately equipotent single oral doses of tecarfarin (50 mg) or warfarin (17.5 mg). Following 7 days of baseline serial blood level collections, each participant received oral fluconazole 400 mg daily for 21 days. A second identical single oral dose of tecarfarin or warfarin was given 14 days after starting fluconazole with serial pharmacokinetic sampling. Key pharmacokinetic parameters C(max), t(max), AUC(0-168), apparent clearance, and t(1/2) demonstrated no tecarfarin-fluconazole interaction but a strong warfarin-fluconazole interaction. The ratio of log-transformed mean AUC(0-168) with versus without fluconazole for tecarfarin was 91.2% (90% confidence interval [CI]: 83.3-99.8) and for racemic warfarin was 213% (90% CI: 202-226). The 90% CI was entirely within the standard 80% to 125% bioequivalence interval for tecarfarin but well outside the bioequivalence interval for warfarin, confirming a clinically significant pharmacokinetic interaction between warfarin and fluconazole. In contrast, tecarfarin pharmacokinetics were apparently unchanged by fluconazole.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"51 4","pages":"561-74"},"PeriodicalIF":2.9,"publicationDate":"2011-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270010370588","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29115646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 26