Journal of Clinical Pharmacology最新文献_第9页

A phase-1, open-label, single-dose study of the pharmacokinetics of buparlisib in subjects with mild to severe hepatic impairment. 布帕利西布在轻度至重度肝功能损害患者中的1期、开放标签、单剂量药代动力学研究。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2016-03-01 Epub Date: 2015-09-14 DOI: 10.1002/jcph.590

Denes Csonka, Katharine Hazell, Edward Waldron, Sebastien Lorenzo, Vincent Duval, Lucia Trandafir, Zhanna D Kobalava

{"title":"A phase-1, open-label, single-dose study of the pharmacokinetics of buparlisib in subjects with mild to severe hepatic impairment.","authors":"Denes Csonka, Katharine Hazell, Edward Waldron, Sebastien Lorenzo, Vincent Duval, Lucia Trandafir, Zhanna D Kobalava","doi":"10.1002/jcph.590","DOIUrl":"https://doi.org/10.1002/jcph.590","url":null,"abstract":"The pharmacokinetics (PK) and safety of single-dose buparlisib (30 mg) were assessed in subjects with mild to severe hepatic impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC∞ ] and Cmax ) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median Tmax 1.0-1.3 h). Buparlisib exposure (AUC∞ ) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%CI 0.81, 1.65), moderate (GMR 1.14; 90%CI 0.80, 1.63), or severe (GMR 1.20; 90%CI 0.84, 1.72) hepatic impairment, relative to healthy controls. Apparent oral clearance was similar across groups. Due to a higher unbound fraction in the severe group (0.21) than all other groups (0.17), subjects with severe hepatic impairment had greater exposure to unbound buparlisib (GMR relative to healthy controls: AUC∞ 1.52; 90%CI 1.09, 2.13; Cmax 1.83; 90%CI 1.42, 2.36). The results indicate that a buparlisib dose adjustment may not be necessary for patients with mild to moderate hepatic impairment. The safety and therapeutic indices should be considered before determining if a dose adjustment is appropriate for patients with severe hepatic impairment. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"316-23"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.590","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33912471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. 内皮素受体拮抗剂马西坦的安全性、耐受性、药代动力学和药效学:健康受试者递增多剂量研究

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-09-04 DOI: 10.1002/jcph.152

Patricia N Sidharta, Paul L M van Giersbergen, Jasper Dingemanse

{"title":"Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects.","authors":"Patricia N Sidharta, Paul L M van Giersbergen, Jasper Dingemanse","doi":"10.1002/jcph.152","DOIUrl":"https://doi.org/10.1002/jcph.152","url":null,"abstract":"This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor antagonist (ERA) with sustained receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1131-8"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.152","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31620436","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: 77

Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or community-acquired bacterial pneumonia. 头孢他啶在急性细菌性皮肤和皮肤结构感染或社区获得性细菌性肺炎患者中的群体药代动力学。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-08-14 DOI: 10.1002/jcph.153

Scott A Van Wart, Alan Forrest, Tatiana Khariton, Christopher M Rubino, Sujata M Bhavnani, Daniel K Reynolds, Todd Riccobene, Paul G Ambrose

{"title":"Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or community-acquired bacterial pneumonia.","authors":"Scott A Van Wart, Alan Forrest, Tatiana Khariton, Christopher M Rubino, Sujata M Bhavnani, Daniel K Reynolds, Todd Riccobene, Paul G Ambrose","doi":"10.1002/jcph.153","DOIUrl":"10.1002/jcph.153","url":null,"abstract":"Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin antibiotic. A population pharmacokinetic (PPK) model for ceftaroline was developed in NONMEM® using data from 185 healthy subjects and 92 patients with acute bacterial skin and skin structure infection (ABSSSI). Data from 128 patients with community-acquired bacterial pneumonia (CABP) were used for external model validation. Healthy subjects received 50-2,000 mg ceftaroline fosamil via intravenous (IV) infusion over 1 hour or intramuscular (IM) injection q12h or q24h. ABSSSI and CABP patients received 600 mg of ceftaroline fosamil IV over 1 hour q12h. A three-compartment model with zero-order IV or parallel first-order IM input and first-order elimination described ceftaroline fosamil PK. A two-compartment model with first-order conversion of prodrug to ceftaroline and parallel linear and saturable elimination described ceftaroline PK. Creatinine clearance was the primary determinant of ceftaroline exposure. Good agreement between the observed data and both population (r(2) = 0.93) and individual post-hoc (r(2) = 0.98) predictions suggests the PPK model can adequately approximate ceftaroline PK using covariate information. Such a PPK model can evaluate dose adjustments for patients with renal impairment and generate ceftaroline exposures for use in pharmacokinetic-pharmacodynamic assessments of efficacy in patients with ABSSSI or CABP. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1155-67"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.153","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31625721","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: 29

Doxylamine pharmacokinetics following single dose oral administration in children ages 2-17 years. 2-17岁儿童单次口服多西胺的药代动力学。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-07-18 DOI: 10.1002/jcph.137

Guhan Balan, Gary A Thompson, Roger Gibb, Lijuan Li, David Hull, Molly Seeck

{"title":"Doxylamine pharmacokinetics following single dose oral administration in children ages 2-17 years.","authors":"Guhan Balan, Gary A Thompson, Roger Gibb, Lijuan Li, David Hull, Molly Seeck","doi":"10.1002/jcph.137","DOIUrl":"https://doi.org/10.1002/jcph.137","url":null,"abstract":"To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1177-85"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31235886","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: 8

Impact of donor and recipient CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus dosage requirements and rejection in Caucasian Spanish liver transplant patients. 供体和受体CYP3A5和ABCB1基因多态性对西班牙白种肝移植患者他克莫司剂量需求和排斥反应的影响

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-09-11 DOI: 10.1002/jcph.154

Miguel Angel Gómez-Bravo, Magdalena Salcedo, Constantino Fondevila, Francisco Suarez, José Castellote, Sebastián Rufian, José Antonio Pons, José María Alamo, Olga Millán, Mercè Brunet

{"title":"Impact of donor and recipient CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus dosage requirements and rejection in Caucasian Spanish liver transplant patients.","authors":"Miguel Angel Gómez-Bravo, Magdalena Salcedo, Constantino Fondevila, Francisco Suarez, José Castellote, Sebastián Rufian, José Antonio Pons, José María Alamo, Olga Millán, Mercè Brunet","doi":"10.1002/jcph.154","DOIUrl":"https://doi.org/10.1002/jcph.154","url":null,"abstract":"Studies of liver transplant (LT) patients, mainly in Asians, have evaluated the influence of the CYP3A5*1 allele and P-glycoprotein gene ABCB1 on tacrolimus pharmacokinetics or biopsy-proven acute rejection (BPAR) incidence, with no conclusive results. To investigate these issues, 98 Caucasian Spanish LT patients with tacrolimus, mycophenolate mofetil and steroids and 88 cadaveric donors were genotyped for the SNPs CYP3A5 6986G>A, ABCB1 1236C>T, ABCB1 2677G>A/T and ABCB1 3435C>T;. On day 7 post-LT, patients with a native CYP3A5*1 allele had significantly lower tacrolimus trough concentrations C0 (P = .03) and dose-adjusted concentrations C0 /D (P = .02) than CYP3A5 *3/*3 homozygotes. Three months post-LT, patients carrying a liver with CYP3A5*1 had significantly lower C0 /D (P = .03) and took significantly higher tacrolimus doses (P = .03) than the corresponding *3/*3 homozygotes. ABCB1 SNPs showed no significant association with tacrolimus variables. The 3-month incidence of BPAR was 10.2%, with no statistically significant differences related to CYP3A5 (14.3% in expresser vs. 9.5% in non-expresser) or ABCB1 genotype of either patient or donor. We conclude that in Caucasian Spanish LT patients, a native or graft-borne CYP3A5*1 allele tends to lower tacrolimus concentrations and increase dosage needs, but has no significant impact on the incidence of BPAR. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1146-54"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31261016","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: 27

Pharmacokinetics and pharmacodynamics of vincristine sulfate liposome injection (VSLI) in adults with acute lymphoblastic leukemia. 硫酸长春新碱脂质体注射液(VSLI)在成人急性淋巴细胞白血病中的药代动力学和药效学。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-08-17 DOI: 10.1002/jcph.155

Jeffrey A Silverman, Laurie Reynolds, Steven R Deitcher

{"title":"Pharmacokinetics and pharmacodynamics of vincristine sulfate liposome injection (VSLI) in adults with acute lymphoblastic leukemia.","authors":"Jeffrey A Silverman, Laurie Reynolds, Steven R Deitcher","doi":"10.1002/jcph.155","DOIUrl":"https://doi.org/10.1002/jcph.155","url":null,"abstract":"Vincristine sulfate liposome injection (VSLI,) is a sphingomyelin and cholesterol nanoparticle formulation of vincristine sulfate (VCR) that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. In contrast to the rapid CL and wide tissue distribution of non-liposomal VCR, VSLI circulates in plasma for a prolonged period of time, with a slow CL of 345 mL/h and relatively small Vd of 3,570 mL. This facilitates enhanced and prolonged tumor-tissue delivery of VCR. The maximum tolerated dose of VSLI, 2.25 mg/m(2) once per week without a dose cap, enables individual and cumulative VCR exposure unachievable with non-liposomal VCR at its labeled dose of 1.4 mg/m(2) . VSLI is associated with a dose-dependent peripheral neurotoxicity albeit at doses that are two to three times that of standard VCR. VCR dose intensification with VSLI correlated with an increased probability of overall response and a strong trend towards increased complete response in adults with relapsed and/or refractory acute lymphoblastic leukemia. Overall, VSLI improves the therapeutic index by facilitating increased dose intensification while maintaining a predictable and manageable safety profile. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1139-45"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31626029","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: 35

Co-medication of pravastatin and paroxetine-a categorical study. 普伐他汀与帕罗西汀联合用药的分类研究。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-08-13 DOI: 10.1002/jcph.151

Li An, Priyadarshini P Ravindran, Swetha Renukunta, Srinivas Denduluri

{"title":"Co-medication of pravastatin and paroxetine-a categorical study.","authors":"Li An, Priyadarshini P Ravindran, Swetha Renukunta, Srinivas Denduluri","doi":"10.1002/jcph.151","DOIUrl":"https://doi.org/10.1002/jcph.151","url":null,"abstract":"Electronic Medical Records (EMRs) are wealthy storehouses of patient information, to which data mining techniques can be prudently applied to reveal clinically significant patterns. Detecting patterns in drug-drug interactions, leading to adverse drug reactions is a powerful application of EMR data mining. Adverse effects of drug treatments can be investigated by mining clinical laboratory tests data which are reliable indicators of abnormal physiological functions. We report here the co-medication effects of pravastatin (HMG-CoA reductase inhibitor) and paroxetine (selective serotonin reuptake inhibitor (SSRI) anti-depressant) on significant clinical parameters, identified through a data mining analysis conducted on the Allscripts data warehouse. We found that the concomitant drug treatments of pravastatin and paroxetine increased the mean values of glucose serum from 113.2 to 132.1 mg/dL and international normalized ratio (INR) from 2.18 to 2.52, respectively. It also decreased the mean values of estimated glomerular filtration rate (eGFR) from 43 to 37 mL/min/1.73 m(3) and blood CO2 levels from 24.8 to 23.9 mEq/L respectively. Our findings indicate that co-medication of pravastatin and paroxetine might have significant impact on blood anti-coagulation, kidney function, and glucose homeostasis. Our methodology can be applied to any EMR data set to reveal co-medication effects of any drug pairs. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1212-9"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31626443","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: 11

Founding an adverse drug reaction (ADR) network: a method for improving doctors spontaneous ADR reporting in a general hospital. 建立药品不良反应(ADR)网络:提高综合医院医生自发上报ADR的方法。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-08-19 DOI: 10.1002/jcph.149

Lee Hilary Goldstein, Maya Berlin, Walid Saliba, Mazen Elias, Matitiyahu Berkovitch

{"title":"Founding an adverse drug reaction (ADR) network: a method for improving doctors spontaneous ADR reporting in a general hospital.","authors":"Lee Hilary Goldstein, Maya Berlin, Walid Saliba, Mazen Elias, Matitiyahu Berkovitch","doi":"10.1002/jcph.149","DOIUrl":"https://doi.org/10.1002/jcph.149","url":null,"abstract":"Adverse drug reactions (ADR) are underreported by doctors despite numerous efforts. We aimed to determine if establishing an \"ADR reporting doctor's network\" within a hospital would increase the quantity of ADRs reported by hospital doctors. One hundred hospital doctors joined the network. Email reminders were sent to network members during the 1 year study period, conveying information about ADRs reported, amusingly and pleasantly reminding them to report ADRs in minimal detail, by phone, email, text message or mail to the Clinical Pharmacology Unit, who would further complete the report. A total of 114 ADRs were reported during the study period in comparison to 48, 26, and 17 in the previous 3 years (2008, 2009, 2010, respectively). In the 3 years prior, doctors reported 41.7% of the reported ADRs whereas in the study period, doctors reported 74.3% of ADRs (P < .001), reflecting an 80% increase in doctors reports. Ninety seven percent of doctors' reports were of ADR network members. Thirty-four (34%) network members reported an ADR during the study period and 31 of the 34 reporters had never reported ADRs before becoming network members. Establishing an ADR network of doctors substantially increases ADR reporting amongst its members. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1220-5"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31579593","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: 25

Integration of biostatistics and pharmacometrics computing platforms for efficient and reproducible PK/PD analysis: a case study. 整合生物统计学和药物计量学计算平台，用于高效和可重复的PK/PD分析:一个案例研究。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-08-29 DOI: 10.1002/jcph.157

Ying C Ou, Arthur Lo, Brian Lee, Phillip Liu, Karen Kimura, Charisse Eary, Alan Hopkins

{"title":"Integration of biostatistics and pharmacometrics computing platforms for efficient and reproducible PK/PD analysis: a case study.","authors":"Ying C Ou, Arthur Lo, Brian Lee, Phillip Liu, Karen Kimura, Charisse Eary, Alan Hopkins","doi":"10.1002/jcph.157","DOIUrl":"https://doi.org/10.1002/jcph.157","url":null,"abstract":"Results of pharmacometric analyses influence high-level decisions such as clinical trial design, drug approval, and labeling. Key challenges for timely delivery of pharmacometric analyses are the data assembly process and tracking and documenting the modeling process and results. Since clinical efficacy and safety data typically reside in the biostatistics computing area, an integrated computing platform for pharmacometric and biostatistical analyses would be ideal. A case study is presented integrating a pharmacometric modeling platform into an existing statistical computing environment (SCE). The feasibility and specific configurations of running common PK/PD programs such as NONMEM and R inside of the SCE are provided. The case study provides an example of an integrated repository that facilitates efficient data assembly for pharmacometrics analyses. The proposed platform encourages a good pharmacometrics working practice to maintain transparency, traceability, and reproducibility of PK/PD models and associated data in supporting drug development and regulatory decisions. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1112-20"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31630583","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

Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor. 肽去甲酰基酶抑制剂GSK1322322口服和静脉给药的安全性、耐受性和药代动力学

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2013-11-01 Epub Date: 2013-08-13 DOI: 10.1002/jcph.150

Odin J Naderer, Lori S Jones, John Zhu, Milena Kurtinecz, Etienne Dumont

{"title":"Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor.","authors":"Odin J Naderer, Lori S Jones, John Zhu, Milena Kurtinecz, Etienne Dumont","doi":"10.1002/jcph.150","DOIUrl":"https://doi.org/10.1002/jcph.150","url":null,"abstract":"GSK1322322 is the first in a new class of antibiotics that targets peptide deformylase (PDF), an essential bacterial enzyme required for protein maturation. This randomized, double-blind, placebo-controlled, eight-cohort phase I trial enrolled 62 healthy volunteers to assess safety, tolerability, and pharmacokinetic profiles of GSK1322322. GSK1322322 was administered as a single oral or intravenous (IV) dose, escalating from 500 to 3,000 mg or repeat IV doses escalating from 500 to 1,500 mg twice daily. Upon repeat IV administration, GSK1322322 exhibits linear pharmacokinetics over time upon repeat doses as shown by time-invariant pharmacokinetics. A dose-proportional increase in area under concentration-time curve was observed after single or repeat IV dosing, whereas clearance at steady state remained generally unchanged across doses. There was minimal accumulation of GSK1322322 after repeat IV twice-daily administration. After oral tablet doses of GSK1322322 1,000 and 1,500 mg, absolute bioavailability was 69% and 56%, respectively. GSK1322322 administration at single and repeat IV doses and at supratherapeutic single IV doses of 2,000 and 3,000 mg was associated with mild-to-moderate drug-related adverse events. On the basis of the pharmacokinetics and tolerability demonstrated in this study, GSK1322322 has the potential to become the first-in-class PDF inhibitor for clinical use. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1168-76"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31625712","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: 15