Journal of Clinical Pharmacology最新文献_第8页

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia. 羟基脲液体制剂在儿童镰状细胞性贫血中的药代动力学和生物等效性。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2016-03-01 Epub Date: 2015-10-15 DOI: 10.1002/jcph.598

Jeremie H Estepp, Chiara Melloni, Courtney D Thornburg, Paweł Wiczling, Zora Rogers, Jennifer A Rothman, Nancy S Green, Robert Liem, Amanda M Brandow, Shelley E Crary, Thomas H Howard, Maurine H Morris, Andrew Lewandowski, Uttam Garg, William J Jusko, Kathleen A Neville

{"title":"Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia.","authors":"Jeremie H Estepp, Chiara Melloni, Courtney D Thornburg, Paweł Wiczling, Zora Rogers, Jennifer A Rothman, Nancy S Green, Robert Liem, Amanda M Brandow, Shelley E Crary, Thomas H Howard, Maurine H Morris, Andrew Lewandowski, Uttam Garg, William J Jusko, Kathleen A Neville","doi":"10.1002/jcph.598","DOIUrl":"https://doi.org/10.1002/jcph.598","url":null,"abstract":"Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"298-306"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.598","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33860721","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: 18

Genetic variation of CYP3A5 influences paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. CYP3A5基因变异影响中国上皮性卵巢癌患者紫杉醇/卡铂诱导的毒性

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2016-03-01 Epub Date: 2015-10-26 DOI: 10.1002/jcph.587

Lei Hu, Qiao-Li Lv, Ying Guo, Lin Cheng, Na-Yiyuan Wu, Chong-Zhen Qin, Hong-Hao Zhou

{"title":"Genetic variation of CYP3A5 influences paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients.","authors":"Lei Hu, Qiao-Li Lv, Ying Guo, Lin Cheng, Na-Yiyuan Wu, Chong-Zhen Qin, Hong-Hao Zhou","doi":"10.1002/jcph.587","DOIUrl":"https://doi.org/10.1002/jcph.587","url":null,"abstract":"Combination chemotherapy with platinum and taxane is the first-line treatment for ovarian cancer. The dose-limiting toxicities of these drugs include neuropathy, leukopenia, and neutropenia, but they exhibit substantial interindividual variability. This study investigated the relationship between CYP3A5 polymorphisms and paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Seventy-five patients with epithelial ovarian cancer were recruited. After combination chemotherapy, genotype analysis was conducted, and toxic effects were evaluated according to the Common Toxicity Criteria. A significant association was found between myelosuppression and the CYP3A5*3 genotype. CYP3A5*3/*1 patients showed a significantly higher risk of developing leukopenia (P < .001; Pearson's χ(2) test) and neutropenia (P < .001; Pearson's χ(2) test) than CYP3A5*3*3 patients. CYP3A5*3/*3 patients had significantly higher median leukocyte and neutrophil nadir counts than CYP3A5*3*1 patients (P < .001, Mann-Whitney U test). However, we did not observe an association between neuropathy and CYP3A5*3 in this study (P =.64; Pearson's χ(2) test). This is the first study to verify the influence of CYP3A5 polymorphisms on paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Our findings suggest that interindividual variability in paclitaxel/carboplatin-induced myelosuppression can be predicted by CYP3A5*3 genotyping and that incorporation of CYP3A5*3 genetic data in treatment selection could help to reduce myelosuppression events, thereby individualizing paclitaxel/carboplatin pharmacotherapy. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"349-54"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34011070","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: 18

Pharmacokinetics of high-dose intravenous melatonin in humans. 人静脉注射大剂量褪黑素的药代动力学。

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.592

Lars P H Andersen, Mads U Werner, Mette M Rosenkilde, Andreas Q Fenger, Marian C Petersen, Jacob Rosenberg, Ismail Gögenur

{"title":"Pharmacokinetics of high-dose intravenous melatonin in humans.","authors":"Lars P H Andersen, Mads U Werner, Mette M Rosenkilde, Andreas Q Fenger, Marian C Petersen, Jacob Rosenberg, Ismail Gögenur","doi":"10.1002/jcph.592","DOIUrl":"https://doi.org/10.1002/jcph.592","url":null,"abstract":"This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221,500.0 (185,637.5-326,175.0) pg/mL and 1,251,500.0 (864,375.0-1,770,500.0) pg/mL, respectively; mean (SD) t1/2 was 42.3 (5.6) minutes and 46.2 (6.2) minutes; mean (SD) Vd was 1.6 (0.9) L/kg and 2.0 (0.8) L/kg; mean (SD) CL was 0.0253 (0.0096) L/min · kg and 0.0300 (0.0120) L/min · kg; and median (IQR) AUC0- ∞ , 8,997,633.0 (6,071,696.2-11,602,811.9) pg · min/mL and 54,685,979.4 (36,028,638.6-105,779,612.0) pg · min/mL. High-dose intravenous melatonin did not induce sedation, evaluated as simple reaction times. No adverse effects were reported in the study. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"324-9"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.592","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34015239","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: 52

Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures. 布美他尼对足月新生儿癫痫发作人群药代动力学的初步评价。

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.596

Vincent Jullien, Ronit M Pressler, Geraldine Boylan, Mats Blennow, Neil Marlow, Catherine Chiron, Gerard Pons

{"title":"Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures.","authors":"Vincent Jullien, Ronit M Pressler, Geraldine Boylan, Mats Blennow, Neil Marlow, Catherine Chiron, Gerard Pons","doi":"10.1002/jcph.596","DOIUrl":"https://doi.org/10.1002/jcph.596","url":null,"abstract":"Recent experimental data suggest bumetanide as a possible therapeutic option in newborn infants with seizures after birth asphyxia. Because pharmacokinetic (PK) data are lacking in this population, who very often benefit from therapeutic cooling, which can modify the PK behavior of a drug, a PK study was conducted in term infants with seizures caused by hypoxic-ischemic encephalopathy. Fourteen infants were included, 13 of them being cooled. Forty-nine blood samples were available for the determination of the plasma concentration of bumetanide. Concentration-time data were analyzed by the use of a population approach performed with Monolix Software. Bumetanide was found to follow a 2-compartment model. The mean values were 0.063 L/h for clearance, 0.28 and 0.44 L for the central and peripheral distribution volumes, respectively, and 0.59 L/h for the distribution clearance. Birth body weight explained the interindividual variability of bumetanide clearance via an allometric model. No relationship was found between bumetanide exposure and its efficacy (reduction in seizure burden) or its toxicity (hearing loss). This study describes the first PK model of bumetanide in hypothermia-treated infants with seizures. ","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"284-90"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.596","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34019788","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: 12

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