Abstract:
PURPOSE:Selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective mitogen-activated protein kinase 1/2 inhibitor with a short half-life, has shown activity across various tumor types. Before initiation of Phase III trials, the site, scale, and color (hypromellose shell from white [Phase II] to blue [Phase III]) of the selumetinib 25mg capsule manufacture was changed. We present 2 crossover trials evaluating Phase III capsules in healthy subjects. METHODS:The relative bioavailability trial was a Phase I, open-label, randomized, 3-treatment, 4-period, 6-sequence crossover trial in healthy male subjects (aged 18-55 years). Subjects received selumetinib 75mg (3 × 25 mg) Phase II or Phase III capsules, or a 35mg oral solution, during 4 dosing periods in 1 of 6 randomized treatment sequences. The food effect trial was a Phase I, open-label, randomized, 2-period crossover trial in healthy male subjects (aged 18-45 years). Subjects were randomized to 1 of 2 sequences to receive selumetinib 75mg (3 × 25 mg) Phase III capsules. In sequence 1, subjects received selumetinib after 10 hours of fasting. Following a washout period, selumetinib was administered after a high-fat meal. In sequence 2, subjects received selumetinib in the fed state, before the fasted state. Pharmacokinetic parameters were determined from serial blood sampling. FINDINGS:Twenty-seven subjects were randomized to the relative bioavailability trial; 26 completed all dosing periods. Mean selumetinib AUC was unchanged (geometric least squares mean ratio [GLSMR], 90.01% [90% CI, 81.74-99.11]). Cmax was 18% lower with the Phase III capsules (GLSMR, 81.97% [90% CI, 69.01-97.36]). A post hoc exploratory statistical analysis excluding outlying observations with later Tmax showed that Phase II and III capsules produced similar exposure in terms of Cmax and AUC. High intrasubject variability for Cmax attributed to the pharmacokinetic sampling schedule was judged to have impacted on the estimated GLSMR. In the food effect trial, 34 subjects completed both study periods. A high-fat meal reduced selumetinib Cmax compared with the fasted state (GLSMR, 49.76% [90% CI, 43.82-56.51]); AUC was minimally changed (GLSMR, 84.08% [90% CI, 80.72-87.59]). Median Tmax was prolonged by 1.49 hours. No deaths or serious adverse events were reported. IMPLICATIONS:Selumetinib 75mg (3 × 25 mg) Phase III capsules are being used in ongoing pivotal Phase III trials and should be administered in the fasted state. Based on findings from the relative bioavailability trial, pharmacokinetic sampling frequency was increased for healthy subject trials, including the food effect trial. ClinicalTrials.gov identifiers: NCT01635023 (relative bioavailability) and NCT01974349 (food effect).
journal_name
Clin Therjournal_title
Clinical therapeuticsauthors
Tomkinson H,McBride E,Martin P,Lisbon E,Dymond AW,Cantarini M,So K,Holt Ddoi
10.1016/j.clinthera.2017.08.022subject
Has Abstractpub_date
2017-11-01 00:00:00pages
2260-2275.e1issue
11eissn
0149-2918issn
1879-114Xpii
S0149-2918(17)30943-8journal_volume
39pub_type
杂志文章,随机对照试验abstract:PURPOSE:The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data f...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2020.10.007
更新日期:2020-12-01 00:00:00
abstract:OBJECTIVE:The aim of this study was to compare the efficacy and safety of nebulized arformoterol 15 microg/2 mL twice daily (ARF15 BID) and 30 microg/4 mL once daily (ARF30 QD) in subjects with moderate to severe chronic obstructive pulmonary disease (COPD). METHODS:In this single-dose, multicenter, randomized, modifi...
journal_title:Clinical therapeutics
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/j.clinthera.2009.08.012
更新日期:2009-08-01 00:00:00
abstract:BACKGROUND:Numerous studies have explored dietary-management strategies for decreasing leukotriene synthesis by inflammatory cells through supplementation with polyunsaturated fatty acids such as gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA). OBJECTIVES:This study sought to determine the optimal daily int...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0149-2918(03)80116-9
更新日期:2003-03-01 00:00:00
abstract:PURPOSE:The goal of this study is to identify and compare all direct costs of intravenous and subcutaneous rituximab given to patients with diffuse large B-cell lymphoma in the Netherlands. METHODS:Using a prospective, observational, bottom-up microcosting study, we collected primary data on the direct medical costs o...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2017.05.342
更新日期:2017-06-01 00:00:00
abstract:PURPOSE:In patients with type 2 diabetes mellitus (T2DM) not achieving glycemic targets using oral antidiabetes drugs (OADs), studies suggest that timely insulin initiation has clinical benefits. Insulin initiation at the early versus late stage of disease progression has not been explored in detail. This retrospective...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2015.11.011
更新日期:2016-01-01 00:00:00
abstract:BACKGROUND:Clinical trials have shown that treatment with disease-modifying therapies (DMTs), such as interferon, at the time of clinically isolated syndrome can delay the onset of multiple sclerosis (MS). OBJECTIVES:The objective of this study was to assess health care utilization and expenditures associated with tre...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2011.05.049
更新日期:2011-07-01 00:00:00
abstract:BACKGROUND:Communicating potential benefits and harm to patients and payers is essential for high-quality care. However, there are no published guidelines or consensuses on how to communicate potential benefits and harm to patients and payers. OBJECTIVE:The goal of this review was to identify key elements for communic...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2011.11.013
更新日期:2011-12-01 00:00:00
abstract:PURPOSE:Our study evaluated adverse events of therapeutic failure (and specifically reduced duration of action) with the use of a branded product, Osmotic Release Oral System (OROS) methylphenidate, which is approved for the treatment of attention deficit/hyperactivity disorder, and a generic product (methylphenidate, ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2017.08.018
更新日期:2017-10-01 00:00:00
abstract:PURPOSE:We undertook a preliminary assessment of the efficacy of administering intravenous dexamethasone (DEX) for relieving the nausea and dizziness accompanying vestibular neuritis (VN). METHODS:Between November 2013 and October 2014, 26 patients with VN were prospectively enrolled in this study. The patients were r...
journal_title:Clinical therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.clinthera.2015.09.010
更新日期:2015-11-01 00:00:00
abstract:PURPOSE:The recommended first-line treatment for young children infected with HIV includes the liquid formulation of the co-formulated protease inhibitors lopinavir/ritonavir (Kaletra® [Abbott Laboratories, Chicago, Illinois]). Clinical reports indicate that some children readily accept the taste of Kaletra, whereas ot...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2017.08.012
更新日期:2017-10-01 00:00:00
abstract::In trying to identify the therapeutic impact of a drug, clinical trials eliminate potentially confounding factors such as comorbidities, poor compliance and treatment errors in diagnosis, dosing, and drug interactions. Elimination of these variables means that attempts to use clinical data as the basis for predicting ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/0149-2918(95)80098-0
更新日期:1995-11-01 00:00:00
abstract:BACKGROUND:Asthma is a common chronic disorder of childhood, and it is frequently accompanied by dental and other oral abnormalities. As such, oral and dental effects of asthma medications have been investigated in several studies. However, the effect of combination therapy with a long-acting beta(2)-agonist and a cort...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章
doi:10.1016/j.clinthera.2007.10.014
更新日期:2007-10-01 00:00:00
abstract::Encapsulation affects the virulence and survival of anaerobic bacteria and their protection from phagocytosis. More encapsulated Bacteroides strains and anaerobic and facultative gram-positive cocci are isolated from patients with clinical infections than from healthy people. The pathogenicity of Bacteroides, Fusobact...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:
更新日期:1987-01-01 00:00:00
abstract::The US population is multiethnic in composition: many languages thrive, and Spanish is the second most frequently spoken language. The Hispanic population is one of the fastest growing ethnic groups in the United States. The majority of Hispanics speak Spanish at home (63%), and a significant proportion speak little o...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/0149-2918(95)80054-9
更新日期:1995-07-01 00:00:00
abstract:OBJECTIVE:The aim of this study was to assess obese patients with hypercholesterolemia whom were prescribed a standardized diet, comparing the action of orlistat, fluvastatin, orlistat with fluvastatin, and placebo on anthropometric measurements, blood pressure (BP), and lipid profile. METHODS:This was a 1-year, rando...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0149-2918(03)80070-x
更新日期:2003-04-01 00:00:00
abstract:PURPOSE:Opioid diversion, misuse, and abuse are rapidly growing problems in the United States; >60% of all drug overdose deaths involve an opioid. At least 49 states now have fully operational prescription drug monitoring programs (PDMPs) to support legitimate medical use of controlled substances; however, there is con...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2017.07.040
更新日期:2017-09-01 00:00:00
abstract:PURPOSE:The genetic polymorphism was one of the major considerations for adjusting doses of warfarin in Thai individuals. As a result, new oral anticoagulants (NOACs) were introduced to achieve therapeutic goals in stroke prevention in atrial fibrillation (SPAF) patients. However, a cost-utility analysis in a populatio...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2014.08.016
更新日期:2014-10-01 00:00:00
abstract::A total of 804 pediatric patients (572 neonates and 232 infants and children) with suspected or documented serious infections were enrolled in a multicenter open study of netilmicin, a new semisynthetic aminoglycoside. All patients were evaluable for safety; 161 (20%) had bacteriologically documented infections and we...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章
doi:
更新日期:1983-01-01 00:00:00
abstract::Patients with Parkinson's disease experience disabling non-motor symptoms, including autonomic dysfunction, cognitive decline, and sleep disorders. Pharmacologic treatments for these symptoms are often ineffective or have intolerable side effects. Therefore, non-pharmacologic interventions are an attractive alternativ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2017.11.004
更新日期:2018-01-01 00:00:00
abstract::The total cost of administering calcium polycarbophil per unit dose (two tablets) was compared with that of administering psyllium mucilloid (one packet dissolved in 8 oz of water) in 20 elderly nursing-home residents. Times for printing labels, checking and initialing labels, gathering materials needed, and preparing...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1990-01-01 00:00:00
abstract:BACKGROUND:Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by mutations in the survival motor neuron gene (SMN1) and the leading genetic cause of infant mortality. Currently, there is no effective treatment other than supportive care. OBJECTIVE:This article provides a general overvi...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2013.11.006
更新日期:2014-01-01 00:00:00
abstract:PURPOSE:The objective of this study was to characterize the population pharmacokinetics of voriconazole and to identify factors that significantly affect pharmacokinetic parameters and to further investigate optimal dosage regimens in Chinese adult patients with hematologic malignancies. METHODS:A prospective populati...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2019.04.027
更新日期:2019-06-01 00:00:00
abstract:BACKGROUND:Patients undergoing general anesthesia for laparoscopic cholecystectomy are at high risk for postoperative emetic symptoms (nausea, vomiting, and retching). Antihistamines, butyrophenones, dopamine receptor antagonists, and selective serotonin receptor antagonists (SSRAs) have been investigated for the preve...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,随机对照试验,收录出版
doi:10.1016/s0149-2918(04)90177-4
更新日期:2004-07-01 00:00:00
abstract:BACKGROUND:Moxifloxacin is a fluoroquinolone antimicrobial agent with proven efficacy against community-acquired respiratory pathogens. Common adverse effects associated with its use include gastro-intestinal symptoms, but nephrotoxicity has not yet been reported to the manufacturer or in the literature (based on a MED...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2005.08.008
更新日期:2005-08-01 00:00:00
abstract:BACKGROUND:Vitamin B12 (cobalamin) deficiency may be caused by inadequate dietary intake of B12 or by conditions that result in malabsorption of the vitamin. Crystalline vitamin B12, usually in the form of cyanocobalamin, is administered parenterally (ie, intramuscularly) or orally for treating deficiency states. Intra...
journal_title:Clinical therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.clinthera.2011.05.088
更新日期:2011-07-01 00:00:00
abstract:BACKGROUND:Rufinamide is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged ≥4 years. OBJECTIVES:The primary purpose of this study was to compare the relative bioavailability and other pharmacokinetics of rufinamide administered as a 400-mg tablet formulation (r...
journal_title:Clinical therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.clinthera.2011.01.016
更新日期:2011-01-01 00:00:00
abstract::Quinfamide, a luminal amebicide, is a dichloroacetyl quinolol used to treat chronic and subacute intestinal amebiasis. Several previous dose-ranging studies have indicated that quinfamide is effective in a total dose of 300, 600, or 1,200 mg. The present study was undertaken to determine the efficacy of 100- and 200-m...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1983-01-01 00:00:00
abstract:PURPOSE:Coadministration of morphine with oral gabapentin has been shown to increase plasma gabapentin concentrations. This study evaluated whether there was any interaction between gabapentin enacarbil (GEn), which is a prodrug of gabapentin, and morphine in terms of pharmacokinetics, pharmacodynamics, safety, and tol...
journal_title:Clinical therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.clinthera.2014.10.015
更新日期:2015-02-01 00:00:00
abstract:BACKGROUND:Many active pharmaceutical ingredients taste bitter and thus are aversive to children as well as many adults. Encapsulation of the medicine in pill or tablet form, an effective method for adults to avoid the unpleasant taste, is problematic for children. Many children cannot or will not swallow solid dose fo...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2013.06.007
更新日期:2013-08-01 00:00:00
abstract::The medical records for 174 patients who underwent cholecystectomy (n = 52) or hip/knee replacement (n = 122) at four community-based medical centers were retrospectively reviewed to determine if using a nonnarcotic alternative to morphine sulfate and/or meperidine as a primary postoperative analgesic could reduce res...
journal_title:Clinical therapeutics
pub_type: 杂志文章,多中心研究
doi:
更新日期:1993-09-01 00:00:00