Abstract:
AIMS:Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor that has been developed as oral glucose lowering drug. The original dosefinding studies focused on optimal glycaemic effects. However, dapagliflozin also affects various cardiorenal risk markers and provides cardiorenal protection. To evaluate whether the currently registered doses of 5 and 10 mg are optimal for cardiorenal efficacy and safety, we characterized the relationship between dapagliflozin exposure and nonglycaemic cardiorenal risk markers as well as adverse events. METHODS:Data were obtained from a pooled database of 13 24-week randomized controlled clinical trials of the clinical development programme of dapagliflozin. The exposure-response relationship was quantified using population pharmacodynamic and repeated time-to-event models. RESULTS:A dose of 10 mg dapagliflozin resulted in an average individual exposure of 638 ng h/mL (95% prediction interval [PI]: 354-1061 ng h/mL), which translated to 71.2% (95% PI: 57.9-80.5%), 61.1% (95% PI: 58.0-64.8%), 91.3% (95% PI: 85.4-94.6%) and 25.7% (95% PI: 23.5-28.3%) of its estimated maximum effect for fasting plasma glucose, haematocrit, serum creatinine and urinary albumin-creatinine ratio, respectively. CONCLUSION:We demonstrate that doses higher than 10 mg could provide additional beneficial effects in haematocrit, systolic blood pressure, urinary albumin-creatinine ratio and uric acid, without obvious increases in the rate of adverse events. These results raise the question whether future outcome studies assessing the benefits of higher than currently registered dapagliflozin doses are merited.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Koomen JV,Stevens J,Heerspink HJLdoi
10.1111/bcp.14318subject
Has Abstractpub_date
2020-11-01 00:00:00pages
2192-2203issue
11eissn
0306-5251issn
1365-2125journal_volume
86pub_type
杂志文章abstract::The current U.K. trial protocol (UKALL XI) for childhood lymphoblastic leukaemia demands mercaptopurine (MP) dose escalation in children who tolerate daily 75 mg/m2 MP (100% dose) without cytopenias. The previous trial (UKALL X) did not. MP metabolism was studied in a group of UKALL XI children (n = 21) who tolerated ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.1996.44921.x
更新日期:1996-10-01 00:00:00
abstract:AIMS:In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impa...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14436
更新日期:2020-06-19 00:00:00
abstract::The effect of isotonic bicycle exercise on beta 2-adrenoceptors and cAMP production in lymphocytes was studied. The origin of the newly exposed receptors was studied by measuring radioligand binding in the presence of hydrophylic or lipophylic 'cold' ligands. During exercise beta 2-adrenoceptor density increased from ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1990.tb05487.x
更新日期:1990-01-01 00:00:00
abstract::1. Ten healthy subjects received two treatments: a single 1 g oral dose of nalidixic acid (NA) followed 1 h later by either an infinitesimal dilution of the drug (NA 7CH) or by succussed water which served as placebo. The study was repeated 18 months later in 10 different subjects. 2. A further 10 healthy subjects rec...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/j.1365-2125.1991.tb05610.x
更新日期:1991-07-01 00:00:00
abstract:AIMS:This study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors. METHODS:We include...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/bcp.12984
更新日期:2016-08-01 00:00:00
abstract:AIMS:The role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes. METHODS:We used a combined in vitro-in vivo approach to determine the ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2010.03789.x
更新日期:2010-12-01 00:00:00
abstract::1. The effects of selective beta-adrenoceptor partial agonist activity on plasma creatine kinase (CK) and skeletal muscle symptoms were studied in normal volunteers. 2. A drug with beta 1-selective partial agonist activity (xamoterol) and one with partial agonist activity acting mainly through beta 2-adrenoceptors (pi...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2125.1990.tb03834.x
更新日期:1990-11-01 00:00:00
abstract::1. The phenotyping parameters for dextromethorphan and mephenytoin were assessed in 48 normal male volunteers following administration of each metabolic probe drug on separate occasions and together according to a randomized 3-way crossover design. 2. Neither the urinary S-/R-mephenytoin ratio nor the dextromethorphan...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2125.1990.tb03653.x
更新日期:1990-04-01 00:00:00
abstract:AIMS:The protease inhibitor indinavir is characterized by an important interindividual pharmacokinetic variability, which results from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A and the multidrug efflux pump P-glycoprotein (P-gp), encoded by MDR1. Using a population pharmacokinetic approach, we in...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2007.02903.x
更新日期:2007-09-01 00:00:00
abstract::The effects of bopindolol, a new beta-adrenoceptor blocker, on the exercise tolerance of 12 in-patients, mean age 57 (5 years), with stable angina pectoris and documented coronary artery disease were evaluated. All patients received on 4 different days a single oral dose of bopindolol 0.5 mg, bopindolol 1.0 mg, bopind...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1991-12-01 00:00:00
abstract::1 The effects of age and sex on the disposition of clobazam (CBZ), a 1.5-benzodiazepine derivative, were evaluated in a series of 29 healthy volunteers aged 18 to 72 years, who ingested single 20 mg oral doses. CBZ kinetics were determined from multiple plasma concentrations measured during 7 days after the dose. 2 CB...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1981.tb01281.x
更新日期:1981-11-01 00:00:00
abstract::Twelve patients with acute uncomplicated falciparum malaria were admitted to the Hospital for Tropical Diseases for 42 days. The patients were treated with halofantrine 500 mg 6 hourly for three doses and halofantrine and its desbutyl metabolite were analysed in plasma by h.p.l.c. Cmax values of halofantrine and desbu...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1991.tb05567.x
更新日期:1991-04-01 00:00:00
abstract::The effects of ranitidine on the pharmacokinetics of metoprolol were examined in two studies. In the first study, pharmacokinetics of single doses of metoprolol were examined in six subjects before, during and after ranitidine administration for 1 week. Peak concentrations of metoprolol were increased on ranitidine bu...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1985.tb02634.x
更新日期:1985-02-01 00:00:00
abstract:AIMS:Topical growth factors accelerate wound healing in patients with diabetic foot ulcers (DFU). Due to the absence of head-to-head comparisons, we carried out Bayesian network meta-analysis to compare the efficacy and safety of growth factors. METHODS:Using an appropriate search strategy, randomized controlled trial...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,meta分析
doi:10.1111/bcp.13470
更新日期:2018-03-01 00:00:00
abstract::Children are not small adults. However, the main thesis of this review will be that children's responses to drugs have much in common with the responses in adults and indeed in other mammals. Often, it is assumed that drug effects differ in children but in reality this perception often arises because the drugs have no...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2125.2005.02445.x
更新日期:2005-06-01 00:00:00
abstract::1. We have compared acute gastric bleeding caused by a new slow release preparation of indomethacin (indomethacin Continus) with that caused by aspirin and other indomethacin preparations. 2. In a randomized crossover study, blood loss into timed gastric aspirates was determined in 20 healthy volunteers after receivin...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2125.1988.tb03382.x
更新日期:1988-08-01 00:00:00
abstract::1 As part of a prospective study on the use of digoxin in a general practice, plasma digoxin concentrations were measured in all patients receiving the drug. 2 A low mean plasma digoxin concentration was observed, suggesting a cautious approach to digitalization. 3 The correlation between plasma digoxin concentration ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1977.tb00720.x
更新日期:1977-06-01 00:00:00
abstract::1 The pharmacokinetics of diazepam following intravenous administration have been investigated in six normal volunteers and nine epileptic patients receiving chronic antiepileptic drug therapy. 2 After intravenous administration, serum diazepam levels declined biexponentially in all subjects. The elimination half-life...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1981.tb01317.x
更新日期:1981-12-01 00:00:00
abstract::1. We compare the sensitivity and specificity of chosen outcome criteria in a placebo-controlled, randomised cross-over study of the efficacy of maintenance therapy with the levodopa/carbidopa combination (Sinemet Plus) alone. Patients were characterised by having idiopathic Parkinsonism with no overt fluctuations in ...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2125.1991.tb05533.x
更新日期:1991-03-01 00:00:00
abstract::Twelve healthy habitual cigarette smokers and eight non-smokers participated in a double-blind placebo controlled study to determine the effect of smoking on the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine. In smokers, cigarette smoking was standardised and started 1 h before (A), or...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2125.1992.tb04025.x
更新日期:1992-02-01 00:00:00
abstract:AIMS:The aim of the present study was to investigate whether differences in total and peak drug exposure upon generic substitution are due to differences between formulations or to intrasubject pharmacokinetic variability of the active substance. METHODS:The study was designed as a retrospective reanalysis of existing...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.12828
更新日期:2016-04-01 00:00:00
abstract:AIM:We encountered a case of fetal toxicity due to ductus arteriosus (DA) constriction in a 36-week pregnant woman who had applied multiple ketoprofen patches. The aim of the present study was to present the case and develop a model to predict quantitatively the fetal toxicity risk of transdermal administration of keto...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13352
更新日期:2017-11-01 00:00:00
abstract::A new anti-spasticity agent, brolitene, has been assessed in patients with spasticity of spinal or cerebral origin. Twenty-seven patients were entered in a double-blind cross-over trial lasting 6 weeks, using a fixed dose of six tablets (1200 mg brolitene) per day. Clinical assessment failed to show any therapeutic ef...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/j.1365-2125.1976.tb00641.x
更新日期:1976-10-01 00:00:00
abstract:AIMS:To determine whether topical ocular chloramphenicol increases the risk of aplastic anaemia and to estimate the magnitude of this risk, if any. METHODS:Population-based prospective case-control surveillance of aplastic anaemia in a community of 4.2 million inhabitants from 1980 to 1995 (67.2 million person-years) ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.1998.00773.x
更新日期:1998-08-01 00:00:00
abstract::1. Apomorphine (1 and 5 micrograms kg-1) and placebo were given to nine normal volunteers, using a Latin-square design and double-blind procedures. The visual perception of static and moving patterns (static and motion contrast sensitivity) was evaluated before and 15 min after the dose administration. 2. Apomorphine ...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2125.1991.tb03950.x
更新日期:1991-11-01 00:00:00
abstract::The disposition of mexiletine has been studied in five subjects on two occasions with urine pH controlled at 5.0 and at 8.0. With acid urine total plasma clearance was similar in all subjects (462 to 497 ml min-1) and the plasma half-life ranged from 3.8 to 9.2 h (mean 6.7 h). With alkaline urine the total plasma clea...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1983.tb02162.x
更新日期:1983-09-01 00:00:00
abstract:AIM:Omalizumab, a humanized IgG monoclonal antibody that binds to human immunoglobulin E (IgE), interrupts the allergic cascade in asthmatic patients. The aim was to compare simultaneously drug exposure and IgE biomarker responses in Japanese and White patient populations. METHODS:An instantaneous equilibrium drug-lig...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1111/j.1365-2125.2006.02803.x
更新日期:2007-05-01 00:00:00
abstract::1. Since salt depletion stimulates the renal prostaglandin system to maintain renal function, the effects of indomethacin and ibuprofen upon renal haemodynamics, electrolyte excretion and renin release were examined in eight healthy male volunteers on a salt restricted diet, before and after frusemide administration. ...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2125.1990.tb03641.x
更新日期:1990-03-01 00:00:00
abstract:AIMS:BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/bcp.12941
更新日期:2016-07-01 00:00:00
abstract:AIMS:To compare single- and multiple-dose duloxetine pharmacokinetics between healthy Japanese and Caucasians. METHODS:Twenty-four subjects of each race were given single oral doses of duloxetine (20, 40 and 60 mg) in a randomized, double-blind study. Another 20 subjects of each race received 20, 40 mg or placebo (2 :...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/j.1365-2125.2006.02770.x
更新日期:2007-03-01 00:00:00