Abstract:
AIMS:AT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in adults and children and to estimate the MTD in children with leukaemia. METHODS:Data from Phase I dose-escalation studies in adults and children were used to build a population pharmacokinetic model (NONMEM v7.3). Potential covariates investigated included body weight, body surface area (BSA), glomerular filtration rate (GFR), age and sex. Model-derived area under the concentration-time curve was used to investigate the relationship between dose and exposure in adults and children. RESULTS:The plasma concentrations of AT9283 (n = 1770) from 92 patients (53 adults, 39 children) were used to build a two-compartment model with all pharmacokinetic parameters scaled using body weight. Renal function (GFR), but not BSA, was a significant covariate for the clearance of AT9283. In children with leukaemia (median weight 16 kg), a flat dose of 500 mg 72 h-1 provided similar drug exposures at the MTD as the adult population. The estimated MTD for children with leukaemia, therefore, is 30 mg kg-1 72 h-1 . CONCLUSION:For adults, GFR was a significant predictor of clearance, whilst body-weight based dosing was more useful than BSA in determining the drug exposure in children. The MTD was estimated to be 30 mg kg-1 72 h-1 children with leukaemia.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Duong JK,Griffin MJ,Hargrave D,Vormoor J,Edwards D,Boddy AVdoi
10.1111/bcp.13260subject
Has Abstractpub_date
2017-08-01 00:00:00pages
1713-1722issue
8eissn
0306-5251issn
1365-2125journal_volume
83pub_type
杂志文章abstract:AIMS:The aim of this study was to investigate the impact of new insights and revised guidelines on initial and follow-up treatment with antihyperglycaemic drugs over the period 1998-2003. METHODS:The InterAction Database (IADB), which contains pharmacy dispensing data from 53 community pharmacies in the Northern and E...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2006.02711.x
更新日期:2006-12-01 00:00:00
abstract::Paracetamol disposition was studied in groups of pregnant and non-pregnant women of comparable age. Paracetamol apparent oral clearance was 58% higher and elimination half-life was 28% lower in the pregnant women compared to the control group. The higher clearance in the pregnant women was due to increased activity of...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1986.tb02901.x
更新日期:1986-09-01 00:00:00
abstract::1. The pharmacokinetics of levodopa and paracetamol after single oral doses have been investigated in eight healthy young volunteers in the fasted state and following isocaloric meals containing either 10.5 g or 30.5 g of protein. 2. The initial peak and maximum plasma drug concentrations and the times at which these ...
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.tb05555.x
更新日期:1991-04-01 00:00:00
abstract::1. The effect of icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) a potent B2-kinin receptor antagonist, was studied on bradykinin-induced vasodilation in the human forearm. 2. Eight healthy normotensive men were studied in a rising dose random-placebo controlled study. Placebo and icatibant (20, 50 and 100 mic...
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.1365-2125.1994.tb04360.x
更新日期:1994-10-01 00:00:00
abstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:Oxycodone is an opioid analgesic that is metabolized mainly in the liver by cytochrome P450 (CYP) 2D6 and 3A4 enzymes. So far, the effects of CYP2D6 or CYP3A4 inhibitors on the pharmacokinetics of oxycodone in humans have not been systematically studied. WHAT THIS STUDY ADDS:Dr...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/j.1365-2125.2010.03653.x
更新日期:2010-07-01 00:00:00
abstract::Ten patients with mild to moderate hypertension were treated for 9 weeks with a tablet formulation of pinacidil. Mean supine blood pressure fell from 174/100 to 148/84 mm Hg and mean supine pulse increased by 3 beats/min. Daily dosage was 40-100 mg, given in two or three divided doses. Plasma urea increased significan...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1984.tb02456.x
更新日期:1984-08-01 00:00:00
abstract:AIMS:Within the new psychoactive substances (NPS) scenario, several hundred different molecules, mostly including synthetic cannabinoids and cathinones, have been identified so far. The aims of the paper were to: (i) identify the number of synthetic cathinones mentioned in a range of psychonaut, NPS-related, online sou...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14132
更新日期:2020-03-01 00:00:00
abstract::A possible route of metabolism of beta-adrenoceptor stimulating drugs used in obstetrics consists of conjugation by the enzyme phenol sulphotransferase. The substrate specificities of the platelet and the placental enzymes towards these drugs were tested. The specific activities of the beta-adrenoceptor agonists were ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1984.tb05009.x
更新日期:1984-01-01 00:00:00
abstract:AIMS:To evaluate the potential ethnic differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of evolocumab in Caucasian and Asian populations using population PK/PD modelling analysis. METHODS:Data from different ethnic groups in 5 Phase I clinical trials, including two American studies, one Japanese study...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13767
更新日期:2019-01-01 00:00:00
abstract::1 The effects of propranolol and atenolol given in random order in a cross-over study to fifteen patients with essential hypertension have been studied. 2 Both drugs were effective in lowering blood pressure and side effects were not markedly different. 3 There was no change in exchangeable sodium or potassium or in t...
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.1365-2125.1980.tb00501.x
更新日期:1980-07-01 00:00:00
abstract:AIMS:To establish whether the SCN1A IVS5-91 G > A polymorphism of the SCN1A gene, which encodes the neuronal sodium channel alpha subunit, affects responsiveness to the antiepileptic drugs (AEDS) carbamazepine and/or phenytoin. METHODS:SCN1A IVS5-91 G > A polymorphism was genotyped in 228 Japanese epileptic patients t...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2008.03203.x
更新日期:2008-08-01 00:00:00
abstract::1. Twenty-two patients with moderately severe essential hypertension were treated for a period of 12 months with guanfacine (BS 100-141), a new centrally-acting antihypertensive agent. A twice daily schedule was followed and the dose range of guanfacine was 1-8 mg daily. 2. In twenty patients satisfactory blood pressu...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/j.1365-2125.1980.tb04906.x
更新日期:1980-01-01 00:00:00
abstract:AIMS:Aldosterone has been found to influence cancer cell growth, cell cycle regulation and cell migration, including in prostate cancer cells. Spironolactone is an aldosterone antagonist used for managing chronic heart failure (HF) with known antiandrogenic effects. We examined the effect of spironolactone exposure amo...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14568
更新日期:2020-09-28 00:00:00
abstract::Cytochrome P450 3A is the main enzyme subfamily involved in the metabolism of a variety of marketed medicines. It is generally believed that the substrate specificity of polymorphic P450 3A5 is similar to that of the predominant P450 3A4 isoform, although some differences in catalytic properties have been found. It ha...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2010.03656.x
更新日期:2010-06-01 00:00:00
abstract:AIMS:The aim of this study was to examine the use of potentially inappropriate medication (PIM) in relation to time before death, to explore whether PIMs are discontinued at the end of life, and the factors associated with this discontinuation. METHODS:We conducted a retrospective register-based mortality cohort study...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13874
更新日期:2019-04-01 00:00:00
abstract::1 The effect of low dose steady state warfarin (0.2 mg and 1 mg daily) on clotting factor activity and vitamin K1 metabolism was studied in seven healthy volunteers. 2 Steady state plasma warfarin concentrations were 41-99 ng ml-1 for the 0.2 mg dose and 157-292 ng ml-1 for the 1 mg dose. 3 There was a significant pro...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1988.tb03274.x
更新日期:1988-01-01 00:00:00
abstract::1. The primary action of the converting enzyme inhibitors to prevent the formation of angiotensin II can explain a decrease in peripheral vascular resistance in patients with elevated, but not in those with normal or reduced plasma renin levels. 2. The inhibition of the breakdown of bradykinin will potentiate the vaso...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2125.1989.tb03585.x
更新日期:1989-01-01 00:00:00
abstract::1. Medication errors are common in general practice and in hospitals. Both errors in the act of writing (prescription errors) and prescribing faults due to erroneous medical decisions can result in harm to patients. 2. Any step in the prescribing process can generate errors. Slips, lapses, or mistakes are sources of e...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2009.03425.x
更新日期:2009-06-01 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:AIMS:To investigate the effect of multiple oral dose treatment with the endothelin receptor antagonist bosentan on the pharmacokinetics of digoxin in healthy subjects. METHODS:This was an open-label, randomized, two-way crossover study in 18 evaluable young male subjects. They received, on two occasions which were sep...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1046/j.1365-2125.1999.00946.x
更新日期:1999-06-01 00:00:00
abstract::1 In healthy male volunteers dazoxiben (UK 37248), an inhibitor of thromboxane synthetase, abolished the arterial and venous vasoconstriction produced in the forearm by cold stimulation. 2 Aspirin alone had no effect on this vasoconstriction but negated the effect of dazoxiben. 3 In vitro dazoxiben increased the produ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1983.tb02118.x
更新日期:1983-01-01 00:00:00
abstract::The pharmacokinetics of piretanide, a new loop diuretic, were studied in four patients with GFR 4.7-14.8 ml/min. An oral dose of piretanide 18 mg was given at 08.00 h in two patients and at 08.00 h and 14.00 h in two. Blood samples were drawn after 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. Serum concentrations of pireta...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/j.1365-2125.1983.tb01509.x
更新日期:1983-03-01 00:00:00
abstract:AIMS:In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N-demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N-demethylation of IMI. METHODS:Healthy subjects were given troleando...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1046/j.1365-2125.1997.00649.x
更新日期:1997-08-01 00:00:00
abstract::Scientific advice (SA) is an important tool offered by regulators to help developers generate robust evidence on a medicine's benefits and risks. Drawing on accumulated experience and looking at the SA provided by the European Medicines Agency in 2018 to advanced therapy medicinal products originally developed by publ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14672
更新日期:2020-11-25 00:00:00
abstract::1 Analgesic nephropathy is part of the analgesic syndrome which has gastrointestinal, haematological, cardiovascular, psychological and psychiatric, and pregnancy and gonadal manifestations; premature ageing may also be a feature. 2 Analgesic nephropathy is a form of renal disease characterized by renal papillary necr...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2125.1980.tb01824.x
更新日期:1980-10-01 00:00:00
abstract:AIMS:To quantify usage of COX-2 inhibitors compared with nonselective NSAIDs and to determine their impact (including financial) on the co-prescription of antipeptic ulcer (anti-PU) drugs. METHODS:The Irish General Medical Services prescription database (covering 1.2 million people) was examined for NSAID prescription...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.2003.02012.x
更新日期:2004-03-01 00:00:00
abstract::The irritable bowel syndrome (IBS) remains a therapeutic challenge in part because of the limited understanding of the pathophysiology. The placebo response rate varies in randomized controlled trials from 20 to 70%, and can persist for up to at least 1 year. It is contentious whether dietary fibre and bulking agents ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1046/j.1365-2125.2003.01966.x
更新日期:2003-10-01 00:00:00
abstract:AIMS:Intravenous formulations of busulfan have recently become available. Although busulfan is used frequently in children as part of a myeloablative regimen prior to bone marrow transplantation, pharmacokinetic data on intravenous busulfan in children are scarce. The aim was to investigate intravenous busulfan pharmac...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.2002.01555.x
更新日期:2002-04-01 00:00:00
abstract::1 The haemodynamic effects of labetalol 50 mg intravenously were studied in 13 hypertensive patients at rest in the supine and upright positions and during exercise using percutaneous right heart and brachial artery catheterization. 2 Labetalol induced immediate significant reductions in systolic and diastolic blood p...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:
更新日期:1976-08-01 00:00:00
abstract::Herbal medicines and products derived from them are a diverse group of products for which different (and often limited) levels of evidence are available. As importantly, such products generally vary in their composition and are at the end of an often poorly understood value chain, which often links producers in biodiv...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bcp.12586
更新日期:2015-07-01 00:00:00