Abstract:
AIMS:Previously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice. METHODS:One thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi-physiological PK model for sunitinib and SU12662 was developed incorporating pre-systemic metabolism using non-linear mixed effects modelling (nonmem). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens. RESULTS:Sunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre-systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h(-1) and 17.1 (RSE 7.4%) l h(-1), respectively for 70 kg patients. Correlation coefficients were estimated between inter-individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy. CONCLUSIONS:A semi-physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre-systemic metabolism. The model was superior to previous PK models in many aspects.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Yu H,Steeghs N,Kloth JS,de Wit D,van Hasselt JG,van Erp NP,Beijnen JH,Schellens JH,Mathijssen RH,Huitema ADdoi
10.1111/bcp.12550subject
Has Abstractpub_date
2015-05-01 00:00:00pages
809-19issue
5eissn
0306-5251issn
1365-2125journal_volume
79pub_type
杂志文章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:AIMS:To determine whether a medicine review and education programme influences the compliance and knowledge of older people in general practice. METHODS:Older people taking at least three medicines were randomly allocated to a control or intervention group. Both groups received three visits from a clinical pharmacist:...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1046/j.1365-2125.2000.00247.x
更新日期:2000-08-01 00:00:00
abstract::1. Changes in undergraduate medical education will involve the development of a core curriculum of material of essential knowledge and of the skills for self directed learning both as a student and a postgraduate. A survey of departments or individuals teaching clinical pharmacology and therapeutics was conducted to c...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1994.tb04253.x
更新日期:1994-02-01 00:00:00
abstract::1. The conversion of haloperidol (HAL) to reduced haloperidol (RHAL) and then back to HAL has been established in vivo and observed in psychiatric patients. The reduction of HAL to RHAL is known to be catalysed by a ketone reductase, while the nature of oxidation back to HAL is the subject of the present study. 2. We ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1991.tb05588.x
更新日期:1991-06-01 00:00:00
abstract:AIMS:The CYP3A metric 4β-hydroxycholesterol (4βOHC) has been shown to correlate with tacrolimus steady-state apparent oral clearance (CL/F). Recently, pretransplant 4βOHC was shown not to predict tacrolimus CL/F after transplantation in a cohort of renal recipients (n = 79). The goal of the current study was determine ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13343
更新日期:2017-11-01 00:00:00
abstract::1. A bicycle exercise test was used to investigate functional capability and haemodynamics in 30 patients with heart failure (13 NYHA Class II, 17 Class III), before and after i.v. xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) 0.2 mg kg-1. 2. Resting heart rate fell from 78 to 74 beats min-1 (P less than 0.0...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-01-01 00:00:00
abstract::1 The disposition of prazosin following oral and intravenous administration has been studied in seven young and seven elderly men, all of whom were in good health and living independently in the community. 2 The elimination half-life (min) of prazosin was 123 +/- 19.4 (s.d.) in the young and 194 +/- 36 in the elderly ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1981.tb01234.x
更新日期:1981-09-01 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 effects of simvastatin and pravastatin on measures of central nervous system activity were investigated in a double-blind, placebo-controlled, randomised crossover study. 2. Twenty-five healthy volunteers sequentially took 40 mg day-1 simvastatin, 40 mg day-1 pravastatin or placebo for 4 weeks, separated by a 4...
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.tb04268.x
更新日期:1994-03-01 00:00:00
abstract:AIMS:The objective of this study is to develop a generic model for tacrolimus pharmacokinetics modelling using a meta-analysis approach, that could serve as a first step towards a prediction tool to inform pharmacokinetics-based optimal dosing of tacrolimus in different populations and indications. METHODS:A systemati...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,meta分析
doi:10.1111/bcp.14110
更新日期:2019-12-01 00:00:00
abstract:AIMS:Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated. METHODS:The kinetics of formation of N- and O-demethylated metabolites, nordihydrocodeine and dihydromorphine, w...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.1997.t01-1-00626.x
更新日期:1997-12-01 00:00:00
abstract::1. An open-label, randomised study was performed to assess the effect of tenidap sodium on the pharmacodynamics and plasma protein binding of warfarin. 2. Fourteen healthy male volunteers received either a single oral dose of 120 mg tenidap sodium or matching placebo capsules from days 11 to 36. A single oral dose of ...
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.1365-2125.1995.tb04499.x
更新日期:1995-01-01 00:00:00
abstract:AIMS:Glucocorticoids suppress the release of tumour necrosis factor-alpha (TNF-alpha) by macrophages in vitro and cause monocytopaenia in vivo. These actions may contribute to anti-inflammatory and immunosuppressant effects. We therefore examined relationships between prednisolone concentration, suppression of monocyte...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1046/j.1365-2125.1997.00586.x
更新日期:1997-04-01 00:00:00
abstract::For people seeking treatment, the course of heroin addiction tends to be chronic and relapsing, and longer duration of treatment is associated with better outcomes. Heroin addiction is strongly associated with deviant behaviour and crime, and the objectives in treating heroin addiction have been a blend of humane supp...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bcp.12051
更新日期:2014-02-01 00:00:00
abstract:AIMS:There are no specific criteria for a step-down or withdrawal dose of omalizumab (OMA). Our purpose was to evaluate the viability of a protocol for OMAlizumab DOse REduction (the OMADORE study) in severe allergic asthma (SAA). METHODS:The study population included 35 SAA patients treated during a minimum period of...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/bcp.13453
更新日期:2018-02-01 00:00:00
abstract::1. Metoprolol (ME), pindolol (PI) and propranolol (PR) were studied in nine subjects at different doses and at 'maximum beta-adrenoceptor blockade' at a defined exercise load. Exercise tests were performed after each dosing period; isoprenaline stimulation was studied at the highest dose level. 2. ME and PR reduced he...
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.tb01769.x
更新日期:1980-10-01 00:00:00
abstract::Model-based prediction on clinical doses for cannabinoids therapy is beneficial in the clinical setting, especially for seriously ill patients with both altered pharmacokinetics and pharmacodynamic responses. The objective of this article is to review the currently available PK and/or PD models of Δ9-tetrahydrocannabi...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13635
更新日期:2018-11-01 00:00:00
abstract::The effect of metronidazole, at a dose of 1.2 g daily, on theophylline disposition was studied in 10 healthy adult volunteers. Neither theophylline half-life, volume of distribution nor total body clearance was altered by the anti-microbial. It is concluded that metronidazole does not impair theophylline metabolism de...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1987.tb03146.x
更新日期:1987-07-01 00:00:00
abstract::1. A novel formulation of nicardipine (50% standard (short acting), 50% sustained release) was evaluated in mild hypertension in a double-blind, randomized, placebo-controlled study, using clinic measurements (Hawksley) augmented by home recorded blood pressures (Copal UA 251). 2. Nicardipine 60 mg twice daily for 28 ...
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.1365-2125.1989.tb03418.x
更新日期:1989-05-01 00:00:00
abstract:AIMS:To describe age- and gender-related prescription patterns of diuretics in community-dwelling elderly, and to compare diuretics to other cardiovascular (CV) medications. METHODS:Cross-sectional study of patient-specific prescription data derived from a panel of 10 Dutch community pharmacies. Determination of propo...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.1998.00793.x
更新日期:1998-10-01 00:00:00
abstract::The antiarrhythmic effects of verapamil were observed before it was appreciated that it was a calcium ion-antagonist. Intravenous verapamil is highly effective in the termination of paroxysmal reciprocating atrioventricular tachycardia, whether associated with preexcitation or involving the atrioventricular node alone...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2125.1986.tb02869.x
更新日期:1986-01-01 00:00:00
abstract:AIMS:Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,meta分析
doi:10.1111/j.1365-2125.2004.02224.x
更新日期:2004-12-01 00:00:00
abstract:AIMS:Several studies have reported the under-representation of women in clinical trials, thereby challenging the external validity of the benefit/risk assessments of launched drugs. Our aim was to determine the extent to which women have been included in clinical trials used for drug registration and to analyse the fra...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.13497
更新日期:2018-04-01 00:00:00
abstract:AIMS:Since patients who regularly take NSAIDS may use sucralfate because of its cytoprotective properties, we examined the influence of this compound on the pharmacokinetics of diclofenac. METHODS:Potassium diclofenac (105 mg) was administered orally to eighteen healthy male volunteers with or without a 5-day pre-trea...
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.1365-2125.1997.tb00040.x
更新日期:1997-01-01 00:00:00
abstract:AIM:To study the possible influence of patient characteristics on abacavir pharmacokinetics. METHODS:A population pharmacokinetic model for abacavir was developed using data from 188 adult patients by the use of a nonlinear mixed effects modelling method performed with NONMEM. RESULTS:Abacavir pharmacokinetics was we...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2004.02259.x
更新日期:2005-02-01 00:00:00
abstract:AIMS:To compare the lung delivery of salbutamol from a commonly used constant output open vent jet nebuliser (Sidestream) with use of both a conventional large volume plastic spacer (Volumatic) and a novel small volume metal spacer (NebuChamber). This was assessed using the early lung absorption profile of salbutamol o...
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.1365-2125.1998.00648.x
更新日期:1998-02-01 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::The effects of separate 7 day pretreatments with sulphinpyrazone (800 mg daily) and cimetidine (1 g daily) on the disposition of (+/-)-verapamil have been examined in eight healthy volunteers (four male, four female). Each subject received single oral (80 mg) and intravenous (0.15 mg/kg) doses of verapamil on differen...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1985.tb02658.x
更新日期:1985-03-01 00:00:00
abstract:AIM:Canagliflozin is an SGLT2 inhibitor approved for the treatment of type-2 diabetes. A dynamic population pharmacokinetic-pharmacodynamic (PK/PD) model relating 24-h canagliflozin exposure profiles to effects on glycosylated haemoglobin was developed to compare the efficacy of once-daily and twice-daily dosing. METH...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/bcp.13180
更新日期:2017-05-01 00:00:00
abstract::1. We report a method for measuring the concentrations of haloperidol (HL) and its major active metabolite, reduced haloperidol (RHL), in human scalp hair. 2. Hair samples were obtained from 59 patients who had been taking HL at fixed daily doses for more than 4 months and whose compliance was good. A morning pre-dose...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1990.tb03618.x
更新日期:1990-02-01 00:00:00