A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance.


AIM:To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. METHODS:Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. RESULTS:In both models, a similar clearance decrease of 7% (range -82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6-8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0-73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. CONCLUSION:These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT.


Br J Clin Pharmacol


Langenhorst JB,Boss J,van Kesteren C,Lalmohamed A,Kuball J,Egberts ACG,Boelens JJ,Huitema ADR,van Maarseveen EM




Has Abstract


2020-08-01 00:00:00












  • Management of Helicobacter pylori eradication--the influence of structured counselling and follow-up.

    abstract:AIMS:Helicobacter pylori (H. pylori) eradication rate varies according to the treatment regimen used and other factors, e.g. antimicrobial resistance and patient compliance. The aim of the present study was to evaluate the influence of patient counselling and follow-up on H. pylori eradication rates and to document the...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Al-Eidan FA,McElnay JC,Scott MG,McConnell JB

    更新日期:2002-02-01 00:00:00

  • Treatment of patients with cocaine-induced arrhythmias: bringing the bench to the bedside.

    abstract::Widespread use of cocaine and its attendant toxicity has produced a wealth of benchwork studies and small animal investigations that evaluated the effects of cocaine on the cardiovascular system. Despite this wealth of knowledge, very little is known about the frequency or types of arrhythmias in patients with signifi...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,评审


    authors: Hoffman RS

    更新日期:2010-05-01 00:00:00

  • Perturbation of paracetamol urinary metabolic ratios by urine flow rate.

    abstract::The effects of high and low urine flow rates on the urinary metabolic ratios for paracetamol glucuronidation, sulphation and oxidation were determined at steady-state in seven healthy young adult volunteers. Metabolic partial clearances were unaffected by urine flow rate, but individual paracetamol metabolic ratios va...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Miners JO,Osborne NJ,Tonkin AL,Birkett DJ

    更新日期:1992-10-01 00:00:00

  • The effects of advanced age and serum α1 -acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients.

    abstract:AIM:α1 -Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective s...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Kenmotsu H,Imamura CK,Ono A,Omori S,Nakashima K,Wakuda K,Taira T,Naito T,Murakami H,Takahashi T,Tanigawara Y

    更新日期:2017-11-01 00:00:00

  • Commentary on the EMA Reflection Paper on the use of extrapolation in the development of medicines for paediatrics.

    abstract::Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have...

    journal_title:British journal of clinical pharmacology



    authors: Ollivier C,Thomson A,Manolis E,Blake K,Karlsson KE,Knibbe CAJ,Pons G,Hemmings R

    更新日期:2019-04-01 00:00:00

  • Effect of beta-adrenoceptor agents on the blood flow in carotid arteries in normal volunteers.

    abstract::The effects on carotid artery blood flow of atenolol (a selective beta 1-adrenoceptor antagonist) and xamoterol (a beta 1-adrenoceptor partial agonist with 43% agonist activity) were measured using a Doppler technique in eight healthy volunteers. Atenolol produced a decrease in blood pressure and blood velocity flow, ...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章


    authors: Fitzgerald DE,Harry JD

    更新日期:1989-01-01 00:00:00

  • Concomitant use of clopidogrel and statins and risk of major adverse cardiovascular events following coronary stent implantation.

    abstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:• The CYP3A4 inhibition by lipophilic statins may attenuate the effectiveness of clopidogrel. • No studies have measured drug exposure in a time-varying manner that detects discontinuation and restart of clopidogrel and statin therapy, allowing clinical quantification of the int...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Schmidt M,Johansen MB,Maeng M,Kaltoft A,Jensen LO,Tilsted HH,Bøtker HE,Baron JA,Sørensen HT

    更新日期:2012-07-01 00:00:00

  • City checking: Piloting the UK's first community-based drug safety testing (drug checking) service in 2 city centres.

    abstract:AIMS:To explore the feasibility of delivering community-based drug safety testing (drug checking), to trial service design characteristics and to compare with festival-based testing. METHODS:In total, 171 substances of concern were submitted on 5 dates at 3 venues in 2 UK cities and tested using up to 6 analytical tec...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Measham F

    更新日期:2020-03-01 00:00:00

  • Systemic exposure to 5-fluorouracil and its metabolite, 5,6-dihydrofluorouracil, and development of a limited sampling strategy for therapeutic drug management of 5-fluorouracil in patients with gastrointestinal malignancy.

    abstract:AIMS:5-Fluorouracil (5-FU) is widely used in combination chemotherapy, and literature suggests pharmacokinetic-guided dosing to improve clinical efficacy and reduce toxicity. This study aimed to determine the pharmacokinetic exposure of both 5-FU and its metabolite, 5,6-dihydrofluorouracil (DHFU), in patients with gast...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Jacob J,Mathew SK,Chacko RT,Aruldhas BW,Singh A,Prabha R,Mathew BS

    更新日期:2020-06-27 00:00:00

  • Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study.

    abstract:AIM:Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case-control study to determine the hepatotoxic risk of a wide range of drugs. METHODS:The Berlin Case-Control Surveillance Study FAKOS included all 51 Berl...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Douros A,Bronder E,Andersohn F,Klimpel A,Thomae M,Sarganas G,Kreutz R,Garbe E

    更新日期:2015-06-01 00:00:00

  • Single and repeated dose comparison of three antihistamines and phenylpropanolamine: psychomotor performance and subjective appraisals of sleep.

    abstract::1 In a double-blind cross-over study, nine healthy male students received placebo, brompheniramine 12 mg), carbinoxamine (12 mg), clemastine (1 mg), and phenylpropanolamine (50 mg) orally. Three doses of each drug were given: at 08.30 h and 21.00 h on the first day of treatment and at 08.30 h on the following day. 2 P...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Seppälä T,Nuotto E,Korttila K

    更新日期:1981-08-01 00:00:00

  • Discontinuation of medications at the end of life: A population study in Belgium, based on linked administrative databases.

    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


    authors: Paque K,De Schreye R,Elseviers M,Vander Stichele R,Pardon K,Dilles T,Christiaens T,Deliens L,Cohen J

    更新日期:2019-04-01 00:00:00

  • Delta-9-tetrahydrocannabinol and gastric emptying.

    abstract::The effects of delta-9-tetrahydrocannabinol (0.5 and 1 mg i.v.) on gastric emptying of liquid were investigated in seven normal volunteers and compared with placebo. Despite significant change in pulse rate and psychological parameters consistent with cannabis activity there was no significant effect on the pattern of...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章


    authors: Bateman DN

    更新日期:1983-06-01 00:00:00

  • Information about adverse drug reactions reported in children: a qualitative review of empirical studies.

    abstract:AIM:To review the literature on adverse drug reactions (ADRs) in children with respect to occurrence, seriousness, type, therapeutic group, age and gender of the child and category of reporter. METHODS:Medline and Embase databases were searched from origin and updated until February 2010. We included empirically based...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,评审


    authors: Aagaard L,Christensen A,Hansen EH

    更新日期:2010-10-01 00:00:00

  • The effects of cimetidine on serum calcium and parathyroid hormone levels in primary hyperparathyroidism.

    abstract::1 Cimetidine has been reported to reduce serum calcium and parathyroid hormone (PTH) levels in primary hyperparathyroidism, but some studies have reported negative findings. 2 A double-blind, controlled trial of cimetidine in this condition was, therefore, conducted. Eight patients were given cimetidine and placebo fo...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Fisken RA,Wilkinson R,Heath DA

    更新日期:1982-11-01 00:00:00

  • The pharmacokinetics of methimazole after oral administration of carbimazole and methimazole, in hyperthyroid patients.

    abstract::1 Methimazole plasma concentrations were measured in two groups of hyperthyroid subjects after the oral administration of either carbimazole or methimazole. 2 With the HPLC method it was also possible to measure the concentration of a methimazole metabolite, 3-methyl-2-thiohydantoin in one patient. 3 Large interindivi...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Skellern GG,Knight BI,Low CK,Alexander WD,McLarty DG,Kalk WJ

    更新日期:1980-02-01 00:00:00

  • Haem arginate improves hepatic oxidative metabolism in variegate porphyria.

    abstract::1. The elimination of antipyrine was investigated before and after intravenous administration of haem arginate (3 mg haem kg-1 day-1 on three or four successive days) to six patients with variegate porphyria in remission. 2. Haem arginate decreased the faecal content of protoporphyrin from 557 +/- 91 to 118 +/- 32 (me...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Tokola O,Mustajoki P,Himberg JJ

    更新日期:1988-12-01 00:00:00

  • Morphine-like insomnia from heroin in nondependent human addicts.

    abstract::1 This study was performed because dose-related effects of heroin on human sleep had not been described previously, and to discover if heroin produces a morphine-like insomnia. 2 After three adaptation nights, the sleep of seven male nondependent opiate addicts was studied following i.m. doses of heroin (3, 6, 12 mg/7...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Kay DC,Pickworth WB,Neider GL

    更新日期:1981-02-01 00:00:00

  • A phase I trial of the safety, tolerability and pharmacokinetics of cannabidiol administered as single-dose oil solution and single and multiple doses of a sublingual wafer in healthy volunteers.

    abstract:AIMS:This study investigated the safety, tolerability and pharmacokinetics after administration of a specific Cannabis sativa cultivar extract, standardised to cannabidiol (CBD) content as sublingual wafer or oil formulation compared to nabiximols oromucosal spray. METHODS:For the single-dose study, the design was an ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Hosseini A,McLachlan AJ,Lickliter JD

    更新日期:2020-10-19 00:00:00

  • Evaluation of the effect on heart rate variability of a beta2-adrenoceptor agonist and antagonist using non-linear scatterplot and sequence methods.

    abstract:AIMS:To examine the impact on heart rate variability (HRV), of agonism or antagonism at the cardiac beta2-adrenoceptor in healthy volunteers, using standard time-domain summary statistics and non-linear methods (scatterplot and quadrant analysis). METHODS:Under double-blind and randomised conditions (Latin square desi...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Hanratty CG,Silke B,Riddell JG

    更新日期:1999-02-01 00:00:00

  • Evaluation of noninvasive blood pressure recording by photoplethysmography in clinical studies using angiotensin challenges.

    abstract:AIMS:Continuous noninvasive blood pressure measurement by photoplethysmography has been regularly used in the experimental paradigm of angiotensin challenges, applied to the phase I clinical testing of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. This work aims to evaluate the performa...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Buclin T,Buchwalder-Csajka C,Brunner HR,Biollaz J

    更新日期:1999-10-01 00:00:00

  • Clinically important drug-drug interactions in poly-treated elderly outpatients: a campaign to improve appropriateness in general practice.

    abstract:AIMS:The aim was to assess the impact of a campaign for general practitioners (GPs) to reduce clinically-important drug-drug interactions (DDIs) in poly-treated elderly patients. METHODS:We compiled a list of 53 DDIs and analyzed reimbursed prescriptions dispensed to poly-treated (≥four drugs) elderly (>65 years) pati...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Raschi E,Piccinni C,Signoretta V,Lionello L,Bonezzi S,Delfino M,Di Candia L,Di Castri L,Pieraccini F,Carati D,Poluzzi E,De Ponti F,Emilia-Romagna elderly poly-treated patients research group.

    更新日期:2015-12-01 00:00:00

  • Salbutamol inhibits metabisulphite-induced bronchoconstriction.

    abstract::The effect of salbutamol on bronchoconstriction induced by inhaled sodium metabisulphite has been studied in 12 atopic subjects. Salbutamol (200 micrograms, 3.5 x 10(-7) M) and matched placebo were administered by identical metered dose inhaler 15 min before a dose-response to sodium metabisulphite (1.25-100 mg ml-1) ...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Iredale MJ,Dixon CM,Ind PW

    更新日期:1991-11-01 00:00:00

  • Limited predictability of amikacin clearance in extreme premature neonates at birth.

    abstract:AIM:Identify and quantify factors describing variability of amikacin clearance in preterm neonates at birth. METHODS:Population pharmacokinetics of amikacin were estimated in a cohort of 205 extreme preterm neonates [post conception age (PCA) 27.8, SD 1.8, range 24-30 weeks; weight 1.07, SD 0.34, range 0.45-1.98 kg, p...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Allegaert K,Anderson BJ,Cossey V,Holford NH

    更新日期:2006-01-01 00:00:00

  • A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers.

    abstract:AIMS:To compare the effects of nabumetone and meloxicam, two cyclo-oxygenase-2 (COX-2) preferential nonsteroidal anti-inflammatory drugs (NSAIDs), on platelet COX-1 activity and platelet function. METHODS:Twelve healthy volunteers (3 male, 9 female, median age 22 years) participated in an open, randomized, cross-over ...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: van Kraaij DJ,Hovestad-Witterland AH,de Metz M,Vollaard EJ

    更新日期:2002-06-01 00:00:00

  • Neuropeptides in hypertension: role of neuropeptide Y and calcitonin gene related peptide.

    abstract::1. The effect of neuropeptide Y (NPY) on cardiovascular function at three levels of the noradrenergic axis where the peptide is known to co-exist with noradrenaline (NA) and or adrenaline (A) was studied in normotensive Sprague-Dawley (SD), Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHR). 2. In the perfuse...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Westfall TC,Han SP,Knuepfer M,Martin J,Chen XL,del Valle K,Ciarleglio A,Naes L

    更新日期:1990-01-01 00:00:00

  • Atenolol elimination in the neonate.

    abstract::The elimination of the cardioselective beta-adrenoceptor antagonist atenolol has been studied in 35 neonates by measuring drug concentration in cord blood and in blood obtained at 24 h by heel stab. Elimination rate was assessed by calculating the slopes of lines joining these two concentration points. The slopes had ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Rubin PC,Butters L,Reynolds B,Evans J,Sumner D,Low RA,Reid JL

    更新日期:1983-12-01 00:00:00

  • Impact of lipophilic vs hydrophilic statins on the clinical outcome and biomarkers of remodelling in heart failure patients: A prospective comparative randomized study.

    abstract:AIMS:There are insufficient direct comparative studies addressing the impact of the type of statin on their respective efficacy in heart failure (HF). The aim of the current study was to compare the effects of lipophilic (atorvastatin) vs hydrophilic (rosuvastatin) on left ventricular function, inflammatory and fibrosi...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: El Said NO,El Wakeel LM,Khorshid H,Darweesh EAG,Ahmed MA

    更新日期:2020-12-08 00:00:00

  • Integrating pharmacology and clinical pharmacology in pharmaceutical companies.

    abstract::Integration of clinical and preclinical pharmacology in pharmaceutical companies could be improved by several key recommendations: Companies should ensure that there is an adequate pool of trained clinical pharmacologists and preclinical pharmacologists. Training should include topics that allow clinical pharmacologis...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Hunter JA

    更新日期:2012-06-01 00:00:00

  • Objective outcome criteria in trials of anti-parkinsonian therapy in the elderly: sensitivity, specificity and reliability of measures of brady- and hypo-kinesia.

    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


    authors: Bowes SG,Clark PK,Charlett A,O'Neill CJ,Leeman AL,Weller C,Nicholson PW,Deshmukh AA,Dobbs SM,Dobbs RJ

    更新日期:1991-03-01 00:00:00