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












  • Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage.

    abstract:UNLABELLED:What is already known about this subject? The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. When administered intravenously to patients soon after stroke, IL-1RA is ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Gueorguieva I,Clark SR,McMahon CJ,Scarth S,Rothwell NJ,Tyrrell PJ,Hopkins SJ,Rowland M

    更新日期:2008-03-01 00:00:00

  • Urinary excretion of aspirin.

    abstract::Six human volunteers were each given single oral doses of aspirin (ASA) ranging from 300-1,500 mg. The unchanged ASA excreted in the urine was proportional to dose and urinary pH. The mean percent (+/- s.d.) of dose excreted was 1.9 +/- 0.67. The clearance for ASA was 1.42 +/- 0.28 1/h. The rate of in vitro hydrolysis...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Elliot Cham B,Dykman JH,Bochner F

    更新日期:1982-10-01 00:00:00

  • Placebo effect in the treatment of duodenal ulcer.

    abstract:AIMS:To assess whether frequency of placebo administration is associated with duodenal ulcer healing. METHODS:A systematic literature review of randomized clinical trials was undertaken. 79 of 80 trials that met the inclusion criteria. The pooled 4 week placebo healing rate of all duodenal ulcer trials that employed a...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,meta分析


    authors: de Craen AJ,Moerman DE,Heisterkamp SH,Tytgat GN,Tijssen JG,Kleijnen J

    更新日期:1999-12-01 00:00:00

  • The kinetics of salivary elimination of cyclophosphamide in man.

    abstract::1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/- 0.24 (s.d.) and showed no time-dependence being rapidly established following intravenous...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Juma FD,Rogers HJ,Trounce JR

    更新日期:1979-11-01 00:00:00

  • Deep vein thrombosis and pulmonary embolism reported in the Prescription Event Monitoring Study of Yasmin.

    abstract:AIM:To evaluate cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) reported in a prescription event monitoring study of Yasmin, an oral contraceptive. METHODS:Reports of DVT/PE and events suggestive of DVT/PE were followed up by questionnaire. RESULTS:Thirteen cases (DVT five; PE eight), each with possib...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Pearce HM,Layton D,Wilton LV,Shakir SA

    更新日期:2005-07-01 00:00:00

  • Integrated semi-physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662.

    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...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Yu H,Steeghs N,Kloth JS,de Wit D,van Hasselt JG,van Erp NP,Beijnen JH,Schellens JH,Mathijssen RH,Huitema AD

    更新日期:2015-05-01 00:00:00

  • Population pharmacokinetic modelling of Emfilermin (recombinant human leukaemia inhibitory factor, r-hLIF) in healthy postmenopausal women and in infertile patients undergoing in vitro fertilization and embryo transfer.

    abstract:AIMS:The aim of this analysis was to develop a population pharmacokinetic model for Emfilermin (recombinant human leukaemia inhibitory factor, r-hLIF) following subcutaneous administration to healthy postmenopausal women and to infertile patients undergoing in vitro fertilization and embryo transfer (IVF-ET). METHODS:...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Goggin T,Nguyen QT,Munafo A

    更新日期:2004-05-01 00:00:00

  • The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function.

    abstract:AIMS:To assess whether hepatic impairment influences the pharmacokinetics of ziprasidone. METHODS:Thirty subjects with normal hepatic function or a primary diagnosis of clinically significant cirrhosis (Child-Pugh A or B) were enrolled into an open-label, multicentre, multiple-dose study. The subjects with chronic, st...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,多中心研究


    authors: Everson G,Lasseter KC,Anderson KE,Bauer LA,Carithens RL Jr,Wilner KD,Johnson A,Anziano RJ,Smolarek TA,Turncliff RZ

    更新日期:2000-01-01 00:00:00

  • Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity.

    abstract:AIMS:To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. METHODS:All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Isbister GK,Hackett LP,Dawson AH,Whyte IM,Smith AJ

    更新日期:2003-10-01 00:00:00

  • Pharmacist-led, video-stimulated feedback to reduce prescribing errors in doctors-in-training: A mixed methods evaluation.

    abstract:AIMS:To develop and evaluate a feasible, authentic pharmacist-led prescribing feedback intervention for doctors-in-training, to reduce prescribing errors. METHODS:This was a mixed methods study. Sixteen postgraduate doctors-in training, rotating though the surgical assessment unit of 1 UK hospital, were filmed taking ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Parker H,Farrell O,Bethune R,Hodgetts A,Mattick K

    更新日期:2019-10-01 00:00:00

  • Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy.

    abstract:AIMS:6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharma...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Adam de Beaumais T,Fakhoury M,Medard Y,Azougagh S,Zhang D,Yakouben K,Jacqz-Aigrain E

    更新日期:2011-04-01 00:00:00

  • Population pharmacokinetic study of gentamicin in a large cohort of premature and term neonates.

    abstract:AIM:This study aims to investigate the clinical and demographic factors influencing gentamicin pharmacokinetics in a large cohort of unselected premature and term newborns and to evaluate optimal regimens in this population. METHODS:All gentamicin concentration data, along with clinical and demographic characteristics...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Fuchs A,Guidi M,Giannoni E,Werner D,Buclin T,Widmer N,Csajka C

    更新日期:2014-11-01 00:00:00

  • Effects, side effects and plasma concentrations of terbutaline in adult asthmatics after inhaling from a dry powder inhaler device at different inhalation flows and volumes.

    abstract::1. The efficacy of a metered dose inhaler (MDI) is highly dependent on the mode of inhalation. The relatively high built-in resistance in the Turbohaler (TBH), a new dry powder inhaler device for inhalation of terbutaline sulphate and budesonide, reduces the flow during inhalation. We compared five different modes of ...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Engel T,Scharling B,Skovsted B,Heinig JH

    更新日期:1992-04-01 00:00:00

  • The psychopharmacological and electrophysiological effects of single doses of caffeine in healthy human subjects.

    abstract::The effects of single doses of anhydrous caffeine (250 mg and 500 mg) and placebo on physiological, psychological measures and subjective feelings were studied in a double-blind, cross-over study in nine healthy subjects who had abstained from caffeine-containing beverages for 24 h before each occasion. Caffeine and c...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Bruce M,Scott N,Lader M,Marks V

    更新日期:1986-07-01 00:00:00

  • Sources of variability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine, and cigarette smoking.

    abstract:AIMS:Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individu...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Benowitz NL,Zevin S,Jacob P 3rd

    更新日期:1997-03-01 00:00:00

  • Pharmacokinetic and pharmacodynamic interactions between phenprocoumon and atenolol or metoprolol.

    abstract::Pharmacological interactions in both directions between phenprocoumon and atenolol and metoprolol were investigated using a crossover trial. Co-administration of phenprocoumon did not significantly affect Cmax, tmax, t1/2,22, AUC for atenolol or metoprolol. Co-administration of metoprolol, but not atenolol, increased ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Spahn H,Kirch W,Mutschler E,Ohnhaus EE,Kitteringham NR,Lögering HJ,Paar D

    更新日期:1984-01-01 00:00:00

  • Studies with abanoquil (UK-52,046) a novel quinoline alpha 1-adrenoceptor antagonist: II. Duration of action, pharmacokinetics and concentration-effect relationships in normotensive subjects.

    abstract::1. This study further examines the quinoline-derivative abanoquil with particular respect to the duration of its alpha 1-adrenoceptor antagonist activity and its concentration-effect relationship following a single intravenous bolus dose of 0.5 micrograms kg-1 in young, normotensive males. 2. alpha 1-adrenoceptor anta...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Schafers RF,Elliott HL,Meredith PA,Miller SH,Reid JL

    更新日期:1991-11-01 00:00:00

  • Effect of renal function on the pharmacokinetics and pharmacodynamics of trandolapril.

    abstract::1. The pharmacokinetics and pharmacodynamics of a single dose of trandolapril, an angiotensin converting enzyme (ACE) inhibitor with an active metabolite, trandolaprilat, which is in part further metabolised prior to renal elimination, were evaluated in 31 subjects with a wide range of renal function (creatinine clear...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Bevan EG,McInnes GT,Aldigier JC,Conte JJ,Grunfeld JP,Harper SJ,Meyer BH,Pauly N,Wilkinson R

    更新日期:1993-02-01 00:00:00

  • Impact of CYP2D6 on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol.

    abstract:AIMS:To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose-adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a therapeutic drug monitoring (TDM) cohort of psychiatric patients. We also studied the functional impact of CYP2D6*41 on dose-adjusted serum concentration...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Waade RB,Solhaug V,Høiseth G

    更新日期:2020-10-28 00:00:00

  • Nonmedical use of alprazolam in the UK: Results from a nationally representative survey.

    abstract::There is concern in the UK about nonmedical use (NMU) of alprazolam (Xanax). We investigated the epidemiology of alprazolam NMU compared with diazepam using data from the Survey of Non-Medical Use of Prescription Drugs (NMURx) programme (collected 28 September-1 December 2017). The survey included 10 019 respondents a...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Hockenhull J,Amioka E,Black JC,Haynes CM,Dargan PI,Dart RC,Wood DM

    更新日期:2019-08-01 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

  • Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy.

    abstract::WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The population pharmacokinetics and limited sampling strategies for ciclosporin monitoring have been extensively studied in renal and liver transplant recipients. Little is known about the pharmacokinetics of ciclosporin in patients undergoing haematopoietic allogeneic stem c...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Wilhelm AJ,de Graaf P,Veldkamp AI,Janssen JJ,Huijgens PC,Swart EL

    更新日期:2012-04-01 00:00:00

  • The effect of 443C81, a mu opioid receptor agonist, on the response to inhaled capsaicin in healthy volunteers.

    abstract::Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by ...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Choudry NB,Gray SJ,Posner J,Fuller RW

    更新日期:1991-11-01 00:00:00

  • Pupillary response to topical tropicamide as a marker for Alzheimer's disease.

    abstract::The mydriatic response to eyedrops of the anticholinergic drug tropicamide at very low concentration (0.01%) was studied in subjects with Alzheimer's disease (AD, n = 10) and multi-infarct dementia (MID, n = 10). There was no significant difference in pupillary response between the two groups. The test is unlikely to ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Treloar AJ,Assin M,Macdonald AJ

    更新日期:1996-03-01 00:00:00

  • A double-blind multicentre trial comparing mianserin with imipramine.

    abstract::1. Fifty-four depressive in-patients aged 18-45 yr, were treated at random, in double-blind conditions, with mianserin 60 mg daily or imipramine 150 mg daily in three divided doses for 4 weeks. Nitrazepam and diazepam were also allowed if necessary. 2. There was no significant difference in antidepressant efficacy bet...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Pichot P,Dreyfus JF,Pull C

    更新日期:1978-01-01 00:00:00

  • Lacidipine: effects on vascular pressor responses throughout the dosage interval in normotensive subjects.

    abstract:AIMS:To assess the duration and consistency of the pharmacological activity of the dihydropyridine calcium antagonist drug, lacidipine. METHODS:Eight healthy normotensive young males participated in a double-blind randomised crossover comparison of single and multiple doses (for 2 weeks) of lacidipine and placebo. 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: Ueda S,Donnelly R,Panfilov V,Morris AD,Elliott HL

    更新日期:1998-08-01 00:00:00

  • Observations on the relationship between anxiety and depressive symptoms during the course of depressive illnesses.

    abstract::1 Roth et al. (1972) have proposed that within the affective disorders there are two distinct syndromes--anxiety and depression--differentiated by the relative predominance of these symptoms, the presence or absence of premorbid maladaptive traits, and the natural outcome of the disorder. 2 Goldberg (1982) on the othe...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Russell GF,De Silva P

    更新日期:1983-01-01 00:00:00

  • Effect of valpromide on the pharmacokinetics of carbamazepine-10, 11-epoxide.

    abstract::The single oral dose pharmacokinetics of carbamazepine-10, 11-epoxide (CBZ-E) were investigated in six normal volunteers during a control session and during concurrent treatment with valpromide (VPM) (300 mg twice daily for 8 days). VPM caused a prolongation of the CBZ-E half-life from 6.4 +/- 1.4 to 20.5 +/- 6.3 h an...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章


    authors: Pisani F,Fazio A,Oteri G,Spina E,Perucca E,Bertilsson L

    更新日期:1988-05-01 00:00:00

  • Halofantrine pharmacokinetics in Kenyan children with non-severe and severe malaria.

    abstract::1. Kenyan children with uncomplicated malaria given oral halofantrine (HF; non-micronised suspension; 8 mg base kg-1 body weight 6 hourly for three doses) showed wide variation in the disposition of HF and desbutylhalofantrine (HFm). 2. Eight Kenyan children with severe (prostrate) falciparum malaria who were receivin...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章


    authors: Watkins WM,Winstanley PA,Mberu EK,Kokwaro G,Murphy SA,Newton CJ,Mwangi I,Forster D,Marsh K

    更新日期:1995-03-01 00:00:00

  • Effect of candesartan, a type 1 angiotensin II receptor antagonist, on bronchial hyper-responsiveness to methacholine in patients with bronchial asthma.

    abstract:AIMS:Angiotensin II is a putative mediator in bronchial asthma. There have been very few studies investigating the involvement of angiotensin II receptors in bronchial hyper-responsiveness in asthmatic patients. We examined the effect of candesartan cilexetil, a specific angiotensin II type 1 (AT1) receptor antagonist,...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Myou S,Fujimura M,Kamio Y,Kita T,Watanabe K,Ishiura Y,Hashimoto T,Nakao S

    更新日期:2002-12-01 00:00:00