Abstract:
AIMS:(i) To model the effects of the monoclonal antibody ATM-027 on the number of target cells and on the receptor density on the cell surface as measured by Fluorescence Activated Cell Sorter analysis, (ii) to investigate the effects of categorizing a continuous scale, and (iii) to simulate a phase II trial from phase I data in order to evaluate the predictive performance of the model by comparison with the actual trial results. METHODS:Based on the data from one phase I and one phase II study in multiple sclerosis (MS) patients, models were developed to characterize the pharmacokinetics and pharmacodynamics of the monoclonal antibody ATM-027 and its effects on Vbeta5.2/5.3+ T cells. The pharmacodynamic variables were the number of target T cells and the expression of its receptor. The latter was modelled in both a categorical and continuous way. The modelling was performed with a nonlinear mixed effects approach using the software NONMEM. The joint continuous models were used to simulate the phase II trial from the phase I data. RESULTS:The pharmacokinetics of ATM-027 were characterized by a two-compartment model with a total volume of distribution of 5.9 litres and a terminal half-life of 22.3 days (phase II parameter estimates) in the typical patient. Continuous receptor expression was modelled using an inhibitory sigmoidal Emax-model. Similar results from the phase I and phase II data were obtained, and EC50 was estimated to be 138 and 148 microg litre(-1), respectively. Categorical receptor expression was modelled using a proportional odds model, and the EC50 values obtained were highly correlated with those from the continuous model. The numbers of target T cells were also modelled and treatment with ATM-027 decreased the number of cells to 25.7% and 28.9% of their baseline values in the phase I and II trials, respectively. EC50s for the decrease in the number of T cells were 83 microg litre(-1) and 307 microg litre(-1), respectively. Simulations of the phase II trial from the phase I models gave good predictions of the dosing regimens administered in the phase II study. CONCLUSION:All aspects of effects of the monoclonal antibody ATM-027 on Vbeta5.2/5.3+ T cells were modelled and the phase II trial was simulated from phase I data. The effects of categorizing a continuous scale were also evaluated.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Zingmark PH,Edenius C,Karlsson MOdoi
10.1111/j.1365-2125.2004.02177.xkeywords:
subject
Has Abstractpub_date
2004-10-01 00:00:00pages
378-89issue
4eissn
0306-5251issn
1365-2125pii
BCP2177journal_volume
58pub_type
临床试验,杂志文章,多中心研究,随机对照试验abstract:AIMS:Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon but potentially debilitating condition, characterised by nonhealing jawbone, with or without mucosal exposure, in the presence of certain drugs. Those already strongly associated with MRONJ include antiresorptives denosumab and bisphosphonates; how...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14681
更新日期:2020-11-27 00:00:00
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
doi:10.1111/j.1365-2125.1983.tb01561.x
更新日期:1983-06-01 00:00:00
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
doi:10.1046/j.1365-2125.1999.00862.x
更新日期:1999-02-01 00:00:00
abstract:AIMS:Carbamazepine (CBZ) is an inducer of cytochrome P450 enzymes, which have been implicated in many drug interactions. However, for immunosuppressant and anti-HIV drugs, whose main site of action is the lymphocyte, induction of P-glycoprotein (Pgp) may also be important. In this study, we have investigated whether CB...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2006.02587.x
更新日期:2006-08-01 00:00:00
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
doi:10.1111/j.1365-2125.2005.02373.x
更新日期:2005-07-01 00:00:00
abstract:AIMS:To evaluate the electroencephalographic (EEG) effects, blood concentrations, vehicle irritation and dose-effect relationships for diazepam administered nasally. METHODS:The study had a cross-over design with eight healthy volunteers (one drop out). It consisted of four legs with four different administrations: 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:10.1046/j.0306-5251.2001.01486.x
更新日期:2001-11-01 00:00:00
abstract::After many years of basic research we have now begun to learn how to manipulate the serotonergic mechanisms within the gut. This has lead to a number of significant advances including 5HT3 antagonists for the treatment of functional diarrhoea, 5HT4 agonists for the treatment of constipation and 5HT1 agonists for the t...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1046/j.1365-2125.2002.01612.x
更新日期:2002-07-01 00:00:00
abstract::Monohydroxy acids (HETEs) and leukotriene B4 (LTB4) metabolites of arachidonic acid were measured in skin of healthy volunteers after ultraviolet B irradiation, and in the uninvolved skin of psoriatics after topical dithranol application. Exudate was collected from suction bullae on control and inflamed abdominal skin...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1985.tb05059.x
更新日期:1985-09-01 00:00:00
abstract:AIMS:Voriconazole is a novel triazole with broad-spectrum antifungal activity. It is likely that some patients receiving voriconazole may also require treatment with the anticoagulant warfarin. Cytochrome P450 isoenzymes are important in the metabolism of both these drugs. This study investigated the effect of voricona...
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.1365-2125.2003.01995.x
更新日期:2003-12-01 00:00:00
abstract::1. The attitudes of general practitioners and hospital physicians to the management of hypertension in the elderly, were examined by responses to a postal questionnaire distributed within the Northern Region, concerning the management of a healthy 75 year old male non-smoker with sustained diastolic or isolated systol...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1995.tb04481.x
更新日期:1995-05-01 00:00:00
abstract::To examine the importance of acute frusemide-induced renin release in the production of the acute peripheral venous and arterial responses to frusemide in man, the effects of two drugs, previously described as inhibitors of acute frusemide-induced renin release, propranolol and digoxin, were examined. Propranolol abol...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1985.tb02664.x
更新日期:1985-04-01 00:00:00
abstract:AIM:Experimental pain models may help to evaluate the mechanisms of analgesics and target the clinical indications for their use. This review, the second in a series of two, addresses how the efficacy of non-opioid analgesics have been assessed in human volunteers using experimental pain models. METHODS:A literature s...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2125.2009.03433.x
更新日期:2009-09-01 00:00:00
abstract::1 A method for the assay of debrisoquine 4-hydroxylase activity in vitro by microsomal fractions of human liver is described. The assay utilises gas chromatography-mass spectrometry with d9-4-hydroxydebrisoquine as internal standard. 2 The limit of detection of 4-hydroxydebrisoquine was 2 ng ml -1 and the coefficient ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1982.tb01430.x
更新日期:1982-05-01 00:00:00
abstract:AIMS:The aim of this study was to use data from an experimental induced blood stage malaria clinical trial to characterize the antimalarial activity of the new compound Actelion-451840 using pharmacokinetic/pharmacodynamic (PK/PD) modelling. Then, using simulations from the model, the dose and dosing regimen necessary ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.12962
更新日期:2016-08-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14468
更新日期:2020-07-08 00:00:00
abstract::The binding of carbamazepine and carbamazepine 10,11-epoxide to serum, albumin and alpha 1-acid glycoprotein (AAG) was determined and compared at drug concentrations ranging from 0.5 to 400 mg/l using equilibrium dialysis and liquid chromatography. The total binding of carbamazepine in serum was determined primarily b...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1984.tb02496.x
更新日期:1984-10-01 00:00:00
abstract::1. Six healthy male human volunteers of mean age 30.8 years (range 23-37) were given single oral doses of xamoterol (20, 50, 100 or 250 mg) and placebo with a 1 week interval between each dose. Xamoterol produced a significant decrease in systolic time intervals (QS2I, LVETI and PEPI) and a significant increase in sys...
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.tb03663.x
更新日期:1990-04-01 00:00:00
abstract::Exposure-response (ER) analysis has emerged as an important tool to interpret QT data from thorough QT (TQT) studies and allows the prediction of effects in the targeted patient population. Recently, ER analysis has also been applied to data from early clinical pharmacology studies, such as single and multiple ascendi...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bcp.12068
更新日期:2013-11-01 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::The effects of locally administered physostigmine and di-isopropylphosphorofluoridate (DFP) were compared on the secretory response of sweat glands to intradermally injected acetylcholine and carbachol in healthy male volunteers (physostigmine: six subjects; DFP: one subject). The response to acetylcholine reached its...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1986.tb05166.x
更新日期:1986-02-01 00:00:00
abstract::1 The inotropic effect of penbutolol, a new beta-adrenergic receptor blocking drug, has been compared with that of propranolol in two similar groups of six subjects each. 2 Inotropic changes were assessed from changes in myocardial contractility index [LV dp-dt/11 T] as well as the slope of the regression line relatin...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1978.tb00875.x
更新日期:1978-12-01 00:00:00
abstract:AIMS:New preventative strategies for stroke are required. One promising strategy is uric acid reduction and xanthine oxidase inhibition with allopurinol. We sought to investigate whether allopurinol improves cerebrovascular reactivity (CVR) following subcortical stroke. METHODS:We performed a randomized, double-blind,...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/j.1365-2125.2009.03497.x
更新日期:2009-11-01 00:00:00
abstract::1. Dose response relationships for salbutamol and a new bronchodilator drug NAB 365 have been obtained in patients with reversible airways obstruction. These show that the latter is about one hundred times more potent than the former. 2. NAB 365 has a very long half-life. The implications of this are discussed. ...
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.1365-2125.1977.tb00669.x
更新日期:1977-02-01 00:00:00
abstract::The pharmacokinetics of intravenous and oral propranolol have been compared in six obese and six normal subjects matched for age and sex. After intravenous administration there was no difference in plasma clearance but the volume of distribution was greater (V = 339 l vs 198 l) and the half-life was longer (t1/2 = 5.0...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1986.tb02837.x
更新日期:1986-05-01 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:AIMS:Potassium channel openers (KCOs) are of potential therapeutic value. Little is known about the effect of these drugs on human conduit arteries used as coronary bypass grafts. The purpose of this study was to determine the effect of the KCO aprikalim (RP52891) on human arteries used as coronary bypass grafts with e...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.1997.00640.x
更新日期:1997-10-01 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::1. The pharmacokinetics and tolerability of a new nonsteroidal anti-inflammatory drug (NSAID), meloxicam, administered i.m., were investigated in two studies conducted in healthy male volunteers. Study 1 was an open, placebo-controlled design in which 32 volunteers were randomized to a single ascending i.m. dose of me...
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.1365-2125.1996.tb00171.x
更新日期:1996-02-01 00:00:00
abstract::A double-blind controlled study comparing the effects of intravenous Diazemuls (0.15 mg kg-1) with midazolam (0.07 mg kg-1) in patients with normal liver function and with cirrhosis and portal hypertension is described. The clinical effect of the two drugs was assessed by serial tests of psychomotor function before an...
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.1365-2125.1986.tb02952.x
更新日期:1986-12-01 00:00:00
abstract::Both the acute blood pressure lowering and renal effects of the calcium antagonist nicardipine and those after 1 week's treatment were investigated in 10 normotensive volunteers and in 10 patients with mild to moderate essential hypertension. After 1 week of placebo, nicardipine was administered orally for 1 week (20 ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1984.tb05022.x
更新日期:1984-07-01 00:00:00