Abstract:
AIMS:Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in clinical development for treatment of opioid-induced constipation (OIC). The aim of the study was to develop a population pharmacokinetic model describing the concentration vs. time profile of orally administered naloxegol, and determine the impact of pre-specified demographic and clinical factors and concomitant medication on population estimates of apparent clearance (CL/F) and apparent central compartment volume of distribution (Vc /F). METHODS:Analysis included 12,844 naloxegol plasma concentrations obtained from 1247 healthy subjects, patients with non-OIC and patients with OIC in 14 phase 1, 2b and 3 clinical studies. Pharmacokinetic analysis used the non-linear mixed effects modelling program. Goodness of fit plots and posterior predictive checks were conducted to confirm concordance with observed data. RESULTS:The final model was a two compartment disposition model with dual absorptions, comprising one first order absorption (ka1 4.56 h(-1) ) and one more complex absorption with a transit compartment (ktr 2.78 h(-1) ). Mean (SE) parameter estimates for CL/F and Vc /F, the parameters assessed for covariate effects, were 115 (3.41) l h(-1) and 160 (27.4) l, respectively. Inter-individual variability was 48% and 51%, respectively. Phase of study, gender, race, concomitant strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers, P-glycoprotein inhibitors or inducers, naloxegol formulation, baseline creatinine clearance and baseline opioid dose had a significant effect on at least one pharmacokinetic parameter. Simulations indicated concomitant strong CYP3A4 inhibitors or inducers had relevant effects on naloxegol exposure. CONCLUSIONS:Administration of strong CYP3A4 inhibitors or inducers had a clinically relevant influence on naloxegol pharmacokinetics.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Al-Huniti N,Chapel S,Xu H,Bui KH,Sostek Mdoi
10.1111/bcp.12756subject
Has Abstractpub_date
2016-01-01 00:00:00pages
89-100issue
1eissn
0306-5251issn
1365-2125journal_volume
81pub_type
杂志文章abstract::1 To assess the potential hazards of nitrazepam therapy of insomnia in the elderly, adverse reactions to nitrazepam were studied in 2111 hospitalized medical patients who received the drug. 2 Manifestations of unwanted central nervous system (CNS) depression (such as drowsiness or 'hangover') were reported in 49 nitra...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1978.tb01646.x
更新日期:1978-05-01 00:00:00
abstract:AIMS:To characterize the pharmacokinetics (PK) of moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, in adults with relapsed or refractory hairy cell leukaemia, we examined data from a phase 1 study (Study 1001; n = 49) and from the pivotal clinical study (Study 1053; n = 74). METHODS:Data from both studies ...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.14250
更新日期:2020-07-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.12130
更新日期:2013-12-01 00:00:00
abstract:AIMS:Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CY...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1046/j.1365-2125.1998.00048.x
更新日期:1998-07-01 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::The airway and cardiovascular effects of intravenous neurokinin A (NKA) and substance P (SP) were compared in six normal subjects. Both SP and NKA increased skin temperature (SkT) and heart rate (HR), but SP was more potent than NKA by factors of 6 and 20 respectively. No change in systolic blood pressure (BP) occurre...
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.1365-2125.1988.tb03302.x
更新日期:1988-02-01 00:00:00
abstract::The effect of charcoal-drug ratio on the antidotal efficacy of oral activated charcoal was studied in six healthy volunteers in a randomized cross-over study and compared with the adsorption capacity of activated charcoal in vitro. Aminosalicylic acid (PAS) 1 g and 5 g were ingested on an empty stomach in 30 ml of wat...
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.1365-2125.1985.tb02712.x
更新日期:1985-06-01 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::1. The inhibitory effect of sufotidine, a new histamine H2-receptor antagonist, on gastric secretion of acid and pepsin was studied in six healthy male volunteers. This was a three-way, cross-over, randomized, double-blind study. On each of 3 study days, the drug in a dose of 600 mg, or placebo, was administered eithe...
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.tb03519.x
更新日期:1989-10-01 00:00:00
abstract::1 Self-poisoning with a selective weedkiller containing 2,4-D and mecoprop in a 39 year old man resulted in prolonged deep coma, pyrexia, hyperventilation, hypoxaemia, myotonia, skeletal muscle damage and electrocardiographic changes consistent with cardiomyopathy. 2 The admission plasma concentrations of 2,4-D and me...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1979.tb00906.x
更新日期:1979-01-01 00:00:00
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...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1111/j.1365-2125.2004.02177.x
更新日期:2004-10-01 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:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:• Clinical cases reported that fatal acute liver failure occurred when paracetamol (acetaminophen) was co-administrated with some tyrosine kinase inhibitors (TKIs). The direct inhibition of UDP-glucuronosyltransferase activities has been identified as a mechanism of potentiation...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2011.03911.x
更新日期:2011-06-01 00:00:00
abstract:AIMS:To evaluate the effect of a 3-day regimen of ibuprofen 600 mg x 4 on acute postoperative swelling and pain and other inflammatory events after third molar surgery compared with a traditional regimen of paracetamol 1000 mg x 4. METHODS:A controlled, randomized, double-blind, cross-over study where 36 patients (26 ...
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.1365-2125.2003.01779.x
更新日期:2003-04-01 00:00:00
abstract:AIM:In short-term studies, hormonal contraceptives (HC) have been suggested to induce a rise in blood pressure (BP) and urinary albumin excretion (UAE), while the effect of HC in renal function (GFR) is still under debate. Data on long-term and withdrawal effects of HC use on these outcomes are, however, not available....
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.2006.02747.x
更新日期:2007-02-01 00:00:00
abstract::The coming of age of molecular biology has resulted in an explosion in our understanding of the pathogenesis of virus related diseases. New pathogens have been identified and characterized as being responsible for old diseases. Empirical clinical evaluation of morbidity and mortality as outcome measures after a therap...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1046/j.1365-2125.2002.01623.x
更新日期:2002-07-01 00:00:00
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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.tb03966.x
更新日期:1991-11-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1979.tb04718.x
更新日期:1979-10-01 00:00:00
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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::1. The efficacy of felodipine a new calcium channel blocker with selective vasodilator activity in the management of severe low output cardiac failure, secondary to coronary heart disease, was determined in 10 patients. 2. Haemodynamic measurements were made at rest and during dynamic exercise and left ventricular fun...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/j.1365-2125.1988.tb05254.x
更新日期:1988-06-01 00:00:00
abstract::1. Ten healthy subjects received two treatments: a single 1 g oral dose of nalidixic acid (NA) followed 1 h later by either an infinitesimal dilution of the drug (NA 7CH) or by succussed water which served as placebo. The study was repeated 18 months later in 10 different subjects. 2. A further 10 healthy subjects rec...
journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/j.1365-2125.1991.tb05610.x
更新日期:1991-07-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1046/j.1365-2125.1999.00068.x
更新日期:1999-11-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1111/bcp.13133
更新日期:2017-03-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1111/bcp.12101
更新日期:2013-11-01 00:00:00
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/j.1365-2125.2007.02990.x
更新日期:2008-01-01 00:00:00
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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.1365-2125.1984.tb02356.x
更新日期:1984-03-01 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
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journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2125.2012.04317.x
更新日期:2013-01-01 00:00:00
abstract::1 A new osmotic pressure mediated delivery system for metoprolol (Lopresor Oros) has been evaluated by measuring the haemodynamic effects and pharmacokinetics after single and multiple oral dosing in young healthy volunteers. 2 Similar studies have been carried out in the same group using equivalent single and multipl...
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.1365-2125.1982.tb01391.x
更新日期:1982-03-01 00:00:00
abstract:AIMS:Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this tri...
journal_title:British journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1111/bcp.13609
更新日期:2018-09-01 00:00:00