Population pharmacokinetics of naloxegol in a population of 1247 healthy subjects and patients.

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 Pharmacol

authors

Al-Huniti N,Chapel S,Xu H,Bui KH,Sostek M

doi

10.1111/bcp.12756

subject

Has Abstract

pub_date

2016-01-01 00:00:00

pages

89-100

issue

1

eissn

0306-5251

issn

1365-2125

journal_volume

81

pub_type

杂志文章
  • Paracetamol elimination in patients with non-insulin dependent diabetes mellitus.

    abstract::The pharmacokinetics and metabolism of an intravenous dose (500 mg) of paracetamol were studied in a group of non-insulin dependent diabetic patients (n = 10) and in a group of healthy control subjects (n = 9). Paracetamol clearance, half-life and the partial clearance to paracetamol glucuronide were not significantly...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1993.tb05672.x

    authors: Kamali F,Thomas SH,Ferner RE

    更新日期:1993-01-01 00:00:00

  • Antiseizure drugs and risk of developing smoking-related chronic obstructive pulmonary disease or lung cancer: A population-based case-control study.

    abstract:AIMS:To determine whether enzyme-inducing antiseizure drugs (ASDs) affect the risk of developing chronic obstructive pulmonary disease (COPD) or lung cancer in smokers. METHODS:Cases of COPD and lung cancer and matched controls without these conditions were identified from a population of smokers with ≥1 prescription ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/bcp.14501

    authors: Leuppi-Taegtmeyer AB,Reinau D,Yilmaz S,Rüegg S,Krähenbühl S,Jick SS,Leuppi JD,Meier CR

    更新日期:2020-08-01 00:00:00

  • Reporting rate of adverse drug reactions to the French pharmacovigilance system with three step 2 analgesic drugs: dextropropoxyphene, tramadol and codeine (in combination with paracetamol).

    abstract:AIMS:Three 'weak' opioid analgesics in association with paracetamol are marketed in France as step 2 analgesics: dextropropoxyphene, tramadol and codeine. These combinations are involved in several adverse drug reactions (ADRs), but no data are available about their comparative reporting rate. The aim was to compare th...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.2009.03472.x

    authors: Tavassoli N,Lapeyre-Mestre M,Sommet A,Montastruc JL,French Association of Regional Pharmacovigilance Centres.

    更新日期:2009-09-01 00:00:00

  • The effect on paracetamol absorption of stimulation and blockade of beta-adrenoceptors.

    abstract::1 The effect of drugs acting on beta-adrenoceptors on the absorption and excretion of paracetamol was studied in 26 volunteers and nine patients with mild hypertension, each subject acting as his/her own control. 2 Isoprenaline given 30 min before paracetamol significantly slowed absorption, the effect being dose rela...

    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.tb00510.x

    authors: Clark RA,Holdsworth CD,Rees MR,Howlett PJ

    更新日期:1980-12-01 00:00:00

  • Pharmacokinetics of physostigmine in man following a single application of a transdermal system.

    abstract::1. The pharmacokinetics of physostigmine were investigated in a three-way cross-over design in six healthy, male volunteers comparing a physostigmine transdermal system (PTS), an oral solution and an i.v. infusion. 2. A single application of the patch over 24 h produced detectable plasma drug concentrations after a 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.1365-2125.1995.tb04410.x

    authors: Walter K,Müller M,Barkworth MF,Nieciecki AV,Stanislaus F

    更新日期:1995-01-01 00:00:00

  • The contribution of genetically determined oxidation status to inter-individual variation in phenacetin disposition.

    abstract::The oxidative O-de-ethylation and aromatic 2-hydroxylation of phenacetin have been investigated in panels of extensive (EM, n = 13) and poor (PM, n = 10) metabolizers of debrisoquine. The EM group excreted in the urine significantly more paracetamol (EM: 40.8 +/- 14.9% dose/0-8 h; PM: 29.2 +/- 8.7% dose/0-8 h, 2P less...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1983.tb04980.x

    authors: Devonshire HW,Kong I,Cooper M,Sloan TP,Idle JR,Smith RL

    更新日期:1983-08-01 00:00:00

  • Effects of locally administered anticholinesterase agents on the secretory response of human eccrine sweat glands to acetylcholine and carbachol.

    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

    authors: Longmore J,Jani B,Bradshaw CM,Szabadi E

    更新日期:1986-02-01 00:00:00

  • A comparison of the clinical and bronchodilating effects of plain and slow-release tablets of terbutaline at steady state.

    abstract::The clinical efficacy, the bronchodilating effect and the side effects of two oral forms of terbutaline were compared in a double-blind, cross-over study involving ten patients with chronic reversible airways obstruction. The administration of plain-tablets, containing 2.5 mg terbutaline sulphate, three times daily at...

    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.tb05178.x

    authors: Pauwels R,Elinck W,Lamont H,van der Straeten M,Ljungholm K

    更新日期:1986-02-01 00:00:00

  • Topical minoxidil: cardiac effects in bald man.

    abstract::Systemic cardiovascular effects during chronic treatment with topical minoxidil vs placebo were evaluated using a double-blind, randomized design for two parallel groups (n = 20 for minoxidil, n = 15 for placebo). During 6 months of follow-up, blood pressure did not change, whereas minoxidil increased heart rate by 3-...

    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.tb03410.x

    authors: Leenen FH,Smith DL,Unger WP

    更新日期:1988-10-01 00:00:00

  • A double-blind crossover comparison of pindolol, metoprolol, atenolol and labetalol in mild to moderate hypertension.

    abstract::1 This study was designed to compare in a double-blind randomized crossover trial, atenolol, labetalol, metoprolol and pindolol. Considerable differences in dose (atenolol 138 +/- 13 mg daily; labetalol 308 +/- 34 mg daily; metoprolol 234 +/- 22 mg daily; and pindolol 24 +/-2 mg daily were required to produce similar ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1979.tb04774.x

    authors: McNeil JJ,Louis WJ

    更新日期:1979-04-01 00:00:00

  • Junior doctor-led 'near-peer' prescribing education for medical students.

    abstract:AIMS:Prescribing errors are common and inadequate preparation of prescribers appears to contribute. A junior doctor-led prescribing tutorial programme has been developed for Edinburgh final year medical students to increase exposure to common prescribing tasks. The aim of this study was to assess the impact of these tu...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/bcp.12147

    authors: Gibson KR,Qureshi ZU,Ross MT,Maxwell SR

    更新日期:2014-01-01 00:00:00

  • Lithium does not alter the renal response to a pressor dose of tyramine in man.

    abstract::Renal clearance of lithium has been used as a marker of proximal tubular function in man. Recently, lithium pre-treatment has been shown to interfere with the natriuretic actions of some natriuretic agents in man. We have therefore investigated the effects of oral lithium carbonate (500 mg) on the natriuretic response...

    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.tb05598.x

    authors: Lang CC,Rahman AR,Struthers AD

    更新日期:1991-06-01 00:00:00

  • Acute hypotensive effect of captopril in man modified by prostaglandin synthesis inhibition.

    abstract::1 A study was carried out to investigate the possible contribution of prostaglandins in captopril-induced hypotension. 2 Healthy volunteers and patients with essential hypertension were given single oral doses of 25 mg and 50 mg captopril respectively before and after cyclo-oxygenase inhibition with indomethacin. 3 Th...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1982.tb02063.x

    authors: Silberbauer K,Stanek B,Templ H

    更新日期:1982-01-01 00:00:00

  • Effect of midazolam on sleep of insomniacs.

    abstract::We studied in a sleep laboratory the effects of bedtime 15 mg midazolam and 20 mg midazolam on the sleep and morning performance of healthy subjects with polygraphically verified sleep onset insomnia. Six subjects received 15 mg midazolam and six subjects received 20 mg midazolam for 14 consecutive nights which were p...

    journal_title:British journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1111/j.1365-2125.1983.tb02279.x

    authors: Vogel GW,Vogel F

    更新日期:1983-01-01 00:00:00

  • The nasal airways response in normal subjects to oxymetazoline spray: randomized double-blind placebo-controlled trial.

    abstract:AIMS:The effects of a single dose of oxymetazoline nasal spray on nasal patency have been compared with placebo using three separate measuring systems in normal subjects. METHODS:The study was a placebo-controlled, randomised double-blind crossover trial. Subjects without ear, nose or throat disease and with resting n...

    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.1365-2125.1999.00972.x

    authors: Bickford L,Shakib S,Taverner D

    更新日期:1999-07-01 00:00:00

  • Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders.

    abstract::Obesity is a major cause of morbidity and mortality through cardio- and cerebrovascular diseases and cancer. The metabolic consequences of obesity include dyslipidaemia, hypertension, proinflammatory atherogenesis, pre-diabetes and Type 2 diabetes. For a significant proportion of patients, pharmacotherapy to tackle ob...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.2009.03549.x

    authors: Heal DJ,Gosden J,Smith SL

    更新日期:2009-12-01 00:00:00

  • Effects of the nitric oxide synthase inhibitor ronopterin (VAS203) on renal function in healthy volunteers.

    abstract:AIMS:Reduced nitric oxide (NO) availability may adversely affect renal perfusion and glomerular filtration. The aim of the present study was to characterize in detail the pharmacological effects of VAS203, an inhibitor of NO synthase, on renal haemodynamics in humans. METHODS:This double-blind, randomized, placebo-con...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1111/bcp.13870

    authors: Ott C,Bosch A,Winzer N,Friedrich S,Schinzel R,Tegtmeier F,Schmieder RE

    更新日期:2019-05-01 00:00:00

  • Estimation of regional metabolism and production of angiotensins in hypertensive subjects.

    abstract::1. We attempted to collect information on the metabolism and production of angiotensins (ANG) in different vascular beds in humans by constant i.v. infusion of mono-iodinated [125I]-ANG I into subjects with essential hypertension, at the time of renal vein catheterization as part of the diagnostic work-up for renovasc...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1989.tb03586.x

    authors: Schalekamp MA,Admiraal PJ,Derkx FH

    更新日期:1989-01-01 00:00:00

  • Single and short-term dosing effects of levocetirizine on adenosine monophosphate bronchoprovocation in atopic asthma.

    abstract:AIMS:Adenosine monophosphate (AMP) acts indirectly via primed airway mast cells to induce bronchial hyper-responsiveness, which in turn correlates with eosinophilic asthmatic inflammation and atopic disease expression. We evaluated single and short-term dosing effects of a modern histamine H1-receptor antagonist, levoc...

    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.1365-2125.2004.02110.x

    authors: Lee DK,Gray RD,Wilson AM,Robb FM,Soutar PC,Lipworth BJ

    更新日期:2004-07-01 00:00:00

  • Influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients.

    abstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:Recent studies on pharmacogenetics of warfarin have implicated apolipoprotein E (APOE) polymorphisms to influence the vitamin K dependent coagulation cascade and hence the efficacy of warfarin. Studies among Caucasian and African Americans showed a significant but conflicting ro...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.2007.03053.x

    authors: Lal S,Sandanaraj E,Jada SR,Kong MC,Lee LH,Goh BC,Lee SC,Chowbay B

    更新日期:2008-02-01 00:00:00

  • Interaction of clopidogrel and statins in secondary prevention after cerebral ischaemia - a randomized, double-blind, double-dummy crossover study.

    abstract:AIMS:Variability in responsiveness to clopidogrel is a clinical problem in secondary prevention after cerebral ischaemia which has been suggested to be linked to competitive metabolization of clopidogrel and cytochrome P450 (CYP) 3A4-oxidated statins such as simvastatin. We assessed the hypothesis that simvastatin, in ...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1111/bcp.12416

    authors: Siepmann T,Heinke D,Kepplinger J,Barlinn K,Gehrisch S,Grählert X,Schwanebeck U,Reichmann H,Puetz V,Bodechtel U,Gahn G

    更新日期:2014-11-01 00:00:00

  • Potential impact of cytochrome P450 3A5 in human liver on drug interactions with triazoles.

    abstract::Cytochrome P450 3A is the main enzyme subfamily involved in the metabolism of a variety of marketed medicines. It is generally believed that the substrate specificity of polymorphic P450 3A5 is similar to that of the predominant P450 3A4 isoform, although some differences in catalytic properties have been found. It ha...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.2010.03656.x

    authors: Yamazaki H,Nakamoto M,Shimizu M,Murayama N,Niwa T

    更新日期:2010-06-01 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

    doi:10.1046/j.1365-2125.1999.00094.x

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

    更新日期:1999-12-01 00:00:00

  • Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.

    abstract:AIM:We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different. METHODS:A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concen...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章,随机对照试验

    doi:10.1111/bcp.12684

    authors: Morganroth J,Wang Y,Thorn M,Kumagai Y,Harris S,Stockbridge N,Kleiman R,Shah R

    更新日期:2015-09-01 00:00:00

  • The antihypertensive efficacy and tolerability of a low dose combination of ramipril and felodipine ER in mild to moderate essential hypertension.

    abstract::1. The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril (2.5 mg) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine (5 mg) were assessed in a double-blind, double dummy placebo controlled, randomi...

    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.1365-2125.1993.tb00371.x

    authors: Bainbridge AD,Macfadyen RJ,Stark S,Lees KR,Reid JL

    更新日期:1993-10-01 00:00:00

  • The effect of food and bile acid administration on the relative bioavailability of cyclosporin.

    abstract::1. The relative bioavailability of cyclosporin was studied in 11 healthy volunteers after single oral capsule doses of cyclosporin on three separate occasions; fasting, with breakfast and with breakfast together with bile acid tablets (400 mg of cholic acid and 100 mg of dehydrocholic acid). 2. There was a significant...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/j.1365-2125.1990.tb03677.x

    authors: Lindholm A,Henricsson S,Dahlqvist R

    更新日期:1990-05-01 00:00:00

  • Unwarranted claims of drug efficacy in pharmaceutical sales visits: are drugs approved on the basis of surrogate outcomes promoted appropriately?

    abstract:AIMS:This study compares physicians' recall of the claims of benefits on cardiovascular disease and diabetes made by pharmaceutical sales representatives for drugs approved on the basis of a surrogate outcome, i.e., an off-label claim, compared with those approved on the basis of a serious morbidity or mortality (clini...

    journal_title:British journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1111/bcp.13360

    authors: Habibi R,Lexchin J,Mintzes B,Holbrook A

    更新日期:2017-11-01 00:00:00

  • The effects of propranolol and digoxin on the acute vascular responses to frusemide in normal man.

    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

    authors: Johnston GD,O'Connor PC,Nicholls DP,Leahey WJ,Finch MB

    更新日期:1985-04-01 00:00:00

  • Comparison of neurokinin A and substance P on cardiovascular and airway function in man.

    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

    authors: Evans TW,Dixon CM,Clarke B,Conradson TB,Barnes PJ

    更新日期:1988-02-01 00:00:00

  • Influence of basal nitric oxide secretion on cardiac function in man.

    abstract::1. Nitric oxide is recognised as an important biological mediator, which is thought to be involved in cardiovascular homeostasis. The purpose of this study was to investigate the effects of basal nitric oxide synthesis on cardiac function in man, by blocking nitric oxide synthesis with NG-monomethyl-L-arginine (L-NMMA...

    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.tb04550.x

    authors: Clarkson PB,Lim PO,MacDonald TM

    更新日期:1995-10-01 00:00:00