Abstract：
:Necitumumab is a second-generation, recombinant, human immunoglobulin G1, epidermal growth factor (EGFR) receptor antibody that specifically blocks the ligand binding site of EGFR. Necitumumab potentially acts by blocking ligand epidermal growth factor (EGF) binding-mediated activation of the EGFR signaling pathway, inhibiting tumor growth, angiogenesis, and anti-apoptotic mechanisms. Necitumumab inhibited the interaction of EGF and EGFR with a concentration that inhibits binding by 50 % of approximately 0.9 nM (0.13 mg/L) and demonstrated antitumor activity during in vivo experiments associated with trough plasma concentrations of approximately 40 mg/L. This work describes the population pharmacokinetics of necitumumab in cancer patients when administered with or without concomitant chemotherapy and evaluates patient characteristics that may guide dosing. Nonlinear mixed-effects modeling of serum concentration data across five clinical studies (phases I-III) indicated that necitumumab exhibited target-mediated drug disposition, commonly observed with monoclonal antibodies, and that pharmacokinetics were expected to be linear in the studied dose ranges when administered as repeated infusions. No age, sex, race, or concomitant medication factors were found influential, while weight was a statistically significant factor for both distribution and elimination. Simulations from the final model indicated that only a limited reduction in patient drug exposure variability would be achieved by weight- or body surface area-based dosing. Necitumumab effective half-life was estimated to approximately 2 weeks, and steady state was achieved within three to four cycles of treatment. The phase III dosing schedule of 800 mg dosed on days 1 and 8 of a 21-day schedule resulted in serum concentrations that exceeded the 40-mg/L threshold indicated by preclinical experiments.
journal_name
Clin Pharmacokinetjournal_title
Clinical pharmacokineticsauthors
Long A,Chigutsa E,Wallin Jdoi
10.1007/s40262-016-0452-xsubject
Has Abstractpub_date
2017-05-01 00:00:00pages
505-514issue
5eissn
0312-5963issn
1179-1926pii
10.1007/s40262-016-0452-xjournal_volume
56pub_type
杂志文章abstract：BACKGROUND AND OBJECTIVES:Imeglimin (IMEG) is the first in a novel class of oral glucose-lowering agents with a unique mechanism of action targeting mitochondrial bioenergetics. We assessed whether repeated co-administration of IMEG and either metformin (MET) or sitagliptin (SITA) would influence the pharmacokinetics o...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.1007/s40262-020-00886-y
更新日期：2020-10-01 00:00:00
abstract：BACKGROUND:Entecavir is an orally administered guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase, which is approved for the treatment of chronic hepatitis B (CHB) infection in adults and children ≥2 years old (USA and EU). OBJECTIVE:To develop simplified entecavir dosing recommendati...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.1007/s40262-016-0420-5
更新日期：2016-12-01 00:00:00
abstract：:Clinical pharmacokinetics emerged as a clinical discipline in the late 1960s and early 1970s. Clinical pharmacokinetic monitoring (CPM) helped many pharmacists to enter the clinical arena, but the focus was more on the pharmacists and tools. With the widespread acceptance of pharmaceutical care and patient-focused pha...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199834040-00001
更新日期：1998-04-01 00:00:00
abstract：:A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.2165/00003088-199834050-00003
更新日期：1998-05-01 00:00:00
abstract：:The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations o...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.2165/00003088-198308020-00004
更新日期：1983-03-01 00:00:00
abstract：:Inpatients (n = 57) on long term prophylaxis with 2 oral phenytoin preparations were followed up via monthly checks of serum drug concentrations. Duplicate serum aliquots were submitted to 2 laboratories, and covariance analysis was used to estimate laboratory error. The laboratory-associated variance of examinations ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.2165/00003088-199120040-00007
更新日期：1991-04-01 00:00:00
abstract：OBJECTIVE:To investigate the effect of concomitant administration of dairy products on the pharmacokinetics and tolerability of moxifloxacin. DESIGN:This was a single-centre, randomised, controlled, nonblinded, 2-way crossover study in healthy volunteers. PARTICIPANTS:12 healthy men (aged 25 to 46 years) were enrolle...
journal_title：Clinical pharmacokinetics
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.2165/00003088-200140001-00005
更新日期：2001-01-01 00:00:00
abstract：:Morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine, collected over 72 h after administration of single intravenous 5 mg and oral 20 mg doses of morphine to 7 healthy volunteers. Systemic plasma clearance of ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.2165/00003088-199324040-00007
更新日期：1993-04-01 00:00:00
abstract：:It has been suggested that the minimum effective serum clozapine concentration for an acceptable clinical response (threshold value) is about 400 micrograms/L. This article argues against the use of therapeutic drug monitoring (TDM) as a tool to obtain clozapine concentrations of > or = 400 micrograms/L in the individ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199834060-00005
更新日期：1998-06-01 00:00:00
abstract：BACKGROUND AND OBJECTIVES:Labetalol is frequently prescribed for the treatment of hypertension during pregnancy; however, the influence of pregnancy on labetalol pharmacokinetics is uncertain, with inconsistent findings reported by previous studies. This study examined the population pharmacokinetics of oral labetalol ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.1007/s40262-013-0123-0
更新日期：2014-04-01 00:00:00
abstract：OBJECTIVE:To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies. METHODS:Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.1007/s40262-017-0509-5
更新日期：2017-10-01 00:00:00
abstract：:25 patients with different degrees of chronic stable renal failure received oral treatment with cimetidine over 6 days and a final dose in the morning of day 7. The doses of cimetidine were reduced according to the degree of renal failure. Plasma concentrations of cimetidine were determined before the morning dose on ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.2165/00003088-198106040-00006
更新日期：1981-07-01 00:00:00
abstract：BACKGROUND AND OBJECTIVE:Tegafur is an oral fluorouracil prodrug used in the treatment of colorectal cancer. The aim of this phase II, crossover, bioequivalence study was to compare the pharmacokinetics (primary objective) and tolerability (secondary objective) of tegafur-uracil (UFT) given as three daily doses (tid, r...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,随机对照试验
doi：10.2165/00003088-200746110-00003
更新日期：2007-01-01 00:00:00
abstract：:Fluorouracil is used clinically against various solid tumours. Both fluorouracil toxicity and pharmacokinetics vary highly within and between individuals. The reasons why doses are not individualised routinely are difficulties in defining, predicting and achieving an optimal fluorouracil exposure or dose because of a ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-200645060-00002
更新日期：2006-01-01 00:00:00
abstract：:Pegfilgrastim is a sustained-duration form of filgrastim, a recombinant methionyl form of human granulocyte colony-stimulating factor (G-CSF), to which a 20 kDa polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. Similar to filgrastim, pegfilgrastim increases the proliferation and d...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/11586040-000000000-00000
更新日期：2011-05-01 00:00:00
abstract：:The effects of liver disease on pharmacokinetics and pharmacodynamics are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area. Four di...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199529050-00005
更新日期：1995-11-01 00:00:00
abstract：:Part I of this article, which appeared in the previous issue of the Journal, covered the following agents: histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine); muscarinic-M1-receptor antagonists (pirenzepine); proton pump inhibitors (omeprazole); site-protective agents (colloidal bismuth...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199019020-00002
更新日期：1990-08-01 00:00:00
abstract：:Bioequivalence of drug formulations plays an important role in drug development. Recently, the Biopharmaceutical Classification System (BCS) has been implemented for the purpose of waiving bioequivalence studies on the basis of the solubility and gastrointestinal permeability of drug substance. Using the rationale of ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-200443150-00004
更新日期：2004-01-01 00:00:00
abstract：:Creatine is a nonessential dietary component that, when supplemented in the diet, has shown physiological benefits in athletes, in animal-based models of disease and in patients with various muscle, neurological and neuromuscular disease. The clinical relevance of creatine supplementation is based primarily on its rol...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-200342060-00005
更新日期：2003-01-01 00:00:00
abstract：:Esmolol is an ultra short-acting intravenous cardioselective beta-antagonist. It has an extremely short elimination half-life (mean: 9 minutes; range: 4 to 16 minutes) and a total body clearance [285 ml/min/kg (17.1 L/h/kg)] approaching 3 times cardiac output and 14 times hepatic blood flow. The alpha-distribution hal...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199528030-00002
更新日期：1995-03-01 00:00:00
abstract：:Warfarin, like all the 4-hydroxycoumarin compounds, has an asymmetric carbon atom. The clinically available warfarin preparations consist of a racemic mixture of equal amounts of 2 distinct S and R isomers, the former being 4-times more potent as anticoagulant and more susceptible to drug interaction. Warfarin is high...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199630040-00003
更新日期：1996-04-01 00:00:00
abstract：:Hydroxymetabolites of the antidepressants nortriptyline and desipramine, like the parent drugs, inhibit neuronal uptake of noradrenaline (norepinephrine). In both plasma and cerebrospinal fluid (CSF), the concentrations of the 10-hydroxymetabolites of nortriptyline (10-OH-NT) are usually higher than those of the paren...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199528010-00004
更新日期：1995-01-01 00:00:00
abstract：:The effects of age and gender on the single and multiple dose pharmacokinetics of zileuton have been examined in a phase I nonblinded study. A total of 27 healthy volunteers were evaluable, 9 in the young group (age range 20 to 40 years; 5 males and 4 females) and 18 in the elderly group (range 65 to 81 years; 9 males...
journal_title：Clinical pharmacokinetics
pub_type： 临床试验,杂志文章
doi：10.2165/00003088-199500292-00007
更新日期：1995-01-01 00:00:00
abstract：:The isoenzymes which catalyse the polymorphic hydroxylations of debrisoquine/sparteine and S-mephenytoin are cytochromes P450 2D6 and P450 2C19 (CYP2D6 and CYP2C19), respectively. CYP2D6 is involved in the stereospecific metabolism of several important groups of drugs, for example antiarrhythmics, antidepressants and ...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199529030-00005
更新日期：1995-09-01 00:00:00
abstract：:Sevoflurane is a comparatively recent addition to the range of inhalational anaesthetics which has been recently released for clinical use. In comparison to older inhalational agents such as isoflurane or halothane, the most important property of sevoflurane is its low solubility in the blood. This results in a more r...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-199936010-00002
更新日期：1999-01-01 00:00:00
abstract：:The pharmacokinetics and antihypertensive effects of felodipine, a new dihydropyridine calcium channel blocker, were studied in elderly hypertensive patients, 67 to 79 years of age and in young healthy subjects, 20 to 34 years of age following oral administration of 5 mg twice daily to steady-state. A single intraveno...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.2165/00003088-198814060-00004
更新日期：1988-06-01 00:00:00
abstract：BACKGROUND AND OBJECTIVE:Taurolidine is known to have antimicrobial activity. Furthermore, at lower concentrations, it has been found to exert a selective antineoplastic effect in vitro and in vivo. The aim of this study was to investigate the pharmacokinetics of taurolidine in vivo following repeated intravenous infus...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.2165/00003088-200746060-00005
更新日期：2007-01-01 00:00:00
abstract：:A pharmacokinetic study of alpha 1-antitrypsin (ATT) was performed in 2 groups of homozygous PiZ-deficient patients (treated and untreated) and 1 group of healthy volunteers. The distribution of the 131I-labelled protein corresponds to a 3-compartment model. The intravenously administered protein diffused quickly to t...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章
doi：10.2165/00003088-199223020-00007
更新日期：1992-08-01 00:00:00
abstract：:Protein binding of antibacterials in plasma and tissues has long been considered a component of their pharmacokinetic parameters, playing a potential role in distribution, excretion and therapeutic effectiveness. Since the beginning of the 'antibacterial era', this factor has been extensively analysed for all antibact...
journal_title：Clinical pharmacokinetics
pub_type： 杂志文章,评审
doi：10.2165/00003088-200241100-00004
更新日期：2002-01-01 00:00:00
abstract：BACKGROUND AND OBJECTIVE:Dalcetrapib, a cholesteryl ester transfer protein (CETP) modulator, is a thioester pro-drug that is rapidly hydrolysed to generate a pharmacologically active thiol. The thiol covalently binds to plasma proteins as mixed disulfides, extensively distributes into plasma lipoprotein fractions, and ...
journal_title：Clinical pharmacokinetics
pub_type： 临床试验,杂志文章
doi：10.1007/s40262-013-0035-z
更新日期：2013-04-01 00:00:00
