Abstract:
:Potential differences in pharmacokinetics (PK) between healthy subjects and patients with cancer were investigated using a physiologically based pharmacokinetic approach integrating demographic and physiological data from patients with cancer. Demographic data such as age, sex and body weight, and clinical laboratory measurements such as albumin, alpha-1 acid glycoprotein (AAG) and hematocrit were collected in ~2500 patients with cancer. A custom oncology population profile was built using the observed relationships among demographic variables and laboratory measurements in Simcyp® software, a population based ADME simulator. Patients with cancer were older compared with the age distribution in a built-in healthy volunteer profile in Simcyp. Hematocrit and albumin levels were lower and AAG levels were higher in patients with cancer. The custom population profile was used to investigate the disease effect on the pharmacokinetics of two probe substrates, saquinavir and midazolam. Higher saquinavir exposure was predicted in patients relative to healthy subjects, which was explained by the altered drug binding due to elevated AAG levels in patients with cancer. Consistent with historical clinical data, similar midazolam exposure was predicted in patients and healthy subjects, supporting the hypothesis that the CYP3A activity is not altered in patients with cancer. These results suggest that the custom oncology population profile is a promising tool for the prediction of PK in patients with cancer. Further evaluation and extension of this population profile with more compounds and more data will be needed.
journal_name
Biopharm Drug Disposjournal_title
Biopharmaceutics & drug dispositionauthors
Cheeti S,Budha NR,Rajan S,Dresser MJ,Jin JYdoi
10.1002/bdd.1830subject
Has Abstractpub_date
2013-04-01 00:00:00pages
141-54issue
3eissn
0142-2782issn
1099-081Xjournal_volume
34pub_type
杂志文章abstract::Previous studies have shown that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment (2.56 nmol/kg i.p. daily×4) increased PepT1, Mrp2, Mrp4, Asbt, but not Mdr1/P-gp in the rat small intestine. In this study, the intestinal everted sac technique, together with various select probes: mannitol (paracellular transport), gl...
journal_title:Biopharmaceutics & drug disposition
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journal_title:Biopharmaceutics & drug disposition
pub_type: 杂志文章
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abstract::Stobadin dihydrochloride was administered p.o. to rats at a dose of 1 mg kg-1 once daily for 25 consecutive days. The peak and trough concentrations of the sum of stobadin metabolites, determined from Days 6-16 of treatment, demonstrated a steady-state. The mean daily excretion of 3H-radioactivity during this period w...
journal_title:Biopharmaceutics & drug disposition
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doi:10.1002/bdd.2510120304
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abstract::Many marketed drugs are chiral and are administered as the racemate, a 50:50 combination of two enantiomers. Pharmacodynamic and pharmacokinetic differences between enantiomers are well documented. Because of enantioselectivity in pharmacokinetics, results of in vitro pharmacodynamic studies involving enantiomers may ...
journal_title:Biopharmaceutics & drug disposition
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journal_title:Biopharmaceutics & drug disposition
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journal_title:Biopharmaceutics & drug disposition
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Biopharmaceutics & drug disposition
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journal_title:Biopharmaceutics & drug disposition
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更新日期:1998-12-01 00:00:00
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journal_title:Biopharmaceutics & drug disposition
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doi:10.1002/bdd.580
更新日期:2007-12-01 00:00:00
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journal_title:Biopharmaceutics & drug disposition
pub_type: 临床试验,杂志文章
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journal_title:Biopharmaceutics & drug disposition
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journal_title:Biopharmaceutics & drug disposition
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更新日期:2020-04-01 00:00:00
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journal_title:Biopharmaceutics & drug disposition
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journal_title:Biopharmaceutics & drug disposition
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更新日期:2008-05-01 00:00:00
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更新日期:1999-09-01 00:00:00
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更新日期:2019-07-01 00:00:00