Linked Life Data

21172907

Source:http://linkedlifedata.com/resource/pubmed/id/21172907

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2011-2-21
pubmed:abstractText
Neuronal acetylcholine nicotinic receptors (nAChRs) are targets for the development of novel treatments of brain diseases. However, adverse effects (for example, emesis or nausea) associated with high drug maximal exposures or C(max) at nAChRs often hinder the advancement of experimental compounds in clinical trials. Therefore, it is essential to explore the feasibility of maintaining exposures below a predetermined C(max) while sustaining targeted CNS effects. By use of a [¹²³I]5-IA [5-[¹²³I]iodo-3-[2(S)-azetidinylmethoxy]pyridine] displacement SPECT imaging paradigm in nonhuman primates, we compared brain nAChR binding activity elicited by either a bolus injection or by slow infusion of an identical dose of a novel neuronal nicotinic agonist, ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], where the slow infusion scheme was derived from a two-compartment pharmacokinetic modeling designed to limit the C(max). We determined [¹²³I]5-IA displacement using doses of ABT-089 (0.04, 0.4, and 1.0 mg/kg i.v.) that encompassed efficacious drug exposures in nonhuman primates and examined the relationship between ABT-089 displacement ratios and plasma exposures. Our results indicated that calculated displacement ratios were quite similar between the two different dosing regimens despite substantial differences in C(max). In addition, displacement ratios correlated well with drug exposures calculated as the area-under-curve (AUC) of plasma concentration and varied in a dose-dependent manner, suggesting that displacement ratios are driven by the AUC of drug plasma exposure but not C(max). Our data demonstrate the feasibility of predicting plasma exposures using a two-compartment pharmacokinetic model and its potential for optimizing dosing regimens.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1521-0103
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
336
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
716-23
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Pharmacokinetic modeling and [¹²³]5-IA-85380 single photon emission computed tomography imaging in baboons: optimization of dosing regimen for ABT-089.
pubmed:affiliation
Advanced Technology, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA. chih-liang.chin@abbott.com
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't