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 Cmax 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 Cmax 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 Cmax. 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 Cmax. 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.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Mar 2011|
ASJC Scopus subject areas
- Molecular Medicine