PT - JOURNAL ARTICLE AU - Chih-Liang Chin AU - Robert A. Carr AU - Daniel A. Llano AU - Olivier Barret AU - Hongyu Xu AU - Jeffrey Batis AU - Andrei O. Koren AU - John P. Seibyl AU - Kennan C. Marsh AU - Gilles Tamagnan AU - Michael W. Decker AU - Mark Day AU - Gerard B. Fox TI - Pharmacokinetic Modeling and [<sup>123</sup>I]5-IA-85380 Single Photon Emission Computed Tomography Imaging in Baboons: Optimization of Dosing Regimen for ABT-089 AID - 10.1124/jpet.110.173609 DP - 2011 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 716--723 VI - 336 IP - 3 4099 - http://jpet.aspetjournals.org/content/336/3/716.short 4100 - http://jpet.aspetjournals.org/content/336/3/716.full SO - J Pharmacol Exp Ther2011 Mar 01; 336 AB - 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 Cmax. Our data demonstrate the feasibility of predicting plasma exposures using a two-compartment pharmacokinetic model and its potential for optimizing dosing regimens.