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PHARMACOKINETICS

Multiple-Dose Plasma Pharmacokinetic and Safety Study of LY450108 and LY451395 (AMPA Receptor Potentiators) and Their Concentration in Cerebrospinal Fluid in Healthy Human Subjects

S. S. Jhee, PharmD, A. S. Chappell, MD, V. Zarotsky, PharmD, S. V. Moran, M. Rosenthal, DO, FAPA, E. Kim, S. Chalon, MD, PhD, N. Toublanc, PhD, J. Brandt, PhD, D. E. Coutant, PhD and L. Ereshefsky, PharmD, BCCP

From California Clinical Trials, Glendale, California (Dr Jhee, Dr Zarotsky, Ms Moran, Dr Rosenthal, Mr Kim, Dr Ereshefsky), and Eli Lilly and Company, Indianapolis, Indiana (Dr Chappell, Dr Chalon, Dr Toublanc, Dr Brandt, Dr Coutant).

The objective of this study was to measure the steady-state cerebrospinal fluid (CSF) concentration of LY450108 and LY451395 (positive modulators of AMPA receptors) in healthy subjects after the administration of 1 mg and 5 mg. Secondary objectives included the evaluation of safety, pharmacokinetics, and steady-state ratio of plasma:CSF concentrations of LY450108 and LY451395 after multiple dosing. This study was an open-label, multiple oral dose study evaluating 1 mg and 5 mg LY450108 and 1 mg and 5 mg LY451395 in 12 (3 subjects per dosing group) healthy subjects, aged 18 to 49 years. Twelve healthy male subjects completed the study. LY450108 and LY451395 were quantifiable in CSF after 1-mg and 5-mg multiple-dose administrations with plasma:CSF ratio of 82:1 and 44:1, respectively. LY450108 and LY451395 1 mg and 5 mg were measured in the CSF. Single and multiple oral doses of LY450108 and LY451395 were determined to be safe and well tolerated in healthy subjects.

Key Words: AMPA receptor potentiators • pharmacokinetics • cerebrospinal fluid • clinical trials • phase I

Address for reprints: S. S. Jhee, PharmD, California Clinical Trials Medical Group, Inc, 1509 Wilson Terrace, 55 Wing Main Floor, Glendale, CA 91206-4007.






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