Amyloid beta (Abeta) may play a central role in the pathogenesis of Alzheimer disease. A functional gamma-secretase inhibitor, LY450139, was developed that inhibits Abeta formation in whole cell assays, transgenic mice, and beagle dogs. The authors wished to determine the safety and tolerability of this drug, and the reduction of Abeta in plasma and cerebrospinal fluid (CSF) after multiple doses. Volunteer subjects (N = 37) were studied using doses from 5 to 50 mg/day given for 14 days. Plasma and CSF concentrations of LY450139, Abeta(1-40) and Abeta(1-X) ("Abeta(total)") were determined, and safety and tolerability were assessed. The plasma half-life of LY450139 was approximately 2.5 hours. Pharmacokinetic analyses showed a linear relationship between dose and plasma concentrations, with a Cmax of 828 +/- 19.2 ng/mL after a 50-mg dose. Plasma Abeta concentrations decreased in a dose-dependent manner over a 6-hour interval following drug administration, with a maximum decrease of approximately 40% relative to baseline. After returning to baseline, Abeta concentrations were transiently increased. CSF Abeta concentrations were unchanged. Adverse events reported by subjects taking 5-mg, 20-mg, or 40-mg doses were similar to those reported by subjects taking placebo. Two of 7 subjects taking 50 mg/day experienced adverse events that may have been drug related. In this phase 1 volunteer study, reported adverse events after taking LY450139 were manageable. A dose-dependent reduction in plasma Abeta was demonstrated, and changes in plasma Abeta concentrations were temporally related to the pharmacokinetic characteristics of LY450139.
This article is available online at http://dmd.aspetjournals.org ABSTRACT:Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake being investigated for the treatment of depression and urinary incontinence. The disposition of duloxetine was studied in four healthy human subjects after a single 20.2-mg (100.6 Ci) oral dose of [ 14 C]duloxetine in an enteric-coated tablet. The mean total recovery of radioactivity (؎ S.E.M.) after 312 h was 90.5% (؎0.4%) with 72.0% (؎1.1%) excreted in the urine. Duloxetine was extensively metabolized to numerous metabolites primarily excreted into the urine in the conjugated form. The major biotransformation pathways for duloxetine involved oxidation of the naphthyl ring at either the 4-, 5-, or 6-positions followed by further oxidation, methylation, and/or conjugation. The major metabolites found in plasma were glucuronide conjugates of the following: 4-hydroxy duloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10), 4, 6-dihydroxy duloxetine (M9), and a sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (M7). The major metabolites found in plasma were also found in the urine, but the urine contained many additional metabolites. In addition to duloxetine, 4-hydroxy duloxetine (M14) and an unidentified polar metabolite were observed in feces. Following [ 14 C]duloxetine administration, C max was reached at a median of 6 h for both duloxetine and total radioactivity. Duloxetine accounted for less than 3% of the circulating radioactivity based on mean area under the curve values. The elimination half-life of total radioactivity (120 h) was substantially longer than that of duloxetine (10.3 h).
Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine.
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