Lack of Exposure in a First-in-Man Study Due to Aldehyde Oxidase Metabolism: Investigated by Use of 14C-microdose, Humanized Mice, Monkey Pharmacokinetics, and In Vitro Methods.

Inclusion of a microdose of 14C-labeled drug in the first-in-man study of new investigational drugs and subsequent analysis by accelerator mass spectrometry has become an integrated part of drug development at Lundbeck. It has been found to be highly informative with regard to investigations of the routes and rates of excretion of the drug and the human metabolite profiles according to metabolites in safety testing guidance and also when additional metabolism-related issues needed to be addressed. In the first-in-man study with the NCE Lu AF09535, contrary to anticipated, surprisingly low exposure was observed when measuring the parent compound using conventional bioanalysis. Parallel accelerator mass spectrometry analysis revealed that the low exposure was almost exclusively attributable to extensive metabolism. The metabolism observed in humans was mediated via a human specific metabolic pathway, whereas an equivalent extent of metabolism was not observed in preclinical species. In vitro, incubation studies in human liver cytosol revealed involvement of aldehyde oxidase (AO) in the biotransformation of Lu AF09535. In vivo, substantially lower plasma exposure of Lu AF09535 was observed in chimeric mice with humanized livers compared with control animals. In addition, Lu AF09535 exhibited very low oral bioavailability in monkeys despite relatively low clearance after intravenous administration in contrast to the pharmacokinetics in rats and dogs, both showing low clearance and high bioavailability. The in vitro and in vivo methods applied were proved useful for identifying and evaluating AO-dependent metabolism. Different strategies to integrate these methods for prediction of in vivo human clearance of AO substrates were evaluated.

The perception and pharmacokinetics of a 20-mg dose of escitalopram orodispersible tablets in a relative bioavailability study in healthy men.

BACKGROUND: Rapidly dissolving oral (orodispersible) drug formulations have been developed to overcome problems related to swallowing. OBJECTIVE: The aim of this study was to compare the bioavailability of orodispersible and conventional immediate-release (IR) escitalopram tablets. METHODS: This was a randomized, open-label, 3-way crossover trial in which healthy men received single doses of orodispersible escitalopram formulations (2 ×10 mg and 1 × 20 mg) and conventional (2 × 10 mg) oral escitalopram tablets. Blood samples for pharmacokinetic analysis were obtained during a 168-hour period after dosing. The safety profile and tolerability were assessed by monitoring of adverse events, physical examinations, ECGs, and clinical laboratory and vital signs assessments. A questionnaire was used to assess the perception of the orodispersible tablet (ODT). RESULTS: The assumed bioequivalence assessment was based on pharmacokinetic and statistical analysis of data from the 29 men who completed the 3 treatments. The serum concentration-time profiles of escitalopram were similar after intake of the 3 treatments. The 90% CI for the mean treatment ratios of the log-transformed C(max), AUC(0-t), and AUC(0-∞) were all within the predefined equivalence range of 80% to 125%. Most subjects (87%) thought that the ODT was pleasant to take, and 85% of subjects thought that it was convenient to take the tablet without water. Most subjects (67%-90%) reported adverse events, with a similar incidence for all treatments. Most adverse events were mild, with somnolence and nausea being the most frequently reported. No clinically relevant changes were observed in physical, biochemical, hematologic, or urinalysis variables during the study. CONCLUSIONS: In this small study population of fasting healthy male volunteers, 2 × 10-mg ODTs or 1 × 20-mg ODT and 2 × 10-mg conventional IR escitalopram tablets met the regulatory criteria for assumed bioequivalence. CLINICALTRIALS.GOV IDENTIFIER: NCT 01395433.