生物等效性和生物利用度杂志

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Pharmacokinetics, Pharmacodynamics, and Safety of Desvenlafaxine, a Serotonin-Norepinephrine Reuptake Inhibitor

Alice Nichols I, Jessica Behrle A, Virginia Parks, Lyette Richards S, Stephanie McGrory B, Joel Posener, Alain Patat and Jeffrey Paul

Study background: Assess safety, tolerability, pharmacokinetics, and pharmacodynamics of desvenlafaxine (administered as desvenlafaxine succinate) in 3 studies with healthy volunteers.

Methods: Study 1, a randomized, open-label, dose proportionality, crossover study, assessed pharmacokinetics and safety of single doses of desvenlafaxine 100, 300, and 600 mg (N=24). Study 2, a randomized, double-blind, placebo-controlled, sequential-group, single-ascending dose study, assessed pharmacokinetics, pharmacodynamics, and safety of desvenlafaxine 150–900 mg and venlafaxine extended-release 150 mg (N=79). Study 3, a doubleblind, placebo-controlled, sequential-group, multiple-ascending dose study, assessed pharmacokinetics, pharmacodynamics, and safety of desvenlafaxine 300, 450, and 600 mg (N=36). In all studies, safety was monitored through adverse events, physical examinations, electrocardiograms, laboratory tests, and vital signs. In study 2, a daytime spectral analysis of electroencephalogram data was conducted; in studies 2 and 3, cognition was assessed using vigilance and psychomotor performance tests.

Results: Following single- and multiple-dose administration, desvenlafaxine Cmax and AUC increased in linear, dose-proportional manner over doses of 100–900 mg. Steady-state plasma concentrations were reached within 4–5 days, and multiple-dose pharmacokinetics were adequately predicted from single-dose pharmacokinetics. The maximum tolerated single dose was 750 mg; vomiting was the dose-limiting adverse event. For multiple doses, the maximum tolerated dose was 450 mg/d; orthostatic hypotension was dose-limiting. Adverse events at doses below the maximum tolerated doses were generally mild and transient. Absolute beta energies significantly increased in all electroencephalogram leads with doses ≥ 450 mg, particularly in front temporal lobes. Single or multiple desvenlafaxine doses did not alter psychomotor function or memory.

Conclusion: Maximum tolerated doses for desvenlafaxine (750 mg, single dose; 450 mg, multiple doses) were well above the recommended therapeutic dose of 50 mg/d for major depressive disorder. Desvenlafaxine exhibited approximately linear, dose-proportional pharmacokinetics across the wide range of doses studied and was not associated with significant alterations in psychomotor function or memory.