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An ascending multiple‐dose study of the safety and pharmacokinetics of a sustained‐release formulation of desvenlafaxine succinate in healthy subjects
Author(s) -
Richards L. S.,
Behrle J. A.,
Nichols A. I.,
Fruncillo R. J.,
Paul J.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.215
Subject(s) - pharmacokinetics , medicine , cmax , tolerability , placebo , adverse effect , pharmacology , nausea , anesthesia , alternative medicine , pathology
Background/Aims To assess the safety, tolerability, and pharmacokinetics (PK) of ascending multiple oral doses of a sustained‐release formulation of desvenlafaxine succinate (DVS‐SR) in healthy subjects. Methods A randomized, placebo‐controlled, ascending multiple‐dose study was conducted with 36 healthy male subjects. In cohorts of 12 subjects (9 DVS‐SR and 3 placebo), 3 dose levels (300, 450, and 600 mg) were given q24h for 14 days after a medium‐fat breakfast. Routine laboratory tests, vital signs, and electrocardiograms (ECG) were measured throughout the study. The plasma concentrations of desvenlafaxine (DV) were analyzed by model‐independent methods. Results DVS‐SR was generally well tolerated at doses up to 450 mg, defined as the maximum tolerated multiple dose. Nausea was a common adverse event in all three dose cohorts. Orthostatic hypotension was observed in 6 of 9 subjects in the 600 mg DVS‐SR dose group. There were no clinically relevant changes in ECG intervals and routine laboratory tests. DV was slowly absorbed with a mean t max occurring 5 to 8 hours after dose administration. C max and AUC increased proportionally over the ranges of 300 to 600 mg and 300 to 450 mg for single and multiple doses, respectively. The single‐dose AUC 0‐∞ and steady‐state AUC 0–24h were similar at each dose level. Conclusion DVS‐SR was safe and well tolerated at multiple doses of up to 450 mg. Single‐dose PK can be used to predict multiple‐dose PK. Clinical Pharmacology & Therapeutics (2005) 77 , P84–P84; doi: 10.1016/j.clpt.2004.12.215