Safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ascending single doses of desvenlafaxine (DVS-233 SR) in healthy subjects

Abstract

Background To assess the safety, tolerability, PK and PD of ascending single oral doses of DVS-SR in healthy subjects. Methods This was a randomized, placebo-controlled, ascending sequential single dose study in 79 healthy male subjects. Doses of 150, 225, 300, 450, 600, 750, and 900 mg were administered after a medium-fat breakfast to cohorts of 10 subjects (6 DVS-SR, 2 placebo and 2 Venlafaxine ER 150 mg[V]). An additional cohort was dosed at 750 mg in a fasted state to assess preliminary food effect. Assessments consist of adverse events reporting, vital signs, ECG and routine laboratory tests, plasma PK desvenlafaxine (DV) profile and PD (psychomotor performance and memory). Results DVS-SR up to 750 mg produced less severe nausea than V. Vomiting occurred in 2 of 6 subjects at 750 mg (maximum tolerated dose) and 4 of 6 subjects at 900 mg. No clinically relevant changes occurred in blood pressure, pulse, ECG intervals (particularly QTc), and routine lab tests. DVS-SR did not impair psychomotor performance and memory. Mean Tmax was 6–8 h and half-life was 9–11 h. for DV after oral dosing. Cmax and AUC increased approximately linearly over the range of 150 to 900 mg. DVS-SR taken with a medium-fat breakfast produced slightly higher DV Cmax and AUC, but food did not alter its slow release profile. Conclusions DVS-SR was safe up to a single dose of 750 mg. The PK profile supports once daily dosing. The slow release characteristics of DVS-SR are not altered by administration with food. Clinical Pharmacology & Therapeutics (2005) 77, P28–P28; doi: 10.1016/j.clpt.2004.11.107