Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor

The pharmacokinetics and safety of duloxetine were evaluated in a single-bl ind, placebo-controlled, escalating multiple-dose study in 12 healthy male subjects. In the treatment group (n = 8), duloxetine was administered orall y at a starting dose of 20 mg twice daily (bid) and escalated at weekly int ervals to 30 mg bid, then to 40 mg bid. The observed plasma concentration-t ime data at all three dose levels were adequately described by a one-compar tment model with a first-order absorption rate constant. The mean oral clea rance, apparent volume of distribution, and half-life values were 114 L/h ( range: 44 to 218 L/h), 1943 L (range: 803 to 3531 L), and 12.5 h (range: 9. 2 to 19.1 h), respectively. Somnolence, nausea, and dry mouth were observed following the initial dose, but they resolved with continuing drug adminis tration. Duloxetine was not associated with clinically significant changes in blood pressure (BP) or heart rate (HR) measured in the standing position . However, in recumbent position, small increases in systolic (less than or equal to 9 mmHg) and diastolic (less than or equal to 5 mmHg) BP and small decreases in HR (less than or equal to 6 beats/min) were observed. Abrupt discontinuation of duloxetine was associated with a small increase in mean HR (less than or equal to 12 beats/min). In 3 subjects, abrupt discontinuat ion wets also associated with transient sleep disturbance. No clinically im portant changes in electrocardiograms, cardiac intervals, clinical laborato ry tests, and neurological functions were observed. These results indicate that duloxetine exhibits linear pharmacokinetics with respect to dose and d uration of treatment and that a multiple oral dose regimen starting at 20 m g bid and gradually escalating up to 40 mg bid was generally well tolerated . Journal of Clinical Pharmacology, 2000;40:161-167 (C)2000 the American Co llege of Clinical Pharmacology.