Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects.

Duloxetine is a dual inhibitor of norepinephrine (NE) and serotonin (5-HT) uptake. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant. The aim of this study was to assess the effects of duloxetine on the 5-HT and NE reuptake processes in healthy human volunteers. Twenty-seven healthy young males without a history of psychiatric disorder were randomly assigned to four groups, each group receiving one of the following daily drug regimens: placebo, clomipramine (a potent 5-HT/NE reuptake blocker) 100 mg/day, duloxetine 20 mg/day, or duloxetine 60 mg/day. In order to assess the NE reuptake process, the pressor response to intravenous tyramine (4 and 6 mg) was measured. Determination of the whole blood 5-HT content was used to evaluate the 5-HT reuptake blockade. These measurements were performed at baseline and repeated after 7 and 14 days of drug intake. Both duloxetine, at doses of 20 to 60 mg/day, and clomipramine significantly interfered with the 5-HT reuptake process, as demonstrated by marked decreases in blood 5-HT concentrations. However, the same doses of duloxetine, unlike clomipramine, failed to impede the usual increase in blood pressure that follows a tyramine intravenous infusion, indicating that clomipramine but not duloxetine blocked NE reuptake. At doses tested in a population of healthy volunteers, duloxetine acted as a selective 5-HT reuptake inhibitor, having no clear effect on the NE reuptake process. Nevertheless, given that the highest dose of duloxetine increased supine systolic blood pressure, it is possible that it represents the threshold regimen for NE reuptake inhibition.

The role of metabolites in bioequivalency assessment. III. Highly variable drugs with linear kinetics and first-pass effect.

PURPOSE: Simulated pharmacokinetic (PK) studies were done to determine the effect of intrinsic clearance (CL(INT)) on the probability of meeting bioequivalence criteria for extent (AUC) and rate (Cmax) of drug absorption when the absorption rate and fraction absorbed (F) were formulated either to be equivalent or to differ by 25%. METHODS: Simulated PK studies were done using a linear first-pass model with CL(INT) values ranging from 15 L/HR to 900 L/HR. Test/Reference absorption rate constants (Ka) and fraction absorbed (Fa) ratios of 1.0 or 1.25 were used for all simulations. The impact of the value of CL(INT) and its intrasubject variation upon the probability of concluding bioequivalence at the two different Ka and F ratios was studied. Additionally, the effect of fraction metabolized i.v., (Fm) on the probabilities of concluding equivalence was studied at values of 0.25 and 0.75. RESULTS: When CL(INT) values were raised above those for liver blood flow, the frequency of trials in which bioequivalence was correctly declared decreased when parent AUC was used as a bioequivalence criterion. Only when CL(INT) exceeded liver blood flow did the metabolite become important in assessing extent of absorption. CONCLUSIONS: The Cmax for the parent drug provided the most accurate assessment of bioequivalence. The Cmax for the metabolite was insensitive to changes related to rate of input, and when CL(INT) exceeded liver blood flow, evaluation of the metabolite Cmax data may lead to a conclusion of bioequivalence for products that were not.