Cardiovascular Safety of the Oral Controlled Absorption System (OCAS) Formulation of Tamsulosin Compared to the Modified Release (MR) Formulation

Abstract

Objective: The potential to interfere with efferent adrenergic drive in the cardiovascular system was tested in elderly healthy subjects for the new oral controlled absorption system (OCAS) 0.4 mg tablet formulation of tamsulosin compared to the modified release (MR) 0.4 mg capsule formulation of tamsulosin after single dosing in the fasted state. Methods: Forty healthy, elderly (≥60 years) male volunteers were to be enrolled in a double-blind, double-dummy, two-period crossover study. After a placebo run-in assessment period, the subjects were randomised to one of the two treatment sequences in which single doses of tamsulosin OCAS 0.4 mg tablets and tamsulosin MR 0.4 mg capsules were tested. Orthostatic stress tests were done at 30 minutes before dosing and at 4, 6 and 8 hours after dosing as the primary cardiovascular safety assessment. Additionally, the effect on pharmacokinetics (PK), vital signs and adverse events was measured. Results: None of the 40 enrolled healthy male volunteers (mean age 67 years) discontinued from the study. Tamsulosin OCAS 0.4 mg and tamsulosin MR 0.4 mg both increased the incidence of positive orthostatic stress tests after single dosing from 2.5% at baseline to 17.5% of all post-dose assessments for tamsulosin OCAS and 31.7% for tamsulosin MR. At all time points, the incidence of a positive orthostatic test outcome following tamsulosin OCAS was lower than following tamsulosin MR (15% versus 35%, 22.5% versus 30%, and 15% versus 30% for tamsulosin OCAS relative to tamsulosin MR at 4, 6 and 8 hours post-dose, respectively). From the analysis of the discordant pairs (that is, those time points that showed a positive test outcome for only one of the two treatments) it emerged that the treatment differences measured overall and at 4 hours after dosing were statistically significant ( p = 0.006 and p = 0.0215 respectively). The analysis of the vital signs at 2, 4, 6, 8 and 10 hours post-dose confirmed that the OCAS formulation caused smaller blood pressure reductions and increases in pulse rate compared to the MR formulation which were statistically significant at 2 and 4 hours post-dosing for the systolic blood pressure and pulse, and at 4 hours post-dosing for the diastolic blood pressure. PK analysis showed a lower maximum plasma concentration (mean C max: 6.8 vs. 17.9 ng/ml) with the OCAS compared to the MR formulation; the time to C max was similar between the treatments (median t max: 6.2 vs. 6.1 hours). Conclusions: Tamsulosin OCAS 0.4 mg demonstrates a lower incidence of positive orthostatic tests following single dosing in fasting healthy elderly subjects compared to tamsulosin MR 0.4 mg. This is probably related to the improved controlled release characteristics (lower C max) of the OCAS formulation. It indicates that on an empty stomach tamsulosin OCAS provides a better cardiovascular safety profile than tamsulosin MR.