Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin

Abstract

What is already known about this subject: Tamsulosin metabolism involves both CYP2D6 and 3A4. However, data on potential drug-drug interactions between tamsulosin and inhibitors of CYP2D6 and 3A4 are limited and information on potential pharmacodynamic consequences of such pharmacokinetic interactions is missing.

What this study adds: This study provides information on the drug-drug interactions of tamsulosin with strong CYP2D6 and strong CYP3A4 inhibitors after single dose administration in healthy subjects.

Aim: To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin.

Methods: Two open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers).

Results: Co-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C(max) and AUC(0,∞) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t(1/2) ) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once daily with a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C(max) and AUC(0,∞) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing.

Conclusion: The exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing.

Figure 1

Plasma concentration–time profiles of tamsulosin HCl after single oral administration of 0.4 mg tamsulosin HCl (upper panel) with and without 20 mg day⁻¹ paroxetine or 400 mg day⁻¹ ketoconazole administration (lower panel). Data are gMean of 23 subjects for each combination treatment and 24 subjects for tamsulosin.

Figure 2

Effect of tamsulosin alone and tamsulosin plus paroxetine (left panels) or plus ketoconazole (right panels) on systolic blood pressure (upper panels), diastolic blood pressure (middle panels) and pulse rate (lower panels). Shown are mean differences and SD from supine to standing position in mmHg (blood pressure) and beats min⁻¹ (pulse rate) as measured prior to tamsulosin administration (‘pre’) and 6 and 24 h thereafter.