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. AIMTo determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin. METHODSTwo open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers). RESULTSCo-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 Cmax 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 (t1/2) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once dailywith a single oral dose of the 0.4 mg tamsulosin increased the gMean values of Cmax 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. CONCLUSIONThe 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.

Ketoconazole‐Associated Liver Injury in Drug‐Drug Interaction Studies in Healthy Volunteers

“…The selected study set consisted of 53 separate DDI studies taken from 46 publications between 2005 and 2015, which included 971 subjects with systemic ketoconazole exposure (Table ). A majority of the studies were conducted at study centers in the United States and Germany (Table ).…”

Tamsulosin Exposure Is Significantly Increased by the CYP2D6*10/*10 Genotype

“…The differences observed in the present study are similar to those reported in a previous drug-drug interaction study with paroxetine, a potent CYP2D6 inhibitor. 10 Generally, CYP2D6 enzymatic activity can be expressed in terms of 4 phenotypes: PM, intermediate metabolizer (IM), extensive metabolizer (EM), and ultra-rapid metabolizer. The CYP2D6*10 allele is associated with reduced substrate affinity, 8 and many in vivo studies have shown that the metabolic capacity of homozygous CYP2D6*10 is between the capacities of EMs and PMs.…”

“…6 In a recent study, coadministration with a potent CYP3A4 inhibitor, ketoconazole, caused a 2.2-and 2.8-fold increase in the C max and AUC of tamsulosin, respectively. 10 Thus, it is possible that genetic polymorphisms in CYP3A4 or CYP3A5, which are considered to have similar substrate specificity, influence tamsulosin pharmacokinetics. To date, more than 19 CYP3A4 variant and subvariant alleles (*1B through *21) have been identified (http:// www.cypalleles.ki.se/cyp3a4.htm); however, there is no consensus on the direct functional correlations of CYP3A4 polymorphisms, which have only minor to moderate clinical importance because of their low allele frequencies and limited alterations on enzyme expression or catalytic function.…”

“…4 In contrast, plasma concentrations of tamsulosin were significantly increased when administered with multiple oral doses of paroxetine, a potent CYP2D6 inhibitor. 10 However, to the best of our knowledge, the influence of different CYP2D6 genotypes on tamsulosin pharmacokinetics has not been reported.…”

A Neuroendocrine Mechanism of Co-Morbidity of Depression-Like Behavior and Myocardial Injury in Rats

“…Although antiplatelet and protective endothelium effects of sertraline have been reported [24], the results from three currently available epidemiological studies assessing the risk of MI in patients treated with SSRIs are controversial with regard to a potential beneficial effect of SSRIs on CVD risk in depressed patients. One study confirmed that sertraline caused concentration-dependent dilation in reconstructed arteries [22], [25]. A high dose of sertraline was able to fully reverse the level of vascular constriction caused by all types of vasoconstrictors.…”