Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

Pharmacokinetics of dapoxetine hydrochloride in healthy Chinese, Japanese, and Caucasian men.

Dapoxetine is a short-acting selective serotonin reuptake inhibitor developed for the on-demand treatment of premature ejaculation and is approved in some European Union countries, as well as Mexico and Korea, for this indication. The pharmacokinetics of dapoxetine 30 mg and 60 mg in healthy Chinese (single dose), Japanese, and Caucasian men (single and multiple dose) were assessed in 2 studies. In the 3 ethnic groups, dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations evident approximately 1 hour after dosing, independent of dose, dosing frequency (single or multiple dosing), or ethnicity. Dapoxetine was eliminated in a biphasic manner with an apparent mean terminal half-life of 14 to 17 hours. There was a dose-proportional increase in dapoxetine maximum plasma concentration (C(max)) and area under concentration-time curves (AUCs). The single-dose pharmacokinetic parameters of dapoxetine metabolites were also similar for the 3 ethnic groups, as were the pharmacokinetics of dapoxetine and its metabolites following single and multiple dosing in Caucasian and Japanese men. Dapoxetine was well tolerated by all 3 ethnic groups.