Assessment of the Drug–Drug Interactions Between Fimasartan and Hydrochlorothiazide in Healthy Volunteers

Abstract

Fimasartan administered alone or in combination with HCTZ was well tolerated at the described dosages. Coadministration of fimasartan increased the urinary excretion of HCTZ and urine volume, but these observations are unlikely to have any clinical relevance.

Pharmacological Profiles of a Highly Potent and Long-Acting Angiotensin II Receptor Antagonist, Fimasartan, in Rats and Dogs after Oral Administration

“…Co., Ltd., Seoul, Republic of Korea) was approved by the Korea Food and Drug Administration (KFDA) in 2010 for the treatment of essential hypertension. Several nonclinical and clinical studies have been conducted on fimasartan, for example, (1) clinical studies have been undertaken on its efficacy and safety in large populations 8,9) and interactions with other concomitant drugs [10][11][12] and (2) nonclinical studies have investigated the mechanistics underlying its other pharmacological activities, such as, its inhibitory effect on catecholamine secretion, 13) its cardioprotective effect, which was attributed to the prevention of mitochondrial damage, 14) its anti-atherosclerotic effect, 15) and its anti-inflammatory potential.…”

Fimasartan: A New Angiotensin Receptor Blocker

“…The authors explained these changes as uremic toxin-and inflammation-mediated decreases of P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2) expression and function in the intestine [18]. To aid the development of a single-pill combination, pharmacokinetic studies evaluated the effect of co-administration of fimasartan with amlodipine or hydrochlorothiazide on the steady-state pharmacokinetics of each drug in healthy volunteers; no significant interactions were shown [19,20]. In addition, no significant drug interactions were observed when fimasartan was used in combination with warfarin or digoxin in healthy volunteers [21,22].…”

Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans

“…Multiple plasma concentration peaks were also present after oral administration of fimasartan in clinical trials (17)(18)(19)(20)(21)(22), indicating that EHC impacts on human PK and potentially pharmacodynamics (PD). It is therefore important to quantitatively understand how EHC affects the systemic fimasartan exposure to enable animal to human scaling and ultimately the prediction of first-in-human (FIH) PK.…”

“…Fimasartan was dissolved in distilled water, and the drug solution (0.3 and 1 mg/kg; n=6 for each group) was dosed as a bolus via the catheter followed by flushing. Blood samples of 3 mL were collected from the cephalic vein at pre-dose (within 5 min) and at 5, 10, 20, and 30 min and 1, 1.5, 2, 3, 4,6,8,12,16,20,24,48, and 72 h after IV injection.…”

“…All dogs were studied under fasting conditions. After dosing, 3 mL of blood were collected from the cephalic vein at pre-dose (within 5 min), and at 10, 20, and 30 min and 1, 1.5, 2, 3, 4,6,8,12,16,20,24,48, and 72 h. Plasma was obtained by centrifugation at 15,000×g at 4°C for 10 min and immediately frozen and stored at −70°C until analysis.…”