Azilsartan Medoxomil + Chlorthalidone

Azilsartan medoxomil is an angiotensin II receptor blocker (ARB). Azilsartan helps blood vessels to widen, and it also helps the body get rid of sodium and water. This combination also contains a diuretic. Chlorthalidone works in the kidneys to flush excess water and salt (sodium) out of the body. Together, these 2 medicines help lower blood pressure in people who need more than 1 medicine to treat their high blood pressure (hypertension).

Absorption: In the gastrointestinal tract, azilsartan medoxomil is rapidly hydrolyzed to azilsartan during absorption, and azilsartan is the active metabolite. Azilsartan medoxomil itself is not detected in plasma after oral administration. The estimated absolute bioavailability of azilsartan after taking azilsartan medoxomil is approximately 60%. Peak plasma concentrations (Cmax) of azilsartan are reached within 1.5 to 3 hours of an oral dose. Food does not affect the bioavailability of azilsartan.

Distribution: The volume of distribution of azilsartan is approximately 16L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. This binding stays constant even at azilsartan plasma concentrations well above the range reached with recommended doses. In whole blood, chlorthalidone is mostly bound to erythrocyte carbonic anhydrase. In plasma, approximately 75% of chlorthalidone is bound to plasma proteins, and 58% of the drug is bound to albumin.

Metabolism and Elimination: Azilsartan medoxomil: Azilsartan is metabolized to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation and is called metabolite M II. The minor one is formed by decarboxylation and is called metabolite M-I. In humans, systemic exposure to the major and minor metabolites was approximately 50% and less than 1% of azilsartan, respectively. M-I and MII do not contribute to the pharmacologic activity of azilsartan medoxomil. CYP2C9 is the major enzyme responsible for azilsartan metabolism. The elimination half-life of azilsartan is approximately 11 hours, and renal clearance is approximately 2.3 mL/min. Steady-state levels of azilsartan are reached within 5 days, and with repeated once-daily dosing no accumulation in plasma occurs.

Chlorthalidone: Most of the drug is excreted unchanged by the kidneys. The nonrenal routes of elimination have yet to be clarified. Data are not available on the percentage of the dose that leaves as unchanged drug and metabolites, the concentration of the drug in body fluids, how much a particular organ or the fetus takes up, or whether it passes across the blood-brain barrier.