Olmesartan medoxomil
Olmesartan medoxomil doses of 2.5 to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.
Hydrochlorothiazide
After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Drug Interactions
Hydrochlorothiazide
Alcohol, barbiturates, or narcotics:Potentiation of orthostatic hypotension may occur.
Skeletal muscle relaxants, non-depolarizing (e.g., tubocurarine):Increased responsiveness to the muscle relaxant may occur.
Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may predispose to digoxin toxicity.
Absorption
Olmesartan:Olmesartan medoxomil is completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (C max) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan.
Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing.
Hydrochlorothiazide:The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (C max) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.
The pharmacokinetics of hydrochlorothiazide is dose proportional in the range of 12.5 to 75 mg.
Distribution
Olmesartan:The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats.
Hydrochlorothiazide:Hydrochlorothiazide binds to albumin (40 to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Metabolism
Olmesartan:Olmesartan does not undergo further metabolism.
Hydrochlorothiazide:Hydrochlorothiazide is not metabolized.
Elimination
Olmesartan:Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.
Hydrochlorothiazide:About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.
Specific populationsOlmesartan medoxomil
Pediatric:The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight. Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.
Geriatric: The pharmacokinetics of olmesartan were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUC ss, τwas 33% higher in elderly patients, corresponding to an approximate 30% reduction in CL R.
Gender: Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and C maxwere 10-15% higher in women than in men.
Renal insufficiency:In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.
Hepatic insufficiency:Increases in AUC 0-∞and C maxfor olmesartan were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.
Hydrochlorothiazide
Renal insufficiency:In a study in individuals with impaired renal function, the mean elimination half-life of hydrochlorothiazide doubled in individuals with mild/moderate renal impairment ( 30< CrCl < 90 mL/min) and tripled in severe renal impairment (≤ 30 mL/min), when compared to individuals with normal renal function (CrCl > 90 mL/min).
Drug Interactions
Olmesartan
No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with digoxin or warfarin in healthy volunteers.
The bioavailability of olmesartan medoxomil was not significantly altered by the co-administration of antacids [Al(OH) 3/Mg(OH) 2].
Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected.
Bile acid sequestering agent colesevelam
Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in C maxand 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in C maxand AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride [see Drug Interactions ( 7.5)].
Hydrochlorothiazide
Drugs that alter gastrointestinal motility:The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.
Cholestyramine:In a dedicated drug interaction study, administration of cholestyramine 2 h before hydrochlorothiazide resulted in a 70% reduction in exposure to hydrochlorothiazide. Further, administration of hydrochlorothiazide 2 h before cholestyramine, resulted in 35% reduction in exposure to hydrochlorothiazide.
Lithium:Diuretic agents reduce the renal clearance of lithium and increase the risk of lithium toxicity [see Drug Interactions ( 7.2)].
Antineoplastic agents (e.g. cyclophosphamide, methotrexate):Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.