OLMESARTAN MEDOXOMIL and HYDROCHLOROTHIAZIDE (Page 5 of 6)

12.3 Pharmacokinetics

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 (Cmax ) 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 (Cmax ) 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 populations

Olmesartan 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; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR .

Gender: Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and Cmax were 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 AUC0-∞ and Cmax for 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 Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Olmesartan medoxomil and hydrochlorothiazide

No carcinogenicity studies with olmesartan medoxomil and hydrochlorothiazide have been conducted.

Olmesartan medoxomil and hydrochlorothiazide in a ratio of 20:12.5 were negative in the Salmonella-Escherichia coli /mammalian microsome reverse mutation test up to the maximum recommended plate concentration for the standard assays. Olmesartan medoxomil and hydrochlorothiazide were tested individually and in combination ratios of 40:12.5, 20:12.5 and 10:12.5, for clastogenic activity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. A positive response was seen for each component and combination ratio. However, no synergism in clastogenic activity was detected between olmesartan medoxomil and hydrochlorothiazide at any combination ratio. Olmesartan medoxomil and hydrochlorothiazide in a ratio of 20:12.5, administered orally, tested negative in the in vivo mouse bone marrow erythrocyte micronucleus assay at administered doses of up to 3144 mg/kg.

No studies of impairment of fertility with olmesartan medoxomil and hydrochlorothiazide have been conducted.

Olmesartan medoxomil

Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil.

Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and both tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney, and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).

Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538, or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. It was also not genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, or the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay and the Aspergillus nidulans non-disjunction assay.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

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