Focus on Azilsartan: A next-generation angiotensin II receptor blocker for the treatment of hypertension

ABSTRACT

Azilsartan medoxomil (TAK-491), the prodrug form of azilsartan (TAK-536), is an angiotensin II receptor blocker (ARB) under review for FDA approval for the treatment of hypertension. Despite the availability of many antihypertensive agents in the United States, hypertension remains inadequately controlled in more than half of those diagnosed with the disease. Hypertensive patients are at risk for development of complications such as diabetes, as well as other cardiovascular and renal diseases. Therefore, an agent with multifunctional purposes would offer an efficacious way of managing hypertension and related complications. Azilsartan medoxomil is a newer-generation ARB with potent antihypertensive effects. Phase 3 trials have established its safety and efficacy at doses of 20 to 80 mg once daily in patients with stages 1 or 2 hypertension. Moreover, in comparative trials, azilsartan medoxomil has shown a more effective blood-pressure-lowering effect than valsartan and olmesartan medoxomil. Also, potent antihypertensive effects were seen when used in combination with chlorthalidone and amlodipine. Preliminary data from animal studies indicate beneficial antidiabetic and cardioprotective properties of this drug. The most common adverse effects are dizziness, increased blood creatine phosphokinase, and diarrhea. Unresolved issues involving azilsartan medoxomil include the extent of its antidiabetic effect, efficacy in the management of other conditions besides hypertension, and its drug interaction profile. (Formulary. 2010; 45:342–349.)

Cardiovascular and renal diseases are common and represent the most frequent causes of morbidity and mortality in contemporary industrialized countries.¹ Cardiovascular and renal diseases can be viewed as progressing along a continuum that begins with cardiovascular risk factors such as hypertension, diabetes, dyslipidemia, and smoking. If untreated, evolving atherosclerotic lesions and organ damage may result in the development of major clinical syndromes such as myocardial infarction (MI), stroke, heart failure, and end-stage renal disease. The late stages of this continuum often are associated with poor outcomes, evidenced by the 50% 1-year mortality rate of New York Heart Association stage IV heart failure patients.¹

Despite the plethora of treatment options for the management of hypertension, 55.9% of patients do not have their BP under adequate control.³ In addition, there is ambiguity concerning the appropriate choice of therapy for hypertensive patients who may present with coexisting conditions such as diabetes.⁵ Prescription volumes of former first-line antihypertensive agents such as beta-blockers and diuretics have declined in recent years because of concerns over their tolerability and efficacy.⁵ Instead, management of hypertension has shifted toward the use of treatment regimens with calcium-channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs).⁵

The renin-angiotensin system (RAS) serves as a primary regulator of both acute and long-term BP, and it exerts deleterious effects on the heart, kidney, and vasculature.¹ Angiotensin II, a component of RAS, exerts a plethora of effects modulated by AT₁ (angiotensin II type 1) receptor stimulation and activation of aldosterone synthesis. It also enhances oxidative stress that ultimately leads to accelerated atherosclerosis progression and plaque destabilization. Furthermore, angiotensin II-triggered intracellular reactions result in myocite and vascular hypertrophy, fibrosis, and apoptosis. Finally, RAS activation may contribute to ongoing remodeling and dilatation of cardiac chambers in chronic heart failure patients, which not only worsens the existing heart failure, but may also cause electrical remodeling associated with the development of atrial fibrillation.^1,6

Many of the ARBs have the ability to decrease rates of cardiovascular morbidity and mortality in patients afflicted with a variety of cardiovascular, renal, and other vascular conditions. Irbesartan, telmisartan, candesartan cilexetil, and valsartan have been shown to decrease BP in hypertensive patients to a greater extent than losartan in comparative trials.¹ Telmisartan represents the sole ARB that has been shown to be noninferior to an ACE inhibitor (ramipril) in lowering the risk of cardiovascular events in hypertensive patients at high risk for experiencing adverse cardiovascular outcomes.¹ Dual blockade of RAS accomplished by valsartan or candesartan cilexetil, in combination with ACE inhibitors, has been shown to decrease the occurrence of the composite end point of all-cause death and hospitalization for heart failure in systolic heart failure patients.¹ Valsartan demonstrated noninferiority to captopril in reducing the risk of cardiovascular events and mortality in post-MI patients with evidence of heart failure or left ventricular dysfunction.¹ Losartan and irbesartan have been shown to prevent the composite end point of death, doubling of serum creatinine, and progression to end-stage renal disease in type 2 diabetes patients with advanced nephropathy (macroproteinuria).¹

At present, many of the currently marketed ARBs are designed to block AT₁ receptors with the dual intent of BP reduction and lowering the risk of cardiovascular events. However, despite the undisputed ability of ARBs to inhibit RAS, many patients continue to have inadequately controlled BP and succumb to associated cardiovascular events and metabolic disturbances that promote diabetes.⁷ Recently, newer-generation ARBs in development have been shown to not only block AT₁ receptors but to potentially confer protection against developing diabetes through partial activation of peroxisome proliferator-activated receptor-g (PPARg).⁷ Azilsartan (pronounced ay" zil sar' tan) medoxomil (TAK-491), one of the newer-generation bifunctional ARBs in development, is under investigation for the treatment of hypertension. A new drug application (NDA) for azilsartan medoxomil was submitted to FDA on April 28, 2010, by Takeda Pharmaceutical.⁸

CHEMISTRY, PHARMACOLOGY, AND PHARMACOKINETICS

Azilsartan [(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate] belongs to a class of ARBs with a molecular weight of 568.5 g/mol.⁹ RAS has a pivotal role in the regulation of BP, tissue perfusion, and fluid balance. Renin release by the juxtaglomerular apparatus of the glomerulus initiates the RAS hormonal cascade, but renin synthesis also occurs in other tissues, including the brain, ovary, and retina. Renin-mediated cleavage of the N-terminal segment of angiotensinogen, a high-molecular-weight globulin, yields angiotensin I, a biologically inert decapeptide. Angiotensin II formation occurs through the hydrolysis of angiotensin I by the membrane-bound exopeptidase ACE. ACE also inactivates vasodilator peptides such as bradykinin and kallidin. Angiotensin II is the major effector peptide of RAS and plays a key role in mediating a broad range of responses including: (1) sodium and fluid retention as a result of the stimulation of aldosterone production and release from the zona glomerulosa of the adrenal cortex; (2) systemic and renal arteriolar vasoconstriction; (3) activation of the sympathetic nervous system; and (4) cell growth.¹⁰

To date, at least 4 subtypes of angiotensin II receptors have been identified, but the AT₁ receptor subtype regulates all of the known clinical effects of angiotensin II.¹¹ All ARBs display high affinities for AT₁ receptors, with concentrations that inhibit 50% of the binding of angiotensin II (IC₅₀) ranging from approximately 1 nmol/L to up to 20 nmol/L.^11,12 In addition, all ARBs exhibit a high degree of protein binding, along with exerting varying degrees of insurmountable blockade.¹¹ Insurmountable blockade is characterized by the nonparallel displacement of angiotensin II response curves observed during in vitro studies. Insurmountable/surmountable antagonism classifies the interaction with the antagonist following a pre-incubation step, whereas competitive/noncompetitive blockade is related to experimental conditions in which there is simultaneous addition of ligand and antagonist. ARBs exert competitive blockade, since studies have demonstrated slow dissociation of these agents from the receptor.¹¹

Azilsartan is structurally related to candesartan, a benzimidazole-7-carboxylic acid derivative, but its 5-oxo-1,2,4-oxadiazole ring distinguishes it from candesartan. The presence of a 5-oxo-1,2,4-oxadiazole ring may increase the lipophilicity of a compound and thus improve its oral bioavailability.¹² Kohara and associates evaluated the binding affinity of azilsartan and numerous other ARBs to the angiotensin II receptor, using a bovine adrenal cortical membrane model to measure IC₅₀ values of the ARBs.¹² Azilsartan displaced [¹²⁵ I]angiotensin II bound to bovine adrenal cortical membranes with an IC₅₀ of 4.2x10^-7 M when 0.2 nM [¹²⁵ I]angiotensin II was used. The respective IC₅₀ values reported for losartan and candesartan were 1.5x10^-7 M and 1.1x10^-7 M. The investigators also assessed the ability of the various ARBs to inhibit pressor response induced by angiotensin II (100 ng/kg IV) in conscious male Sprague-Dawley rats. Following a 1 mg/kg oral dose, azilsartan inhibited the pressor response completely at 3 hours and 7 hours post-dose. Similarly, candesartan displayed complete inhibition of pressor response 3 hours post-dose (1 mg/kg) and 92% inhibition of pressor response 7 hours post-dose, whereas losartan showed 3 hour/7 hour inhibition of pressor responses of 21%/34%. A 10-fold reduction in the oral dose of azilsartan yielded 75% and 64% inhibition of pressor response at 3 hours and 7 hours, respectively.¹²

Iwai et al evaluated the effects of azilsartan and candesartan cilexetil on insulin resistance using type 2 diabetic KK-A^y mice.¹³ The KK-A^y mice received laboratory chow containing azilsartan or candesartan at doses of 0.0005%, 0.001%, and 0.005% for 2 weeks. At 2 weeks, an oral glucose tolerance test was performed after a 16-hour fast. Azilsartan and candesartan showed dose-dependent reductions in the increase in plasma glucose levels after a glucose load. Azilsartan, but not candesartan, significantly inhibited increases in glucose concentration at the middle dose of 0.001%. Both drugs significantly inhibited the increase in glucose concentration at the highest dose of 0.005%, but azilsartan showed more potent suppression of glucose levels than did candesartan. Azilsartan treatment induced significant glucose uptake in skeletal muscle and adipose tissue at all doses, whereas candesartan did not promote glucose uptake at the lowest dose. Moreover, at the higher doses, azilsartan tended to increase glucose uptake to a greater extent than candesartan. Both drugs exhibited dose-dependent suppression of tumor necrosis factor (TNF-α) in adipose tissue, but at the highest dose, azilsartan's inhibitory effect surpassed that of candesartan on TNF-α expression. Azilsartan and candesartan increased the expression of adiponectin, PPARg, C/EBP-a (CCAAT/enhancer-binding protein alpha), and aP2 (adipocyte protein 2) in adipose tissue. Reduction in TNF-α production may result in improved insulin resistance, and increased expression in adiponectin has been shown to reduce atherosclerotic changes. The investigators concluded that azilsartan may have the potential to serve as a treatment option for metabolic syndrome patients, who usually present with insulin resistance and atherosclerosis.

The role of ARBs in ameliorating ischemia reperfusion (IR) injury has not been fully elucidated. It has been proposed that myocardial protective effects against IR injury could be facilitated by activation of AT₂ receptors of angiotensin II, while damaging effects of AT₁ receptors are negated by ARBs.¹⁴ Ye and colleagues evaluated the impact of 4-day pretreatment of male Sprague-Dawley rats with azilsartan medoxomil alone (0.3-10 mg/kg/d) or in combination with pioglitazone 2.5 mg/kg/d (azilsartan 1-3 mg/kg/d), a PPARg agonist, and pioglitazone monotherapy (1.0-2.5 mg/kg/d) on myocardial infarct size.¹⁴ The highest dose of azilsartan medoxomil resulted in the smallest infarct size, followed by the combination regimen of pioglitazone 2.5 mg/kg/d and azilsartan medoxomil 3.0 mg/kg/d. Combination therapy conferred additive protective effects, as infarct size was significantly decreased in both combination regimens compared with azilsartan medoxomil alone and pioglitazone monotherapy. Azilsartan alone or in combination with pioglitazone, along with pioglitazone monotherapy attenuated left ventricular remodeling and improved left ventricular function 35 days post-MI. Additional beneficial effects attributed to pretreatment with azilsartan medoxomil included (1) protection against IR injury as a result of increased Akt and ERK_1/2 (anti-extracellular signal regulating kinase) phosphorylation, and (2) potential reduction in cell death secondary to apoptosis via inhibition of Bax (protein from Bcl-2 family of proteins) activation.

EFFICACY AND SAFETY

The NDA for azilsartan medoxomil included supporting data from 7 phase 3 clinical trials that included more than 5,900 patients. The safety and efficacy of this agent was evaluated for initial therapy as a once-daily oral monotherapy regimen, or as part of a combination regimen that included a dihydropyridine CCB (amlodipine) or a thiazide diuretic (chlorthalidone). Furthermore, phase 3 trial investigators assessed the comparative BP-lowering effects of azilsartan medoxomil and other ARBs, including olmesartan medoxomil and valsartan, along with the ACE inhibitor ramipril. The results have been submitted to FDA, and results from 5 phase 3 clinical trials have been published as abstracts.⁸

Phase 3 clinical trials that evaluated the efficacy of azilsartan medoxomil in combination with chlorthalidone included patients with baseline systolic BP in the range of 160 to 190 mmHg, and required proof of adequate contraception in female subjects of child-bearing age. Exclusion criteria included: (1) diastolic BP of 119 mmHg or higher; (2) poor-quality baseline 24-hour ambulatory BP monitoring (ABPM) data; (3) night-shift employment; (4) upper-arm circumference below 24 cm or above 42 cm; (5) noncompliance (missed or took more than 30% of doses) during placebo run-in period; (6) recent history (usually within 6 months) of MI, heart failure, unstable angina, coronary artery bypass graft surgery, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack; (7) clinically significant cardiac conduction defect; (8) hemodynamically significant left ventricular outflow obstruction due to aortic valve disease; (9) severe renal disease or renal artery stenosis; (10) history of cancer that was not in remission for a minimum of 5 years before receiving the initial dose of study drug; (11) poorly controlled type 1 or type 2 diabetes mellitus; (12) hypokalemia/hyperkalemia; (13) active liver disease, jaundice, or alanine/aspartate aminotransferase level exceeding 2.5 times upper limit of normal; (14) hypersensitivity to study drug; and (15) receiving medications that may interfere with evaluation of study drug.¹⁵ The inclusion criteria for phase 3 clinical trials that compared the efficacy of azilsartan medoxomil to that of valsartan, olmesartan medoxomil, or ramipril differed with regard to baseline trough (sitting) systolic BP, since a lower range of 150 to 180 mmHg was required for study inclusion.¹⁵ The exclusion criteria for phase 3 monotherapy trials paralleled the ones used in phase 3 combination therapy trials, except that patients with clinically significant renal impairment (creatinine clearance <30 mL/min/1.73 m² ) were excluded, and patients with baseline trough (sitting) diastolic BP ≥114 mmHg were not allowed to enroll in the studies.

A 6-week, multicenter, double-blind, randomized controlled study of 1,272 patients defined the BP-lowering efficacy of azilsartan medoxomil at once daily doses of 20 mg, 40 mg, and 80 mg.¹⁶ Comparators included placebo and olmesartan medoxomil 40 mg once daily. Change in 24-hr mean systolic BP by ABPM was the primary outcome measure. The study population with evaluable ABPM data consisted of 73% Caucasians, 11% African Americans, and 12% Hispanics. Patients had a mean body mass index of 30.2±6 kg/m² , and their mean age was 58±11 years. At 6 weeks, the 80-, 40-, and 20-mg doses of azilsartan medoxomil reduced 24-hour, placebo-corrected mean ABPM systolic BPs by 13.2 mmHg, 12.1 mmHg, and 10.8 mmHg respectively, compared with a decrease of 11.2 mmHg with olmesartan medoxomil 40 mg. The differences were nonsignificant between azilsartan medoxomil 20 mg, 40 mg, and 80 mg, along with olmesartan medoxomil 40 mg.

A similar clinical trial compared the BP-lowering effects of azilsartan medoxomil with valsartan, olmesartan medoxomil, and placebo, involving 1,291 primary hypertensive patients, of whom 54% were men.¹⁷ This study differed from the one that compared the antihypertensive efficacy of azilsartan medoxomil with that of olmesartan, by virtue of its up-titration study design, which had patients titrated from an initial intermediate dose to maximal doses of study drugs at 2 weeks. Patients underwent randomization to receive azilsartan medoxomil 40 mg/d, azilsartan medoxomil 80 mg/d, olmesartan medoxomil 40 mg/d, valsartan 320 mg/d, or placebo over a period of 6 weeks. The primary end point of this study was also the measurement of 24-hour mean change of systolic BP by ABPM. Changes in 24-hour mean systolic BP were -0.3 mmHg, -13.4 mmHg, -14.5 mmHg, -10.2 mmHg, -12.0 mmHg for placebo, azilsartan medoxomil 40 mg, azilsartan medoxomil 80 mg, valsartan 320 mg, and olmesartan 40 mg, respectively. Azilsartan medoxomil 80 mg/d showed superiority to both maximum-dose valsartan (4.3 mmHg lower; P<.001) and maximum-dose olmesartan medoxomil (2.5 mmHg lower; P=.009), while azilsartan medoxomil 40 mg showed noninferiority to maximum-dose olmesartan medoxomil (1.4 mmHg lower, P=.14).

The combination of azilsartan medoxomil with other antihypertensive agents has also been tested in phase 3 clinical trials to compare and contrast their BP-lowering effects.^18-20 Among the highlights of the American Society of Hypertension's 25^th Annual Scientific Meeting and Exposition was a phase 3, double-blind, randomized clinical trial comparing the less-commonly prescribed chlorthalidone and hydrochlorothiazide (HCTZ), both in combination with azilsartan medoxomil.¹⁸ The aim of the study was to examine the efficacy, safety, and tolerability of azilsartan medoxomil 40 mg administered in a fixed-dose combination with chlorthalidone 12.5 mg (titrated to 25 mg if needed) and azilsartan medoxomil 40 mg in free combination with HCTZ 12.5 mg (titrated to 25 mg if needed). The patient population consisted of 609 patients with baseline sitting systolic BPs of 160 to 190 mmHg. Change in sitting systolic BP from baseline to weeks 6 and 10 was the primary outcome measure. At week 6, systolic BP reductions were 35.1 mmHg and 29.5 mmHg for azilsartan medoxomil/chlorthalidone and azilsartan medoxomil/HCTZ, respectively (P<.001). At week 10, systolic BP reductions were also significantly greater with azilsartan medoxomil/chlorthalidone at 37.8 mmHg, compared to azilsartan medoxomil/HCTZ at 32.8 mmHg (P<.001). Serious adverse effects occurred in 2.0% of azilsartan medoxomil/chlorthalidone-treated patients and in 1.7% of azilsartan medoxomil/HCTZ-treated patients, while respective discontinuation rates due to medication-associated adverse effects were 9.3% for the azilsartan medoxomil/chlorthalidone group and 7.3% for the azilsartan medoxomil/HCTZ group.

Sica and associates examined the BP-lowering effects of azilsartan medoxomil 40 mg and 80 mg co-administered with chlorthalidone on 24-hr mean systolic BP by ABPM, the primary outcome measure of their study of 448 patients with stage 2 hypertension.¹⁹ The mean age of the patients was 59 years, and 16% were African Americans. Treatment with both combination regimens was associated with a significantly greater BP reduction versus chlorthalidone alone (absolute reduction, 15.5 to 15.9 mmHg, P<.001). More patients taking chlorthalidone alone experienced hypokalemia than patients who received azilsartan medoxomil in combination with chlorthalidone. Hypotension and reversible elevations in serum creatinine occurred more frequently in azilsartan medoxomil/chlorthalidone-treated patients than in chlorthalidone-treated patients.

The antihypertensive effects of azilsartan medoxomil 40 mg and 80 mg daily in combination with amlodipine 5 mg daily compared with amlodipine monotherapy was evaluated in a 6-week, double-blind, randomized study that included 562 patients with stage 2 hypertension.²⁰ Males comprised approximately half of the study population, and the mean age of the subjects was 58 years. Change in systolic BP by ABPM was the primary outcome measure. Azilsartan medoxomil 40 mg and azilsartan medoxomil 80 mg plus amlodipine 5 mg produced significant placebo-corrected decreases in 24-hour systolic BP by ABPM (-11.2 and -10.9 mmHg, respectively; P<.001 vs amlodipine). Peripheral edema occurred in 4.9% of amlodipine-treated patients and in 2.1% of patients who received azilsartan medoxomil in combination with amlodipine.

ADVERSE EFFECTS

Angiotensin II receptor antagonists exhibit an excellent tolerability profile, given that the incidence of side effects does not differ from placebo.^21–27 Some of the more common but infrequent adverse effects associated with the 7 currently marketed ARBs in the United States include upper-respiratory tract infection, dizziness, headache, fatigue, abdominal pain, back pain, sinusitis, and diarrhea. Phase 3 clinical trials of azilsartan medoxomil showed that the most commonly reported adverse effects associated with the use of this agent included dizziness (2.1%), increased creatine phosphokinase (1.1%), and diarrhea (1.0%).⁸

DRUG INTERACTIONS

Drug interaction information for azilsartan medoxomil has not been published. Reversible increases in serum lithium concentration and toxicity have been reported during concomitant administration of lithium and ARBs, thus concomitant use of lithium and azilsartan medoxomil could theoretically lead to an increase in serum lithium concentration and toxicity.²¹ Since the use of potassium-sparing diuretics or potassium supplements concurrently with an ARB can increase the potential for hyperkalemia, it would be prudent to avoid concomitant administration of these agents with azilsartan medoxomil.²¹ Nonsteroidal anti-inflammatory drug (NSAID) use in patients taking ARBs may result in deterioration of renal function.²¹ Consequently, the use of NSAIDs should probably be discouraged in a patient taking azilsartan medoxomil. Use of rifampin or fluconazole in patients taking losartan has resulted in 30% and 40% respective reductions in the AUC (area under the plasma concentration time curve) of the active metabolite of losartan.²¹ Concomitant administration of digoxin and telmisartan has been shown to increase peak and trough plasma concentrations of digoxin by 49% and 20%, respectively.²⁶ The propensity of azilsartan medoxomil to interact with digoxin, rifampin, and fluconazole has not been established.

DOSING AND ADMINISTRATION

Azilsartan doses ranging from 20 to 80 mg/d have been evaluated in numerous phase 3 trials.^16–20 In at least 1 clinical trial, patients were initially given 20 mg/d for 2 weeks and were then titrated to 40 or 80 mg/d.¹⁷ One phase 3 clinical trial showed no differences in BP-lowering efficacy between lower (20 mg/d) and higher doses (80 mg/d) of azilsartan medoxomil with regard to changes in systolic BP by ABPM.¹⁶ However, a different phase 3 clinical study showed superior BP-lowering effects of azilsartan medoxomil 80 mg once daily compared with maximum doses of valsartan and olmesartan medoxomil.¹⁷ Based on these data, 20 to 80 mg once a day would be a reasonable dose range for hypertensive patients receiving azilsartan medoxomil.

FORMULARY CONSIDERATION

At present, there are 7 ARBs marketed in the United States. Many of the ARBs have the ability to decrease rates of cardiovascular morbidity and mortality in patients afflicted with a variety of cardiovascular, renal, and other vascular conditions. Telmisartan represents the only ARB with the FDA indication of cardiovascular risk reduction in patients 55 years of age or older at heightened risk of developing major cardiovascular events who cannot take ACE inhibitors. Two ARBs, valsartan and candesartan cilexetil, are indicated for use in the treatment of patients with systolic heart failure. Valsartan has the additional indication for use in MI patients with evidence of heart failure or left ventricular dysfunction. Losartan and irbesartan represent the 2 ARBs with the indication for prevention of death and progression of renal impairment in type 2 diabetes patients with advanced nephropathy.

Azilsartan medoxomil (TAK-491) is a next-generation ARB that has been studied in numerous phase 3 clinical trials and is structurally related to candesartan. Phase 3 clinical trials have compared this agent's BP-lowering effect to that of valsartan and olmesartan medoxomil, both of which have demonstrated superior antihypertensive effects relative to losartan. Results indicated that maximum-dose azilsartan medoxomil showed superior efficacy in lowering 24-hour mean systolic BP by ambulatory BP measurement in hypertensive patients compared to maximum doses of valsartan and olmesartan medoxomil.

Phase 3 clinical trials have also studied azilsartan medoxomil in combination with chlorthalidone for the treatment of hypertensive patients. Results from large-scale clinical trials have shown that azilsartan medoxomil with chlorthalidone demonstrated greater reduction in systolic BP than azilsartan in combination with hydrochlorothiazide. Further studies are needed to establish azilsartan's metabolic benefits to see whether it can offset or even override chlorthalidone's adverse effects on glucose metabolism. If so, azilsartan and chlorthalidone combination may prove to be an attractive option from a metabolic and hemodynamic perspective.

Issues that have not been addressed in published clinical trials include the drug interaction profile of azilsartan medoxomil, its pharmacokinetic profile, and its efficacy in the management of conditions other than hypertension, such as heart failure, MI, and diabetic nephropathy. Until additional indications for azilsartan medoxomil are evaluated in phase 3 clinical trials, azilsartan medoxomil's place on a formulary remains unclear.

Ms Singh and Mr Fung Fung are pharmacy doctoral candidates at University of the Pacific School of Pharmacy, Stockton, Calif. Dr Song is associate professor of pharmacy practice at University of the Pacific School of Pharmacy; regional coordinator, San Jose Clinical Experience Program; and SCVH&HS PGY1 pharmacy residency coordinator, Department of Pharmacy Services, Santa Clara Valley Medical Center, San Jose, Calif.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, medical editor, Department of Pharmacy Services, University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn., and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, associate professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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