Azilsartan medoxomil

Azilsartan medoxomil is an orally active prodrug that is rapidly converted to the active moiety, azilsartan, which selectively antagonises the effects of angiotensin II by blocking its binding to the AT₁ receptor in multiple tissues. Angiotensin II is the principal pressor agent of the RAAS, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.

Blockade of the AT₁ receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increases in plasma renin activity and angiotensin II circulating levels do not overcome the antihypertensive effect of azilsartan.

Following oral administration, azilsartan medoxomil is rapidly hydrolyzed to the active moiety azilsartan in the gastrointestinal tract and/or during absorption. Based on in vitro studies, carboxymethylenebutenolidase is involved in the hydrolysis in the intestine and liver. In addition, plasma esterases are involved in the hydrolysis of azilsartan medoxomil to azilsartan.

Absorption

The estimated absolute oral bioavailability of azilsartan medoxomil based on plasma levels of azilsartan is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations (C_max) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.

Distribution

The volume of distribution of azilsartan is approximately 16 litres. Azilsartan is highly bound to plasma proteins (>99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.

Biotransformation

Azilsartan is metabolised to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% that of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of azilsartan medoxomil. The major enzyme responsible for azilsartan metabolism is CYP2C9.

Elimination

Following an oral dose of ¹⁴C-labelled azilsartan medoxomil, approximately 55% of radioactivity was recovered in faeces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. 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 achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.

Linearity/non-linearity

Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.

Characteristics in specific groups of patients

Paediatric population

The population pharmacokinetics of azilsartan following oral doses of azilsartan medoxomil were evaluated in hypertensive children aged 6 to <18 years in a single dose study as well as in a multiple dose study of 10 mg to a maximum of 80 mg for 6 weeks. Generally, a dose proportional increase of the maximum concentration (C_max,ss) and exposure (AUC_ss) of azilsartan was observed. Exposure of azilsartan was dependent on body weight, generally a higher exposure was observed for paediatric patients weighing ≤50 kg compared to those weighing >50 kg. The azilsartan exposure was similar between children and adults when allometric scaling was applied.

Older people

Pharmacokinetics of azilsartan do not differ significantly between young (age range 18-45 years) and elderly (age range 65-85 years) patients.

Renal impairment

In patients with mild, moderate, and severe renal impairment azilsartan total exposure (AUC) was +30%, +25% and +95% increased. No increase (+5%) was observed in end-stage renal disease patients who were dialysed. However, there is no clinical experience in patients with severe renal impairment or end stage renal disease. Hemodialysis does not remove azilsartan from the systemic circulation.

Hepatic impairment

Administration of azilsartan medoxomil for up to 5 days in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment resulted in slight increase in azilsartan exposure (AUC increased by 1.3 to 1.6 fold). Azilsartan medoxomil has not been studied in patients with severe hepatic impairment.

Gender

Pharmacokinetics of azilsartan do not differ significantly between males and females. No dose adjustment is necessary based on gender.

Race

Pharmacokinetics of azilsartan do not differ significantly between black and white populations. No dose adjustment is necessary based on race.

In preclinical safety studies, azilsartan medoxomil and M-II, the major human metabolite, were examined for repeated-dose toxicity, reproduction toxicity, mutagenicity and carcinogenicity.

In the repeated-dose toxicity studies, doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters, changes in the kidney and renal haemodynamics, as well as increased serum potassium in normotensive animals. These effects, which were prevented by oral saline supplementation, do not have clinical significance in treatment of hypertension.

In rats and dogs, increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of angiotensin converting enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical significance.

Azilsartan and M-II crossed the placenta and were found in the fetuses of pregnant rats and were excreted into the milk of lactating rats. In the reproduction toxicity studies, there were no effects on male or female fertility. There is no evidence of a teratogenic effect, but animal studies indicated some hazardous potential to the postnatal development of the offspring such as lower body weight, a slight delay in physical development (delayed incisor eruption, pinna detachment, eye opening), and higher mortality.

Azilsartan and M-II showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice.

Juvenile animal studies

Juvenile oral toxicity studies up to 3 months in duration in rats (2 or 3 weeks old) with azilsartan medoxomil, alone or in combination with M-II, showed that juvenile rats may be more susceptible to angiotensin-related altered renal morphology and function when exposed from postnatal week 2, corresponding with the period of growth and maturation of the renal system. The growth and maturation stage of the human renal system extends to about 2 years of age.