Irbesartan

Irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT₁) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT₁ receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT₁) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.

Absorption

After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan.

Distribution

Plasma protein binding is approximately 96%, with negligible binding to cellular blood components.

The volume of distribution is 53-93 litres.

Biotransformation

Following oral or intravenous administration of ¹⁴C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.

Linearity/non-linearity

Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg.

A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157-176 and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours.

Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and C_max values were also somewhat greater in older subjects (≥65 years) than those of young subjects (18-40 years).

However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people.

Elimination

Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of ¹⁴C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.

Paediatric population

The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that C_max, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing.

Renal impairment

In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis.

Hepatic impairment

In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered.

Studies have not been performed in patients with severe hepatic impairment.

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (≥250 mg/kg/day in rats and ≥100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit).

At very high doses (≥500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥90 mg/kg/day, in macaques at ≥10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance.

There was no evidence of mutagenicity, clastogenicity or carcinogenicity.

Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. Irbesartan is excreted in the milk of lactating rats.

Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit.