Maria R. Marino

The Pharmacokinetics of Irbesartan in Hypertensive Children and Adolescents

An open‐label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1–12 years) and adolescents (13–16 years) with hypertension. Patients received single once‐daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high‐performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day1, and up to 48 hours after the final dose. The plasma concentration‐time profiles were similar between the 6‐ to 12‐year and the 13‐ to 16‐year age groups and to that previously determined from a study of adult subjects receiving 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and maybe a treatment option for pediatric hypertensive patients.

Pharmacokinetics and pharmacodynamics of irbesartan in healthy subjects

The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT1 blocker irbesartan were assessed in healthy subjects. In this single‐center, placebo‐controlled, double‐blind within dose group, sequential, dose‐ascending study, 48 men were randomized to receive irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group), followed by 3 days of placebo, and then multiple doses of irbesartan or placebo once daily for 7 days. The values for plasma area under the concentration—time curve (AUC) of irbesartan were dose proportional up to 600 mg. There were no significant differences between the dose groups in time to maximum concentration (tmax) or half‐life (t1/2) after single and multiple doses. After multiple doses, urinary recovery was significantly lower in the 600‐mg and 900‐mg dose groups compared with the 150‐mg and 300‐mg dose groups. Steady‐state concentrations of irbesartan were achieved within 3 days of administration with no clinically important accumulation. Irbesartan produced dose‐dependent increases in plasma renin activity and AII levels. Irbesartan was well tolerated at doses from 150 mg to 900 mg daily; a maximally tolerated dose was not reached. Modest decreases in blood pressure without orthostatic symptoms were observed at irbesartan doses of 300 mg or higher. These results demonstrated the dose‐proportionality of irbesartan 150 mg to 600 mg and indicated that doses up to 900 mg daily were well tolerated.

The pharmacokinetics of irbesartan in renal failure and maintenance hemodialysis

An open‐label, multiple‐dose, parallel‐group study was conducted to evaluate the pharmacokinetics of the angiotensin II receptor antagonist irbesartan in subjects with varying degrees of renal function.

Pharmacokinetics and Pharmacodynamics of Irbesartan in Patients with Hepatic Cirrhosis

The effect of hepatic impairment on the clinical pharmacology of the angiotensin II (AII) receptor antagonist irbesartan was assessed by comparing pharmacokinetic and pharmacodynamic parameters in 10 patients with hepatic cirrhosis with a matched group of 10 healthy volunteers. The pharmacokinetics and pharmacodynamics of irbesartan, 300 mg taken orally once daily, were evaluated after single‐ and multiple‐dose (7 consecutive days) administration to normotensive subjects in an open‐label, multiple‐dose, parallel group study. Pharmacokinetic data obtained after administration of single and multiple doses of irbesartan showed no significant difference between the two groups in time to maximum observed plasma concentration of drug (tmax), half‐life (t1/2), area under the plasma concentration‐time curve (AUC), apparent oral clearance (Clt/F), renal clearance (Clr), and accumulation index (AI). Steady‐state levels of irbesartan were reached within 3 days in both treatment groups. After irbesartan administration on day 1, mean increases from baseline in plasma AII levels and plasma renin activity (PRA) were greater in the group with cirrhosis than in the control group. On day 7, mean increases from baseline in PRA were greater in the control group than in the group with cirrhosis. No discontinuations or serious adverse events occurred during the study. The pharmacokinetics of irbesartan after repeated oral administration were not significantly affected in patients with mild‐to‐moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.

Drug interactions with irbesartan.

AbstractIrbesartan is an angiotensin II receptor antagonist indicated for the treatment of patients with hypertension. Although irbesartan does not require biotransformation for its pharmacological activity, it does undergo metabolism via the cytochrome P450 (CYP) 2C9 isoenzyme and negligible metabolism by the CYP3A4 isoenzyme. The long term treatment of patients with hypertension is generally required for effective management of the disease, and the use of concurrent medications is usually inevitable. This paper reviews the drug and food interaction trials involving irbesartan that have been conducted to date.Based on the available literature, no significant interactions have been identified between irbesartan and hydrochlorothiazide, nifedipine, simvastatin, tolbutamide, warfarin, magnesium and aluminum hydroxides, digoxin or food. Fluconazole did increase the steady-state peak plasma concentration (by 19%) and area under the concentration-time curve (by 63%) of irbesartan, but these increases are not likely to be clinically significant. In summary, irbesartan has demonstrated minimal potential for drug or food interactions in trials conducted to date.

Pharmacokinetics of Irbesartan are not altered in special populations

Summary:Studies were conducted to determine whether pharmacokinetics of irbesartan (IRBE), a potent, long-acting angiotensin (AT)-II receptor antagonist selective for AT-II type 1 receptor subtype, are altered in patients with renal impairment (RI), hepatic impairment (HI), or heart failure (HF) or

Effect of Hydrochlorothiazide on the Pharmacokinetics and Pharmacodynamics of the Angiotensin II Blocker Irbesartan

SummaryThe primary objective of this study was to assess the effect of hydrochlorothiazide on the pharmacokinetics of irbesartan in patients with mild-to-moderate hypertension. In addition, this study compared the pharmacodynamic and tolerability profiles of irbesartan administered both alone and in combination with hydrochlorothiazide. The study consisted of a placebo lead-in period (period A) to establish the stability of blood pressure (seated diastolic blood pressure 95 to 110mm Hg), a 7-day, single-blind treatment period (irbesartan 150mg every day) (period B), and a 7-day, double-blind treatment period [irbesartan 150mg every day plus either placebo (n = 18) or hydrochlorothiazide 25mg every day (n = 18)] (period C). Non-Black men and women 45 to 65 years of age with hypertension were included. The pharmacokinetic profile [maximum concentration of irbesartan in plasma (Cmax), time taken to reach Cmax (tmax), and the area under the plasma concentration versus time curve during a dosage interval (AUCtau)] of irbesartan was unaffected by the addition of hydrochlorothiazide. Mean changes in 24-hour AUC values for seated blood pressures from day 7 of period B to day 7 of period C were significantly lower in patients treated with irbesartan plus hydrochlorothiazide compared with those of patients treated with irbesartan plus placebo. Plasma angiotensin II levels, plasma renin activity, and urinary excretion of sodium, chloride and potassium were significantly increased, whereas urinary aldosterone and creatinine excretion remained unchanged with concomitant hydrochlorothiazide administration.Adding hydrochlorothiazide to irbesartan: (a) does not alter the pharmacokinetics of irbesartan, (b) produces further reductions in blood pressure, (c) produces further increases in plasma angiotensin II levels and plasma renin activity, and (d) is not associated with any clinically important tolerability concerns.

Irbesartan Does Not Affect the Pharmacokinetics of Simvastatin in Healthy Subjects

This open‐label, single‐dose, crossover study was conducted to assess the effect of irbesartan on the pharmacokinetics of total simvastatin acid in 14 healthy subjects. Subjects were randomized to receive one simvastatin 40 mg tablet or one simvastatin 40 mg tablet + one irbesartan 300 mg tablet. Subjects were crossed over to the other treatment after a 7‐ to 10‐day washout period. Serum samples were collected at specified times before and over a 24‐hour period after dosing. Safety was assessed by monitoring vital signs, laboratory tests, and adverse events. Irbesartan did not exhibit a clinically significant effect on the peak serum concentration and area under the concentration versus time curve to infinity (AUC0‐∞) of total simvastatin acid. The mean AUC0‐∞ of total simvastatin acid was 74.55 ng × h/mL when simvastatin was given alone and 67.55 ng × h/mL when simvastatin and irbesartan were given concomitantly. The time to peak serum concentration for both treatments was 3 hours. No serious adverse events occurred during the study, and both agents were well tolerated. In summary, irbesartan had no significant effect on the single‐dose pharmacokinetics of total simvastatin acid.

The effect of ravuconazole on the pharmacokinetics of nelfinavir in healthy male volunteers.

An open‐label, nonrandomized study was conducted to assess the effect of ravuconazole on the pharmacokinetics of concomitantly administered nelfinavir. Healthy volunteers received 750 mg nelfinavir on day 1, 750 mg nelfinavir and 400 mg ravuconazole on day 2, 400 mg ravuconazole on days 3 to 28, and 750 mg nelfinavir and 400 mg ravuconazole on day 29. The geometric means of Cmax and area under the curve of nelfinavir coadministered with ravuconazole were 30.7% and 31.9% higher on day 2 and 7.9% and 16.2% lower on day 29, respectively, compared to the corresponding values on day 1. These findings are consistent with the potential for ravuconazole to both inhibit and induce CYP3A isozymes. The alterations in the systemic exposure to nelfinavir were within the range defined by the 90% confidence interval. The study data indicate that coadministration of ravuconazole did not result in a clinically significant change in the plasma levels of nelfinavir.

Effect of Nifedipine on the Steady-State Pharmacokinetics and Pharmacodynamics of Irbesartan in Healthy Subjects

Background: In clinical practice, nifedipine has the potential to alter the pharmacokinetics, and therefore possibly the pharmacodynamics and efficacy or safety, of irbesartan. The objectives of the current study were to determine the effects of concomitant administration of nifedipine on the steady-state pharmacokinetics and pharmacodynamics of irbesartan in 12 healthy subjects. Methods and Results: This was an open-label, randomized, crossover study. Each subject received irbesartan 300 mg once daily for 4 days in one period and irbesartan 300 mg once daily plus long-acting nifedipine (Procardia XL, Pratt Pharmaceuticals, New York, NY) 30 mg once daily for 4 days in the other period. The order of treatment periods was random ized, and a minimum 7-day washout phase separated the two periods. Steady state was achieved by day 3. On day 4, no significant differences were observed between the two treatments with respect to maximum concentration of irbesartan at the end of the dosing interval (Cmax) or the area under the plasma concentration versus time curve during a dos ing interval (AUCtau) of irbesartan. Steady-state Cmax and AUCtau met the criteria for bioequivalence when irbesartan was administered alone or with nifedipine. On day 4, mean plasma renin activity was somewhat higher at every point but one when irbesartan was administered with nifedipine; however, no significant difference was observed between the two treatments in mean 24-hour AUC values. On day 4, there was a modest overall decrease from baseline in mean blood pressure for both treatments. No significant differences were observed between the two treatments in mean 24-hour AUC values for seated diastolic or systolic blood pressure. No serious adverse events were reported. Conclusions: Concomitant administration of nifedipine 30 mg with irbesartan 300 mg for 4 days in healthy subjects (1) does not alter the steady-state pharmacokinetic parameters of irbesartan, (2) results in Cmax and AUCtau values for irbesartan that meet the criteria for bioequivalence, and (3) is well tolerated.