Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects

Harrell, Robert E.; Karim, Aziz; Zhang, Wencan; Dudkowski, Caroline

doi:10.1007/s40262-015-0333-8

Cited by 8 publications

(10 citation statements)

References 12 publications

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“…Peak plasma concentrations of azilsartan are reached within 1.5–3 hours after oral administration of the prodrug, and the elimination half‐life of azilsartan is approximately 11 hours. Coadministration with food has minimal effects on bioavailability . Chlorthalidone reaches peak plasma concentrations about 2–6 hours after oral administration, and the drug has a half‐life of about 42 hours .…”

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confidence: 56%

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Effects of Food Intake on the Pharmacokinetics of Azilsartan Medoxomil and Chlorthalidone Alone and in Fixed‐Dose Combination in Healthy Adults

Dudkowski

Karim

Munsaka

2016

Clinical Pharm in Drug Dev

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Azilsartan medoxomil is a long‐acting angiotensin II receptor blocker used to treat hypertension as monotherapy or in fixed‐dose combination (FDC) with chlorthalidone. This study assessed the effects of food intake on the plasma pharmacokinetics of the active moiety, azilsartan, and of chlorthalidone when administered as separate tablets or in FDC. Cohort 1 (n = 24) received azilsartan medoxomil (80 mg) and chlorthalidone (25 mg) once in a fasted condition and once 30 minutes after the initiation of a high‐fat meal (fed). Cohort 2 (n = 24) received the same drugs as an FDC tablet in the fasted and fed conditions. In cohort 1, the fed‐fasted ratios for AUC0–inf and Cmax were 108.3 (101.6–115.5) and 103.7 (94.3–114.1), respectively, for azilsartan and 112.3 (106.5–118.4) and 100.3 (90.6–111.1), respectively, for chlorthalidone. In cohort 2, the corresponding ratios were 78.6 (67.6–91.4) and 78.6 (64.4–96.0) for azilsartan and 101.0 (96.5–86.7) and 75.9 (66.5–86.7) for chlorthalidone. The combination therapies were well tolerated, and food intake had no consistent effect on adverse events. Food intake had a somewhat greater effect on plasma pharmacokinetics after administration of the FDC tablet than after administration of separate tablets, but the effects of food on the plasma pharmacokinetics of the FDC were not expected to be clinically meaningful.

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confidence: 56%

“…Coadministration with food has minimal effects on bioavailability. 8 Chlorthalidone reaches peak plasma concentrations about 2-6 hours after oral administration, and the drug has a half-life of about 42 hours. 9 There is no evidence of significant pharmacokinetic interactions between azilsartan medoxomil and chlorthalidone.…”

mentioning

confidence: 99%

Effects of Food Intake on the Pharmacokinetics of Azilsartan Medoxomil and Chlorthalidone Alone and in Fixed‐Dose Combination in Healthy Adults

Dudkowski

Karim

Munsaka

2016

Clinical Pharm in Drug Dev

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“…The differences in the pharmacokinetics of AZL between the sexes and races (white and black) have also been examined. These studies revealed no clinically significant differences in AZL exposure for these populations …”

Section: Discussionmentioning

confidence: 82%

“…These studies revealed no clinically significant differences in AZL exposure for these populations. [19][20][21] In this single-center, open-label, parallel-group study in 32 subjects with mild to moderate hepatic impairment, the single-dose and multiple-dose pharmacokinetic profiles of AZL and its metabolite M-II were studied. Subjects with mild or moderate hepatic impairment did have increases in mean plasma exposure to AZL of up to 64% and to M-II of up to 40% compared with matched control subjects.…”

Section: Discussionmentioning

confidence: 99%

Single‐Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment

Dudkowski

Karim

Zhao

et al. 2017

The Journal of Clinical Pharma

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Azilsartan medoxomil (AZL‐M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose‐dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M‐II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single‐center, open‐label, phase 1 parallel‐group study that examined the single‐dose (day 1) and multiple‐dose (days 4–8) — 40 mg — pharmacokinetics of AZL and M‐II in 16 subjects with mild and moderate hepatic impairment by Child‐Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M‐II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M‐II. Single and multiple doses of AZL‐M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL‐M is required for subjects with mild and moderate hepatic impairment.

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“…AZL is highly bound to human plasma proteins (>99%), mainly serum albumin. The volume of distribution of AZL is approximately 16 L. The pharmacokinetic characteristics of AZL are practically identical to those of its prodrug azilsartan medoxomil …”

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confidence: 89%

Clinical Evaluation of the Tolerability and Pharmacokinetics of Azilsartan, a Potent Angiotensin Receptor Blocker, in Healthy Chinese Subjects

Liu

Sheng

et al. 2019

Clinical Pharm in Drug Dev

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Azilsartan (AZL), the active metabolite of azilsartan medoxomil, is the newest angiotensin receptor blocker that has been approved for the treatment of hypertension in 2012 in Japan. The present study aimed to evaluate the safety and pharmacokinetic properties of AZL in healthy Chinese subjects. We performed 2 phase 1 studies to investigate the pharmacokinetics and safety of AZL in healthy Chinese adults after a single dose (20 mg or 40 mg) or multiple doses of AZL (40 mg/d for 7 days; Study I) and after a single 40-mg dose under the fasted and fed conditions (Study II). Noncompartmental analysis and nonlinear mixed-effects modeling were used to analyze the pharmacokinetic properties of AZL. Twenty-seven healthy volunteers (14 men and 13 women) aged 20-32 years were enrolled and completed the study. During single dosing of AZL, the pharmacokinetics of AZL exhibited a linear profile between dosage and area under the concentration-time curve. There is no AZL accumulation after multiple doses. Food had no effect on the pharmacokinetic characteristics of AZL. AZL concentrations were best fit with a 2-compartment model, and the typical value of clearance was 1.63 L/h. Body weight had an impact on both the apparent clearance and peripheral volume of distribution. The pharmacokinetic parameters were consistent with previous studies in non-Chinese subjects. Modelbased simulations indicated that a 45-kg subject would have approximately double the AZL exposure of a 90-kg subject. Whether the exposure difference has clinical significance needs to be confirmed in further studies among patients.Azilsartan (AZL), the active moiety of azilsartan medoxomil, is an angiotensin receptor blocker. In 2012 AZL was approved for the treatment of hypertension in Japan. For the management of hypertension, AZL should be administered at a dose of 20 mg once daily (maximum dose, 40 mg once daily) according to the label information for Azilva. [1][2][3] After oral administration, plasma concentrations of AZL peak within 1.8-2.4 hours, and the elimination half-life (t ½ ) is approximately 13 hours. 4 AZL is eliminated through both renal clearance and hepatic metabolism. 4 Its renal clearance is 0.138 L/h, and its apparent oral clearance is 1.5 L/h. AZL is highly bound to human plasma proteins (>99%), mainly serum albumin. The volume of distribution of AZL is approximately 16 L. The pharmacokinetic characteristics of AZL are practically identical to those of its prodrug azilsartan medoxomil. [4][5][6][7] Cytochrome P-450 (CYP)2C9 is the major enzyme responsible for AZL metabolism. Because the frequency of CYP2C9 polymorphic alleles shows

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Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects

Cited by 8 publications

References 12 publications

Effects of Food Intake on the Pharmacokinetics of Azilsartan Medoxomil and Chlorthalidone Alone and in Fixed‐Dose Combination in Healthy Adults

Effects of Food Intake on the Pharmacokinetics of Azilsartan Medoxomil and Chlorthalidone Alone and in Fixed‐Dose Combination in Healthy Adults

Single‐Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment

Clinical Evaluation of the Tolerability and Pharmacokinetics of Azilsartan, a Potent Angiotensin Receptor Blocker, in Healthy Chinese Subjects

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