Single-dose pharmacokinetics and safety of azilsartan medoxomil in children and adolescents with hypertension as compared to healthy adults

Abstract

PurposeThis open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12–16 years [cohort 1a; n = 9]; 6–11 years [cohort 2; n = 8]; 4–5 years [cohort 3; n = 3]).MethodsModel-based simulations were performed to guide dosing, especially in 1–5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20–60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg.ResultsExposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized Cmax and AUC0–∞, was ∼15–30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8–25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25–50-kg subjects require half the adult dose (10–40 mg), whereas 50–100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine).ConclusionsThis dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1987-8) contains supplementary material, which is available to authorized users.

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

“…In the current study the mean CL/F of AZL was 1.6 L/h, which is close to the values of 1.47‐1.5 L/h reported in white and black subjects . Thus, no substantial differences in CL/F were found among racial/ethnic groups.…”

Low body mass index is a risk factor for hyperkalaemia associated with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers treatments

“…Body size such as BMI and total body weight is relevant for pharmacokinetics parameters including clearance and the volume of distribution . In previous reports, the clearance of perindopril and azilsartan declined in low body weight patients compared with that in high body weight patients . The incidence of hyperkalaemia associated with ACEI and ARB treatments is higher in non‐obese patients than that in obese patients .…”

“…13,14 In previous reports, the clearance of perindopril and azilsartan declined in low body weight patients compared with that in high body weight patients. 18,19 The incidence of hyperkalaemia associated with ACEI and ARB treatments is higher in non-obese patients than that in obese patients. 6 Furthermore, our results indicate the incidence of hyperkalaemia is the highest in underweight patients.…”

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

“…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 …”

“…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.…”