Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label, Multicenter Study

Abstract

IntroductionAzilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients.MethodsIn this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg.ResultsMean maximum plasma concentration (Cmax) of azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (Tmax) of unchanged azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC0–24) and 0 h to infinity (AUC0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to azilsartan occurred during the study.ConclusionOur data suggest that pediatric patients weighing less than 50 kg may have approximately 2-fold greater exposure to azilsartan than those weighing at least 50 kg at the same dose. Exposure to azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose.Trial RegistrationClinicalTrials.gov identifier, NCT02451150.FundingTakeda Pharmaceutical Co. Ltd.

Safety and efficacy of azilsartan in paediatric patients with hypertension: a phase 3, single-arm, open-label, prospective study

“…Previous clinical trials in the United States and Europe have indicated that the BP-lowering effects of ARBs (candesartan, cilexetil and valsartan) in children are consistent with those in adults [9,10]. A single-dose, phase 3 study evaluating the pharmacokinetics and safety of azilsartan in Japanese children with hypertension reported no unexpected safety issues [11]. The Japanese study also showed that for the same dose, exposure to azilsartan in paediatric patients weighing ≥ 50 kg was comparable to that in healthy adults; however, in children weighing < 50 kg, the exposure was approximately twice as high [11].…”

“…A single-dose, phase 3 study evaluating the pharmacokinetics and safety of azilsartan in Japanese children with hypertension reported no unexpected safety issues [11]. The Japanese study also showed that for the same dose, exposure to azilsartan in paediatric patients weighing ≥ 50 kg was comparable to that in healthy adults; however, in children weighing < 50 kg, the exposure was approximately twice as high [11]. Herein, we evaluate the long-term safety and efficacy of azilsartan in young patients with hypertension in Japan.…”

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

“…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 …”

“…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 . AZL is eliminated through both renal clearance and hepatic metabolism . Its renal clearance is 0.138 L/h, and its apparent oral clearance is 1.5 L/h.…”