The purpose of this study was to assess the pharmacokinetics (PK) and safety of a single
dose of azilsartan medoxomil in children with hypertension, and comparative PK in healthy
adults.
Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536 Metabolite M-II.
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536 Metabolite M-II
Maximum Observed Plasma Concentration (Cmax) for TAK-536
Maximum Observed Plasma Concentration (Cmax) for TAK-536 Metabolite M-II
Time to Reach Cmax (Tmax) for TAK-536
Time to Reach Cmax (Tmax) for TAK-536 Metabolite M-II
Terminal Elimination Half-life (T1/2) for TAK-536
Terminal Elimination Half-life (T1/2) for TAK-536 Metabolite M-II
Apparent Oral Clearance (CL/F) for TAK-536
Total Amount of Drug Excreted in Urine From Time 0 to 24 Hours Postdose (Ae[0-t]) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)
Total Amount of Drug Excreted in Urine From Time 0 to 24 Hours Postdose (Ae[0-t]) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)
Fraction of Unchanged Drug Excreted in Urine From 0 to 24 Hours Postdose (Fe%) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)
Fraction of Unchanged Drug Excreted in Urine From 0 to 24 Hours Postdose (Fe%) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)
Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)
Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)
Inclusion Criteria:
For Pediatric Participants:
Must have a diagnosis of hypertension (SBP and/or DBP ≥95th percentile for
age/gender/height).
- For Cohorts 1 and 2 only, is within the weight range of 20 kg (44 pounds) to 100 kg
(220 pounds), inclusive, at Screening.
- For Cohort 3 only, weighs at least 8. 0 kg (17. 6 pounds) at Screening.
- Participants greater than or equal to 6 years of age must have the ability to swallow
a tablet of the size 6. 0 millimeter diameter and 3. 5 millimeter thickness.
- Has no known history of hepatitis B, hepatitis C, and human immunodeficiency virus.
- For Cohort 3 only, may be renal transplant patient if all other inclusion and none of
the exclusion criteria are met, along with additional criteria.
- Must have been at a constant weight, or expected weight gain for that particular age,
for 30 days with no change to the dose of their diuretic drugs.
For Healthy Adult Participants:
- Weighs at least 50 kilograms (110 pounds) and has a screening body mass index between
18 and 32 kilograms/m2, inclusive.
- Is in good health as determined by the physician
- Has a negative test result for hepatitis B surface antigen and antibody to hepatitis
C virus, and has no known history of human immunodeficiency virus.
- Must have a negative urine test result for selected substances of abuse .
- Has a diastolic blood pressure between 60 and 90 mm Hg, inclusive, and a systolic
blood pressure between 100 and 140 mm Hg, inclusive.
For All Participants:
- Females of child bearing potential who are sexually active, as well as sexually
active male participants, agree to routinely use adequate contraception from
Screening until 30 days after receiving the last dose of study medication.
- Has clinical laboratory results within the reference range for the testing laboratory
unless the results are deemed not clinically significant by the investigator.
Exclusion Criteria:
For Pediatric Participants:
- Is currently treated with more than 2 antihypertensive agents.
- Has sitting trough clinic systolic blood pressure greater than 15 mm Hg or diastolic
blood pressure greater than 10 mm Hg above the 99th percentile for age, gender, and
height at Check-in .
- Has renovascular disease affecting both kidneys or a solitary kidney, dialysis
treatment, severe nephrotic syndrome and not in remission.
- For Cohort 1 and 2 only, a previous renal transplant.
- Has a creatinine clearance less than 30 mL/min/1. 73 m2.
For all participants:
- Has previously received azilsartan or azilsartan medoxomil.
- Has a known hypersensitivity or allergy to any angiotensin type II receptor blockers
or to any of the excipients in the azilsartan medoxomil formulation to be taken.
- Has a history or clinical manifestations of severe cardiovascular disease,
psychiatric disease, and any conditions that would interfere with gastrointestinal
absorption.
- Has hemodynamically significant left ventricular outflow obstruction due to aortic
valvular disease, cardiomyopathy, or uncorrected coarctation of the aorta.
- Has been diagnosed with malignant or accelerated hypertension.
- Has severe hepatic impairment.
- Has a serum albumin less than 2. 5 g/dL.
- Has a glycosylated hemoglobin value greater than 8. 5%.
- Has alanine aminotransferase, aspartate aminotransferase greater than 2 times the
upper limit of normal, or total bilirubin greater than 1. 5 times the upper limit of
normal, active liver disease, or jaundice.
- Has hyperkalemia as defined by the laboratory normal reference range or any pertinent
electrolyte disorders.
- Is participating in another investigational study or has taken an investigational
drug within 30 days prior to Check-in .
- Has a history of drug abuse or a history of alcohol abuse within 1 year prior to
study Check-in.
- Has a history of abdominal surgery or thoracic or nonperipheral vascular surgery
within 6 months prior to study Check-in.
- Has a history of cancer, other than basal cell carcinoma or stage I squamous cell
carcinoma of the skin that has not been in remission for at least 5 years prior to
study Check-in.
- Has taken any cytotoxic drugs within 12 months prior to study Check-in .
- Has a history or presence of a clinically significant abnormal 12-lead
electrocardiogram as determined by the investigator or sponsor/designee.
- Has poor peripheral venous access.
- Has any other condition or prior therapy that, in the opinion of the investigator,
would make the participant unsuitable for the study.
- Has taken or requires the use of any medications, supplements, or food products
within the stated time periods, including:
- Pediatric participants taking angiotensin-converting enzyme inhibitors and other
angiotensin II receptor blockers will be required to withhold these medications
from the morning of Day - 1 until the 24 hour pharmacokinetic sample is completed
on Day 2.
- Only pediatric participants will be allowed to take medications for primary
renal or urologic conditions or hypertension as long as they have been on a
stable dose of their medication for at least 30 days prior to Check-in (Day - 1)
and those medications are not potent cytochrome P-450 inhibitors or inducers.
- Nutraceuticals including herbal or dietary preparations such as ginseng, kava
kava, and ginkgo biloba.
- Over-the-counter medications.
- Vitamin supplements except for pediatric participants only.
- Alcohol-containing products.
- Products that contain caffeine or xanthine-related compounds.
- Foods or beverages containing grapefruit juice or Seville-type oranges.
