A Comparative Single-Dose Pharmacokinetic (PK) and Safety Study of Azilsartan Medoxomil in Children With Hypertension and in Healthy Adults

A Comparative Single-Dose Pharmacokinetic and Safety Study of TAK-491 Between Infants, Children, and Adolescents With Hypertension and Healthy Adults

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01078376

Enrollment

Registered

2010-03-02

Start date

2010-05-31

Completion date

2013-09-30

Last updated

2014-07-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypertension

Keywords

Pediatrics, Blood Pressure, High, Drug Therapy

Brief summary

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.

Detailed description

Within the past 10 years, the incidence of high blood pressure (hypertension) in children and adolescents has increased all over the world. This increase is connected in part to a growing number of people who are overweight and do not eat right or exercise enough. In younger children though, high blood pressure is a common consequence of underlying diseases, such as renal diseases. This study looked at a blood pressure medicine called TAK-491 (azilsartan medoxomil) to see how it works in children who have hypertension. Azilsartan medoxomil is a prodrug that converts into TAK-536 (azilsartan), a blood pressure lowering medicine that had not been tested in children. To be eligible to take part in this study, children with a diagnosis of hypertension (primary or secondary) must have been between the ages of 1 year and 16 years old (up to their 17th birthday). Each child was given one dose of azilsartan medoxomil, followed by a number of blood tests and assessments within 24 hours after taking azilsartan medoxomil to see how the medication is working. Adults who do not have hypertension also took part in this study to provide comparison. This study took place in 9 sites in the UK and USA. A total of 20 children with hypertension and 9 adults without hypertension participated in this study. This study lasted about 43 days. This included a 28 day screening period, a 2 day treatment phase and a follow up period. Each participant taking part in this study may have been requested to remain in a hospital for one overnight stay during the course of the study. Each participant was contacted by telephone 6 days and 15 days after taking azilsartan medoxomil. Takeda has decided to close Cohort 3 (participants between 1 and 6 years of age with hypertension) enrollment early and end this study with the agreement of both the US Food and Drug Administration (FDA) and the Pediatric Committee (PDCO) at the European Medicines Agency. Requests to the FDA and PDCO were submitted to close the study without completion of enrollment in Cohort 3 due to difficulty enrolling this particular patient population. Takeda proposed an alternative option to collect PK data in this age subset by utilizing PK modeling to determine the appropriate doses in children 1-5 years of age in lieu of completing Cohort 3. The FDA and PDCO agreed with this approach.

Interventions

DRUGAzilsartan medoxomil (TAK-491)

Azilsartan medoxomil 80 mg, tablets, orally, one day only

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

1 Years to 45 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Time to Reach Cmax (Tmax) for TAK-536	Day 1	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax, as observed on Day 1.
Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536	Day 1	AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]).
Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536 Metabolite M-II.	Day 1	AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]).
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536	Day 1	Area under the plasma concentration-time curve from time 0 to infinity, calculated as AUC(0-inf)=AUC(0-tlqc) + Clast/λz.
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536 Metabolite M-II	Day 1	Area under the plasma concentration-time curve from time 0 to infinity, calculated as AUC(0-inf)=AUC(0-tlqc) + Clast/λz.
Maximum Observed Plasma Concentration (Cmax) for TAK-536	Day 1	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Maximum Observed Plasma Concentration (Cmax) for TAK-536 Metabolite M-II	Day 1	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time to Reach Cmax (Tmax) for TAK-536 Metabolite M-II	Day 1	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax, as observed on Day 1.
Terminal Elimination Half-life (T1/2) for TAK-536	Day 1	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Terminal Elimination Half-life (T1/2) for TAK-536 Metabolite M-II	Day 1	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Apparent Oral Clearance (CL/F) for TAK-536	Day 1	CL/F is apparent clearance of the drug from the plasma, expressed in L/hr.
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)	Day 1	—
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)	Day 1	—
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)	Day 1	Fe=\[Ae(0-24)/dose\]×100 (molecular weight adjusted for metabolites.
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)	Day 1	Fe=\[Ae(0-24)/dose\]×100 (molecular weight adjusted for metabolites.
Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)	Day 1	Renal clearance, calculated as CLr=Ae(0-24)/AUC(0-24).
Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)	Day 1	Renal clearance, calculated as CLr=Ae(0-24)/AUC(0-24).

Countries

United Kingdom, United States

Participant flow

Recruitment details

Participants took part in the study at 6 sites in the United States and 3 sites in the United Kingdom from 10 May 2010 to 10 July 2013.

Pre-assignment details

Children between the ages of 1 to 16 years (including up to their 17th birthday) with hypertension and gender-matched healthy adults aged 18 to 45 years, inclusive, were enrolled in 1 of 3 cohorts.

Participants by arm

Arm	Count
Cohort 1: Healthy Adults Azilsartan medoxomil 80 mg, tablets, orally, one day only	9
Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg Azilsartan medoxomil 40-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 40 to \< 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.	9
Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg Azilsartan medoxomil 20-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 20 to \< 40 kg received a 20 mg dose, participants 40 to \< 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.	8
Cohort 3: Children (≥1 to <6 Years Old) Azilsartan medoxomil 0.66 mg/kg participant body weight, granules, reconstituted orally, one day only	3
Total	29

Baseline characteristics

Characteristic	Cohort 3: Children (≥1 to <6 Years Old)	Total	Cohort 1: Healthy Adults	Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg	Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg
Age, Continuous	4.7 years STANDARD_DEVIATION 0.58	16.2 years STANDARD_DEVIATION 9.81	28.3 years STANDARD_DEVIATION 7.78	14.2 years STANDARD_DEVIATION 1.64	9.1 years STANDARD_DEVIATION 2.1
Body Mass Index (BMI)	15.67 kg/m^2 STANDARD_DEVIATION 0.551	24.54 kg/m^2 STANDARD_DEVIATION 6.625	25.06 kg/m^2 STANDARD_DEVIATION 3.345	27.22 kg/m^2 STANDARD_DEVIATION 6.611	24.29 kg/m^2 STANDARD_DEVIATION 8.327
Height	107.7 cm STANDARD_DEVIATION 11.06	153.6 cm STANDARD_DEVIATION 23.45	172.6 cm STANDARD_DEVIATION 9.7	163.1 cm STANDARD_DEVIATION 11.72	138.6 cm STANDARD_DEVIATION 12.74
Race/Ethnicity, Customized Asian	0 participants	1 participants	0 participants	0 participants	1 participants
Race/Ethnicity, Customized Black or African American	2 participants	7 participants	1 participants	2 participants	2 participants
Race/Ethnicity, Customized Hispanic or Latino	0 participants	5 participants	4 participants	0 participants	1 participants
Race/Ethnicity, Customized Not Hispanic or Latino	3 participants	20 participants	5 participants	7 participants	5 participants
Race/Ethnicity, Customized Not Reported	0 participants	4 participants	0 participants	2 participants	2 participants
Race/Ethnicity, Customized White	1 participants	21 participants	8 participants	7 participants	5 participants
Sex: Female, Male Female	2 Participants	11 Participants	2 Participants	2 Participants	5 Participants
Sex: Female, Male Male	1 Participants	18 Participants	7 Participants	7 Participants	3 Participants
Weight	18.30 kg STANDARD_DEVIATION 4.026	60.69 kg STANDARD_DEVIATION 23.859	74.64 kg STANDARD_DEVIATION 11.207	71.71 kg STANDARD_DEVIATION 15.512	48.50 kg STANDARD_DEVIATION 22.523

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	2 / 9	5 / 9	3 / 8	0 / 3
serious Total, serious adverse events	0 / 9	0 / 9	0 / 8	0 / 3

Outcome results

Primary