Pharmacokinetics, Pharmacodynamics, and Safety of Alogliptin in Children, Adolescents and Adults With Type 2 Diabetes Mellitus

A Comparative, Randomized, Open-Label, Multi-Center, Single Dose Pharmacokinetic, Pharmacodynamic and Safety Study of Alogliptin (12.5 mg and 25 mg) Between Children, Adolescents, and Adults With Type 2 (Non-Insulin Dependent) Diabetes Mellitus

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00957268

Enrollment

Registered

2009-08-12

Start date

2009-09-30

Completion date

2013-11-30

Last updated

2015-01-29

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

Conditions

Diabetes Mellitus, Type 2

Keywords

Type 2 diabetes mellitus, Non-insulin dependent diabetes mellitus, Drug therapy, Pediatrics

Brief summary

The purpose of this study is to determine the pharmacokinetic and safety profile of alogliptin in children, adolescents, and adults with type 2 diabetes mellitus.

Detailed description

Alogliptin is a selective, orally available inhibitor of dipeptidyl peptidase-4 being developed by Takeda Global Research & Development as a treatment for type 2 diabetes mellitus. Inhibition of dipeptidyl peptidase-4 (DPP-4) prolongs the action of 2 important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are responsible for increasing insulin synthesis, regulating β-cell proliferation, inhibiting gastric emptying, and inhibiting glucagon secretion. To date, alogliptin has not been studied in participants less than 18 years of age. As with adults, there is growing evidence of an increase in the prevalence of type 2 diabetes mellitus in children and adolescents. This study is designed to determine the pharmacokinetic, pharmacodynamic, and safety profiles of alogliptin in children and adolescents with type 2 diabetes mellitus. These profiles will be compared with those of similarly matched adult participants with type 2 diabetes mellitus. Pharmacokinetic, pharmacodynamics, and safety endpoints will be analyzed.

Interventions

DRUGAlogliptin

Alogliptin tablets

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

10 Years to 65 Years

Healthy volunteers

Inclusion criteria

for children and adolescent participants only (Groups 1 and 2, respectively): 1. Participant was male or female between 10 and 17 years of age. 2. Participant or parent or legal guardian was capable of understanding and complying with the protocol requirements. 3. Participant was capable of understanding an informed consent form (ICF) or assenting to participate. The parent or legal guardian of the participant must have been able to understand and sign an ICF prior to the initiation of any study procedures. 4. Participant weighed at least 36 kg (79 pounds) and had a Screening body mass index (BMI) of at least 18 kg/m\^2. 5. Participants had a diagnosis of type 2 diabetes mellitus (T2DM) (non-insulin dependent) based on diagnostic criteria of the American Diabetes Association (ADA). Criteria included: 1. Fasting plasma glucose level of ≥ 126 mg/dL where fasting is defined as no caloric intake for at least 8 hours, or 2. 2-hour plasma glucose level of ≥ 200 mg/dL during an oral glucose tolerance test, or 3. random plasma glucose level of ≥ 200 mg/dL, or 4. glycated hemoglobin (HbA1c) ≥ 6.5%. 6. Diagnosis could have been historical (documented), or participants could have been diagnosed for this study. 7. Participants had a fasting serum C-peptide concentration ≥ 0.8 ng/mL (≥ 0.26 nmol/L) at the Screening Visit only. 8. Participants may have been taking concomitant metformin if the dose was stable for at least 30 days prior to Day 1 (day of first dosing). Inclusion criteria for adult participants only (Group 3): 9. Participant was male or female, and between 18 and 65 years of age, inclusive for gender and race matched adult participants with T2DM only. 10. Participant was capable of understanding and complying with protocol requirements and was willing to sign the ICF prior to the initiation of any study procedures for gender and race matched adult participants with T2DM only. 11. Participant weighed at least 50 kg (110 pounds) and had a Screening BMI between 23 kg/m\^2 and 45 kg/m\^2 (except for Asian or Asian-descendant participants for whom the range was between 20 kg/m\^2 and 35 kg/m\^2), inclusive for gender and race matched T2DM adult participants only. 12. Participants had a diagnosis of T2DM (non-insulin dependent) based on diagnostic criteria of the ADA. Criteria included: 1. Fasting plasma glucose level of ≥ 126 mg/dL where fasting is defined as no caloric intake for at least 8 hours, or 2. 2-hour plasma glucose level of ≥ 200 mg/dL during an oral glucose tolerance test, or 3. random plasma glucose level of ≥ 200 mg/dL, or 4. HbA1c ≥ 6.5%. 13. Diagnosis could have been historical (documented) or participants could have been diagnosed for this study. 14. Participants may have been taking concomitant metformin if the dose was stable for at least 30 days prior to Day 1. 15. Participants may have been taking statin or antihypertensive drugs if the dose was stable for at least 30 days prior to Day 1. Inclusion criteria for all participants (Groups 1, 2, and 3): 16. Female participants of childbearing potential and male participants who were sexually active agreed to routinely use adequate contraception from Screening until 30 days after receiving the dose of study drug. NOTE: Women not of childbearing potential were defined as those who were surgically sterilized (hysterectomy, bilateral oophorectomy, tubal ligation) or who were postmenopausal (defined as at least 45 years of age and 1 year since last regular menses). 17. Participant had a negative urine test result for selected substances of abuse (including alcohol and cotinine) at Screening and Check-in (Day -1). 18. Participant had clinical chemistry, hematology, and complete urinalysis (fasted for at least 8 hours) results within the reference range for the testing laboratory (except results associated with T2DM) unless the out-of-range results were deemed not clinically meaningful by the investigator or sponsor. 19. Participant had a negative test result for hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV), and no known history of human immunodeficiency virus.

Exclusion criteria

1. Participant was currently participating in another investigational study or took an investigational drug within 30 days prior to Day 1. 2. Participant received alogliptin previously. 3. Participant was a study site employee, or was an immediate family member (ie, spouse, parent, child, or sibling) of a study site employee involved in conduct of this study. 4. Participant received or donated blood or blood products within 30 days prior to Screening or planned to donate blood during the study. 5. Participant had a known hypersensitivity to alogliptin or related compounds. 6. Participant had a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as consumption of more than 4 alcoholic drinks per day) within 1 year prior to study Day 1. 7. Participant had an acute, clinically significant illness (excluding T2DM) within 30 days prior to study Day 1. 8. Participant had any other condition or prior therapy that, in the opinion of the investigator, would have made the participant unsuitable for the study. 9. Participant had a history or clinical manifestations of significant metabolic (excluding T2DM), hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal, urologic, immunologic, musculoskeletal, or psychiatric disorder. 10. Participant had a hemoglobin value \< 12 g/dL. 11. Participant had a systolic blood pressure \> 140 mm Hg or had a diastolic blood pressure \> 90 mmHg at Screening or Check-in (Day -1). 12. Adult participant had an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than 2 times the upper limit of normal (ULN), active liver disease, or jaundice at the Screening Visit or on Check-in (Day -1). 13. Pediatric participant had an ALT or AST level greater than 1.5 times the ULN at the Screening Visit or on Check-in (Day -1). 14. Participant had a serum creatinine level \> 1.5 mg/dL. 15. Participant had a creatinine clearance (CrCl) \< 50 mL/min (normalized to body surface area of 1.73 m\^2). 16. Participant had a history of abdominal surgery (except laparoscopic cholecystectomy or uncomplicated appendectomy) or thoracic or nonperipheral vascular surgery within 6 months prior to Day 1. 17. Participant had a history or presence of a clinically significant abnormal 12-lead electrocardiogram (ECG) result as determined by the investigator or Takeda at Screening or Check-in (Day -1). 18. Participant had a history of cancer, other than basal cell carcinoma or Stage I squamous cell carcinoma of the skin that had not been in remission for at least 5 years prior to the first dose of study drug. 19. If female, participant was pregnant or lactating or intending to become pregnant before, during, or within 30 days after receiving study drug. 20. If male, participant intended to impregnate others during the study or for 30 days after receiving study drug. 21. Participant consumed or was unable to abstain from consumption of products containing alcohol, caffeine, or xanthine, and food or beverages containing grapefruit juice or Seville-type oranges within 72 hours prior to study Day 1 and for the duration of the study. 22. Participant used any tobacco (ie, nicotine) products (including but not limited to cigarettes, pipe, cigar, chewing tobacco, nicotine patch, or nicotine gum) within 6 weeks prior to study Day 1, and was unwilling to abstain from these products for the duration of the study. 23. Participant used any nutraceutical preparations within 28 days prior to study Day 1. 24. Participant was currently taking ketoconazole, fluconazole, gemfibrozil, rifampin, or carbamazepine or taken within 28 days prior to Check-in (Day -1). 25. Participant had poor peripheral venous access. 26. Participant had a medical history of clinical or laboratory evidence to indicate a diagnosis of type 1 diabetes or secondary forms of diabetes, including maturity-onset diabetes of the young (MODY).

Design outcomes

Primary

Measure	Time frame	Description
Cmax: Maximum Observed Plasma Concentration for Alogliptin	1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alogliptin	1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alogliptin	1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose	AUC(0-inf) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau\]), where tau is the length of the dosing interval in this study).

Secondary

Measure	Time frame	Description
Observed Effect at 24 Hours Post-dose (E24) of Dipeptidyl Peptidase-4 (DPP-4) Inhibition	1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose	The observed effect at 24 hours post-dose (E24) of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.
Area Under the Plasma Effect-Time Curve From Time 0 to 24 Hours Post-dose (AUEC[0-24]) of the Baseline-corrected Glucagon-like Peptide-1 (GLP-1) Concentration	1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose	The area under the plasma effect-time curve from time 0 to 24 hours post-dose (AUEC\[0-24\]) of baseline-corrected glucagon-like peptide-1 was determined from the concentration-time curve. Baseline-corrected glucagon-like peptide-1 concentrations were calculated as the post-dose concentration at each post-dose time point minus the baseline (pre-dose) concentration.
Area Under the Plasma Effect-Time Curve From Time 0 to 24 Hours Post-dose (AUEC[0-24]) of Dipeptidyl Peptidase-4 (DPP-4) Inhibition	1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose	The area under the plasma effect-time curve from time 0 to 24 hours post-dose (AUEC\[0-24\]) of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.
Time to Reach the Maximum Observed Effect of the Baseline-corrected Glucagon-like Peptide-1 (GLP-1) Concentration	1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose	The time to reach the maximum observed effect of baseline-corrected glucagon-like peptide-1 was determined from the concentration-time curve. Baseline-corrected glucagon-like peptide-1 concentrations were calculated as the post-dose concentration at each post-dose time point minus the baseline (pre-dose) concentration.
Observed Effect at 24 Hours Post-dose (E24) of the Baseline-corrected Glucagon-like Peptide-1 (GLP-1) Concentration	1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose	The observed effect at 24 hours post-dose (E24) of baseline-corrected glucagon-like peptide-1 was determined from the concentration-time curve. Baseline-corrected glucagon-like peptide-1 concentrations were calculated as the post-dose concentration at each post-dose time point minus the baseline (pre-dose) concentration.
Maximum Observed Effect (Emax) of the Baseline-corrected Glucagon-like Peptide-1 (GLP-1) Concentration	1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose	The maximum observed effect (Emax) of baseline-corrected glucagon-like peptide-1 was determined from the concentration-time curve. Baseline-corrected glucagon-like peptide-1 concentrations were calculated as the post-dose concentration at each post-dose time point minus the baseline (pre-dose) concentration.
Maximum Observed Effect (Emax) of Dipeptidyl Peptidase-4 (DPP-4) Inhibition	1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose	The maximum observed effect (Emax) of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.
Time to Reach the Maximum Observed Effect of Dipeptidyl Peptidase-4 (DPP-4) Inhibition	1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose	The time to reach the maximum observed effect of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.

Countries

United States

Participant flow

Recruitment details

Participants took part in the study at 6 investigative sites in the United States from 17 Sep 2009 to 22 Nov 2013.

Pre-assignment details

Participants aged 10 to 65 with a diagnosis of type 2 diabetes mellitus were enrolled in 1 of 5 treatment groups and received 12.5 or 25 mg alogliptin once.

Participants by arm

Arm	Count
Alogliptin 12.5 mg (Age 10 to < 14 Years) Alogliptin 12.5 mg QD, tablets, orally, 1 dose only.	5
Alogliptin 25 mg (Age 10 to < 14 Years) Alogliptin 25 mg QD, tablets, orally, 1 dose only.	4
Alogliptin 12.5 mg (Age 14 to < 18 Years) Alogliptin 12.5 mg QD, tablets, orally, 1 dose only.	8
Alogliptin 25 mg (Age 14 to < 18 Years) Alogliptin 25 mg QD, tablets, orally, 1 dose only.	7
Alogliptin 25 mg (Age 18 to 65 Years) Alogliptin 25 mg QD, tablets, orally, 1 dose only.	22
Total	46

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Voluntary Withdrawal	0	0	1	0	0

Baseline characteristics

Characteristic	Alogliptin 25 mg (Age 10 to < 14 Years)	Alogliptin 12.5 mg (Age 14 to < 18 Years)	Alogliptin 25 mg (Age 14 to < 18 Years)	Alogliptin 12.5 mg (Age 10 to < 14 Years)	Alogliptin 25 mg (Age 18 to 65 Years)	Total
Age, Continuous	12.0 years STANDARD_DEVIATION 0.82	15.4 years STANDARD_DEVIATION 0.92	15.1 years STANDARD_DEVIATION 0.69	12.4 years STANDARD_DEVIATION 0.89	51.3 years STANDARD_DEVIATION 8.24	31.96 years STANDARD_DEVIATION 19.67
Body Mass Index (BMI)	36.16 kg/m^2 STANDARD_DEVIATION 3.422	40.92 kg/m^2 STANDARD_DEVIATION 9.19	36.46 kg/m^2 STANDARD_DEVIATION 6.764	33.22 kg/m^2 STANDARD_DEVIATION 4.621	32.84 kg/m^2 STANDARD_DEVIATION 4.49	35.01 kg/m^2 STANDARD_DEVIATION 6.439
Height	165.8 cm STANDARD_DEVIATION 8.88	168.6 cm STANDARD_DEVIATION 5.71	168.9 cm STANDARD_DEVIATION 9.03	162.4 cm STANDARD_DEVIATION 8.56	167.5 cm STANDARD_DEVIATION 9.81	167.2 cm STANDARD_DEVIATION 8.73
Race/Ethnicity, Customized Asian Black or African American	3 participants	4 participants	5 participants	5 participants	15 participants	32 participants
Race/Ethnicity, Customized Hispanic or Latino	1 participants	1 participants	1 participants	0 participants	4 participants	7 participants
Race/Ethnicity, Customized Non-Hispanic or Latino	3 participants	7 participants	6 participants	5 participants	18 participants	39 participants
Race/Ethnicity, Customized White	1 participants	4 participants	2 participants	0 participants	7 participants	14 participants
Sex: Female, Male Female	3 Participants	6 Participants	5 Participants	4 Participants	16 Participants	34 Participants
Sex: Female, Male Male	1 Participants	2 Participants	2 Participants	1 Participants	6 Participants	12 Participants
Smoking Status Current Smoker	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants
Smoking Status Ex-smoker	0 participants	0 participants	0 participants	0 participants	8 participants	8 participants
Smoking Status Never Smoked	4 participants	8 participants	7 participants	5 participants	14 participants	38 participants
Weight	98.90 kg STANDARD_DEVIATION 11.957	116.28 kg STANDARD_DEVIATION 33.163	103.71 kg STANDARD_DEVIATION 17.103	86.62 kg STANDARD_DEVIATION 13.979	92.25 kg STANDARD_DEVIATION 16.454	97.14 kg STANDARD_DEVIATION 21.409

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	3 / 5	1 / 4	5 / 8	2 / 7	9 / 22
serious Total, serious adverse events	0 / 5	0 / 4	0 / 8	0 / 7	0 / 22

Outcome results

Primary

AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alogliptin

AUC(0-inf) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau\]), where tau is the length of the dosing interval in this study).

Time frame: 1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose

Population: Pharmacokinetic set: All participants who received at least 1 dose of study drug and who had at least 1 measureable plasma concentration of alogliptin.

Arm	Measure	Value (MEAN)	Dispersion
Alogliptin 12.5 mg (Age 10 to < 14 Years)	AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alogliptin	789.29 ng•hr/mL	Standard Deviation 144.0995
Alogliptin 25 mg (Age 10 to < 14 Years)	AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alogliptin	1221.98 ng•hr/mL	Standard Deviation 128.0268
Alogliptin 12.5 mg (Age 14 to < 18 Years)	AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alogliptin	688.63 ng•hr/mL	Standard Deviation 188.7887
Alogliptin 25 mg (Age 14 to < 18 Years)	AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alogliptin	1318.41 ng•hr/mL	Standard Deviation 123.6279
Alogliptin 25 mg (Age 18 to 65 Years)	AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alogliptin	1704.02 ng•hr/mL	Standard Deviation 270.6604

Primary

Cmax: Maximum Observed Plasma Concentration for Alogliptin

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

Time frame: 1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose

Population: Pharmacokinetic set: All participants who received at least 1 dose of study drug and who had at least 1 measureable plasma concentration of alogliptin.

Arm	Measure	Value (MEAN)	Dispersion
Alogliptin 12.5 mg (Age 10 to < 14 Years)	Cmax: Maximum Observed Plasma Concentration for Alogliptin	57.82 ng/mL	Standard Deviation 31.5546
Alogliptin 25 mg (Age 10 to < 14 Years)	Cmax: Maximum Observed Plasma Concentration for Alogliptin	101.38 ng/mL	Standard Deviation 23.4277
Alogliptin 12.5 mg (Age 14 to < 18 Years)	Cmax: Maximum Observed Plasma Concentration for Alogliptin	44.24 ng/mL	Standard Deviation 16.7907
Alogliptin 25 mg (Age 14 to < 18 Years)	Cmax: Maximum Observed Plasma Concentration for Alogliptin	96.74 ng/mL	Standard Deviation 28.3818
Alogliptin 25 mg (Age 18 to 65 Years)	Cmax: Maximum Observed Plasma Concentration for Alogliptin	136.50 ng/mL	Standard Deviation 34.2169

Primary

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alogliptin

Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

Time frame: 1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose

Population: Pharmacokinetic set: All participants who received at least 1 dose of study drug and who had at least 1 measureable plasma concentration of alogliptin.

Arm	Measure	Value (MEAN)	Dispersion
Alogliptin 12.5 mg (Age 10 to < 14 Years)	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alogliptin	3.24 hr	Standard Deviation 1.106
Alogliptin 25 mg (Age 10 to < 14 Years)	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alogliptin	2.04 hr	Standard Deviation 0.0462
Alogliptin 12.5 mg (Age 14 to < 18 Years)	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alogliptin	5.58 hr	Standard Deviation 8.2052
Alogliptin 25 mg (Age 14 to < 18 Years)	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alogliptin	2.86 hr	Standard Deviation 1.4707
Alogliptin 25 mg (Age 18 to 65 Years)	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alogliptin	2.09 hr	Standard Deviation 1.1566

Secondary

Area Under the Plasma Effect-Time Curve From Time 0 to 24 Hours Post-dose (AUEC[0-24]) of Dipeptidyl Peptidase-4 (DPP-4) Inhibition

The area under the plasma effect-time curve from time 0 to 24 hours post-dose (AUEC\[0-24\]) of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.