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

Phase 1

Completed

• Conditions: Diabetes Mellitus, Type 2
• Interventions: Drug: Alogliptin

• Registration Number: NCT00957268
• Lead Sponsor: Takeda

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.

Study Timeline

• Study First Submitted: 2009-08-06
• Study First Submitted QC: 2009-08-11
• Study First Posted: 2009-08-12
• Study Start: 2009-09
• Primary Completion: 2013-11
• Study Completion: 2013-11
• Results First Submitted: 2014-11-21
• Status Verified: 2015-01
• Results First Submitted QC: 2015-01-26
• Last Update Submitted: 2015-01-26
• Results First Posted: 2015-01-29
• Last Update Posted: 2015-01-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

Not provided

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Alogliptin 25 mg (age 18 to 65 years)	Alogliptin	Alogliptin 25 mg, tablets, orally, 1 dose only.
Alogliptin 12.5 mg (age 10 to < 14 years)	Alogliptin	Alogliptin 12.5 mg, tablets, orally, 1 dose only.
Alogliptin 25 mg (age 10 to < 14 years)	Alogliptin	Alogliptin 25 mg, tablets, orally, 1 dose only.
Alogliptin 12.5 mg (age 14 to < 18 years)	Alogliptin	Alogliptin 12.5 mg, tablets, orally, 1 dose only.
Alogliptin 25 mg (age 14 to < 18 years)	Alogliptin	Alogliptin 25 mg, tablets, orally, 1 dose only.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.