Relative Bioavailability of Two Different Batches of a Linagliptin / Metformin Combination Tablet in Healthy Volunteers

Relative Bioavailability of Two Different Batches of a 2.5 mg Linagliptin / 1000 mg Metformin Fixed Dose Combination Tablet (FDC) in Healthy Male and Female Volunteers (an Open-label, Randomised, Single Dose, Two-way Crossover, Phase I Trial)

The objective of the current study is to investigate the relative bioavailability of two different batches of a 2.5 mg linagliptin / 1000 mg metformin fixed dose combination tablet (FDC).

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Linagliptin/Metformin (standard batch); Drug: Linagliptin/Metformin (side batch)

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Ingelheim, Germany
    • 1288.6.1 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Healthy males and females according to the following criteria: Based upon a complete medical history, including physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), clinical laboratory tests
2. Age 21 to 50 years (incl.)
3. Body Mass Index (BMI) 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation

Exclusion criteria:

1. Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance
2. Any evidence of a clinically relevant concomitant disease
3. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
4. Surgery of the gastrointestinal tract (except appendectomy)
5. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
6. History of relevant orthostatic hypotension, fainting spells or blackouts
7. Chronic or relevant acute infections
8. History of relevant allergy or hypersensitivity (including allergy to drug or its excipients)
9. Intake of drugs within one month or less than 10 half-lives of the respective drug prior to first study drug administration
10. Participation in another trial with an investigational drug within 2 months prior to administration or during the trial
11. Smoker (more than 10 cigarettes or 3 cigars 3 pipes daily)
12. Alcohol abuse (average consumption of more than 20 g/day in females and 30 g/day in males)
13. Drug abuse
14. Blood donation (more than 100 mL within four weeks prior to day 1 of visit 2)
15. Any laboratory value outside the reference range that is of clinical relevance

16. Inability to comply with dietary regimen of trial site

    For female subjects of childbearing potential only:

17. Positive pregnancy test, pregnancy or planning to become pregnant 1 month before study or within 2 months after study completion
18. No adequate contraception 1 month before study and until 2 month after study completion, e.g. not any of the following: implants, injectables, combined hormonal contraceptives, hormonal IUD (intrauterine device), sexual abstinence for at least 1 month prior to first study drug administration, vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (including hysterectomy). Females, who do not have a vasectomised partner, are not sexually abstinent or surgically sterile will be asked to use an additional barrier method (e.g. condom).
19. Lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Linagliptin/Metformin (standard batch); Fixed dose combination tablet	Drug: Linagliptin/Metformin (standard batch); Fixed dose combination tablet
Experimental: Linagliptin/Metformin (side batch); Fixed dose combination tablet	Drug: Linagliptin/Metformin (side batch); Fixed dose combination tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Linagliptin: Maximum Measured Concentration (Cmax)	Geometric mean of Cmax of Linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval 0 to 72 Hours (AUC0-72)	Geometric mean of AUC0-72 of Linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: Cmax	Geometric Mean of Cmax of Metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: AUC0-tz	Geometric Mean of AUC0-tz of Metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Linagliptin: AUC0-infinity	Geometric mean of AUC0-infinity of Linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Linagliptin: Percentage of AUCtz-∞ Obtained by Extrapolation	Geometric Mean of percentage of AUCtz-∞ of linagliptin, where percentage is the unit of measurement.	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Linagliptin: Time to Maximum Measured Concentration of the Analyte in Plasma (Tmax)	Median of the t_max of linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Linagliptin: λz (Terminal Elimination Rate Constant in Plasma)	Geometric mean of the λ_z of linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
t1/2 (Terminal Half-life of the Analyte in Plasma)	Geometric mean of the t1/2 of linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Linagliptin: MRTpo (Mean Residence Time of the Analyte in the Body After Peroral Administration)	Geometric mean of the MRTpo of linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Linagliptin: Apparent Clearance of the Analyte in Plasma After Extravascular Administration (CL/F)	Geometric mean of the CL/F of linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Linagliptin: Apparent Volume of Distribution During the Terminal Phase Following an Extravascular Dose (Vz/F)	Geometric mean of the Vz/F of linagliptin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: AUC0-infinity	Geometric Mean of AUC0-infinity of Metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: Percentage of AUCtz-∞ Obtained by Extrapolation	Geometric Mean of the percentage of AUCtz-infinity of Metformin, where percentage is the unit of measurement.	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: Tmax	Median of tmax of metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: λz (Terminal Elimination Rate Constant in Plasma)	Geometric mean of λz of metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: t1/2 (Terminal Half-life of the Analyte in Plasma)	Geometric mean of t1/2 of metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: MRTpo (Mean Residence Time of the Analyte in the Body After Peroral Administration)	Geometric mean of MRTpo of metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: CL/F	Geometric mean of CL/F of metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Metformin: Vz/F	Geometric mean of Vz/F of metformin	Day 1 to 35 for period 1, and Day 36 to 70 for period 2
Electrocardiogram (ECG), Vital Signs, Physical Finding or Laboratory Finding Abnormalities	12-lead-Electrocardiogram (ECG), vital sign (blood pressure and pulse rate), physical finding and laboratory abnormalities	Day 1 to 4 for period 1, and day 36 to 39 for period 2
Participants With Treatment Emergent Adverse Events	Number of patients with treatment emergent AEs	Day 1 to 4 for period 1, and day 36 to 39 for period 2
Participants Who Discontinued the Trial Because of an Adverse Event	Number of participants who discontinued the trial because of an adverse event	Day 1 to 4 for period 1, and day 36 to 39 for period 2
Assessment of Tolerability by the Investigator	Qualitative variable assessing the tolerability by the investigator	Day 1 to 4 for period 1, and day 36 to 39 for period 2

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: October 4, 2010
• First Submitted That Met QC Criteria: October 6, 2010
• First Posted (Estimate): October 7, 2010

Study Record Updates

• Last Update Posted (Estimate): June 27, 2014
• Last Update Submitted That Met QC Criteria: June 18, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Linagliptin
• Other Study ID Numbers: 1288.6; 2010-019291-75 (EudraCT Number: EudraCT)