Steady State Pharmacokinetics of Telmisartan, Ramipril or the Combination Following Repeated Oral Doses to Healthy Male and Female Volunteers

Steady State Pharmacokinetics of 80 mg Telmisartan (Micardis®), 10 mg Ramipril (Delix®) or the Combination Following Repeated Oral Doses to Healthy Male and Female Volunteers (an Open-label, Randomised, Multiple-dose, Three-way Crossover Study)

The main objective was to investigate the effect of concurrent dosing of 10 mg ramipril and 80 mg telmisartan on the multiple-dose pharmacokinetics of telmisartan and ramipril. Therefore the relative bioavailability of telmisartan and ramipril given in combination was determined in comparison with either telmisartan or ramipril given alone.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Telmisartan; Drug: Ramipril

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy males and females according to the following criteria based upon a complete medical history, including the physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead electrocardiogram (ECG), clinical laboratory tests
• Age ≥18 and ≤55 years
• Body mass index (BMI) ≥18.5 and ≤29.9 kg/m2
• Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation

Exclusion Criteria:

• Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance
• Any evidence of a clinically relevant concomitant disease
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Surgery of the gastrointestinal tract (except appendectomy)
• Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
• History of relevant orthostatic hypotension, fainting spells or blackouts
• Chronic or relevant acute infections
• History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
• Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial
• Use of drugs which might reasonably influence the results of the trial (especially unspecific inducing agents like St.John´s wort (Hypericum perforatum) or inhibitors like cimetidine) or drugs that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration of trial drug or during the trial
• Participation in another trial with an investigational drug within two months prior to administration or during the trial
• Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day)
• Alcohol abuse (more than 60 g/day) or inability to stop alcoholic beverages for 24 hours prior to dosing and up to the last sampling time point
• Drug abuse
• Blood donation (more than 100 mL within four weeks prior to administration of trial drug or during the trial)
• Excessive physical activities (within one week prior to administration of trial drug or during the trial)
• Any laboratory value outside the reference range that is of clinical relevance
• Inability to comply with dietary regimen of trial site
• A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms)
• A history of additional risk factors for torsade de pointes (e.g., heart failure, hyperkalaemia, hypokalemia, family history of Long QT Syndrome)
• Any history of relevant low blood pressure
• Supine blood pressure at screening of systolic <110 mm Hg and diastolic <60 mm Hg
• History of urticaria
• History of angioneurotic edema
• Hereditary fructose intolerance
• Salt and/or volume depletion

For female subjects:

• Pregnancy or planning to become pregnant during the study or within 1 months of study completion
• Positive pregnancy test
• Not willing or unable to use a reliable method of contraception such as implants, injectables, combined oral contraceptives, sterilisation, intrauterine device, double barrier method, sexual abstinence for at least 1 month, or vasectomised partner as only method of contraception for at least 6 months prior to participation in the trial, during and up to 1 month after completion/termination of the trial
• Chronic use of oral contraception containing ethinyl estradiol as the only method of contraception
• Currently lactating

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Telmisartan + Ramipril; 5 days qd	Drug: Telmisartan; Other Names: Micardis®; Drug: Ramipril; Other Names: Delix®
Active Comparator: Telmisartan; 5 days qd	Drug: Telmisartan; Other Names: Micardis®
Active Comparator: Ramipril; 5 days qd	Drug: Ramipril; Other Names: Delix®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
AUCτ,ss (area under the concentration-time curve in plasma at steady state over a uniform dosing interval τ)	up to 72 hours after last drug administration of each treatment
Cmax,ss (maximum measured concentration in plasma at steady state over a uniform dosing interval τ)	up to 72 hours after last drug administration of each treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Concentration of the analytes in plasma	2, 4, and 12 hours after administration of the first dose of each treatment on day 1
pre-dose concentration of the analytes in plasma immediately before the administration of the next dose	pre-dose up to day 5 of each treatment
tmax,ss (time from last dosing to the maximum concentration of the analytes in plasma at steady state)	up to 72 hours after last drug administration of each treatment
Cmin,ss (minimum concentration of the analytes in plasma at steady state over a uniform dosing interval τ)	up to 72 hours after last drug administration of each treatment
Cpre,ss (pre-dose concentration of the analytes in plasma immediately before the administration of the next dose at steady state)	pre-dose up to day 5 of each treatment
Cavg (average concentration of the analytes in plasma at steady state)	up to 72 hours after last drug administration of each treatment
λz,ss (terminal rate constant in plasma at steady state)	up to 72 hours after last drug administration of each treatment
t1/2, ss (terminal half-life of the analyte in plasma at steady state)	up to 72 hours after last drug administration of each treatment
MRTpo,ss (mean residence time of the analyte in the body at steady state after oral administration)	up to 72 hours after last drug administration of each treatment
CL/F,ss (apparent clearance of the analyte in plasma at steady state after extravascular multiple dose administration)	up to 72 hours after last drug administration of each treatment
Vz/F,ss (apparent volume of distribution of the analyte in plasma at steady state after extravascular multiple dose administration)	up to 72 hours after last drug administration of each treatment
PTF (Peak-Trough Fluctuation)	up to 72 hours after last drug administration of each treatment
AUC0-tz,ss (Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point)	up to 72 hours after last drug administration of each treatment
Number of patients with adverse events	up to day 76
Number of patients with clinically relevant changes in Vital Signs (Blood Pressure, Pulse rate)	up to day 76
Number of patients with clinically relevant changes in 12-lead electrocardiogram	up to day 76
Number of patients with clinically relevant changes in laboratory tests	up to day 76
Assessment of tolerability by the investigator on a 4-point scale	Day 8 of each treatment

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): September 1, 2007

Study Registration Dates

• First Submitted: August 12, 2014
• First Submitted That Met QC Criteria: August 12, 2014
• First Posted (Estimate): August 13, 2014

Study Record Updates

• Last Update Posted (Estimate): August 13, 2014
• Last Update Submitted That Met QC Criteria: August 12, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Telmisartan; Ramipril
• Other Study ID Numbers: 1236.6