Bioavailability of Dabigatran With or Without Clarithromycin in Healthy Volunteers

Boehringer Ingelheim20 enrolled

Overview

To investigate whether and to what extent the reported potent P-gp inhibitor clarithromycin affects pharmacokinetic parameters (area under the curve (AUC) and maximal concentration (Cmax)) of dabigatran.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Healthy

Interventions

Dabigatran etexilateDRUG

ClarithromycinDRUG

Eligibility

Sex: ALLMin age: 18 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy males and females ≥18 and ≤50 years of age, based on a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests. * Body mass index (BMI) ranging from 18.5 to 29.9 kg/m2 * Signed and dated written informed consent prior to admission to the study in accordance with GCP 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 or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration 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) * Drug abuse * Blood donation (more than 100 mL within 4 weeks prior to administration or during the trial) * Excessive physical activities (within one week prior to administration 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, hypokalaemia, family history of Long QT Syndrome) * In addition, the following exclusion criteria applied to females: * Pregnancy / positive pregnancy test, or planning to become pregnant during the study or within 1 month of study completion * No adequate contraception during the study and until 1 month of study completion, (implants, injectables, combined oral contraceptives, intrauterine device, sexual abstinence \[for at least 1 month prior to enrolment\], vasectomised partner \[vasectomy performed at least 1 year prior to enrolment\], or surgical sterilisation \[including hysterectomy\] were considered adequate contraception. Females whose partner was not vasectomised, were not sexually abstinent, or surgically sterile were asked to use barrier contraception methods (e.g. condom, diaphragm with spermicide) * Lactation period * Intake of medication, which influenced blood coagulation, including acetylsalicylic acid and oral vitamin K antagonists, among others

Outcomes

Primary Outcomes

AUC0-∞ of total dabigatran (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity)

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

Cmax of total dabigatran (maximum measured concentration of the analyte in plasma)

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

Secondary Outcomes

AUC0-∞ of free dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

Cmax of free dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

Cmax of clarithromycin

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

AUC0-12 of clarithromycin (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 12 h)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

AUC0-tz of clarythromycin (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)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

Data from ClinicalTrials.gov

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AUCτ,1 of clarythromycin (area under the concentration time curve over one dosing interval after the first dose)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

AUC0-24 of clarythromycin (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 h after the administration)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

tmax of clarythromycin (time from dosing to the maximum concentration of the analyte in plasma)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

λz (terminal rate constant in plasma) of clarythromycin

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

t1/2 of clarythromycin (terminal half-life of the analyte in plasma)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

MRTpo of clarythromycin (mean residence time of the analyte in the body after oral administration)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

CL/F of clarythromycin (apparent clearance of the analyte in the plasma after extravascular administration)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

Vz/F of clarythromycin (apparent volume of distribution during the terminal phase λz following an extravascular dose)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after first dose of clarythromycin on day 1 of visit 3

AUC0-tz of dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

AUCτ,1 of dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

AUC0-24 of dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

tmax of dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

λz of dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

t1/2 of dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

MRTpo of dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

CL/F of dabigatran

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

Vz/F of dabigatran (free and total)

Time frame: Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34 hours after administration of study drug on day 1 of visits 2, 3, and 5

AUCτ,ss of clarythromycin (area under the concentration-time curve of the analyte in plasma within the uniform dosing interval τ)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

AUC0-tz,ss of clarythromycin (area under the concentration-time curve of the analyte in plasma from the time point 0 after the last dose at steady state to the last quantifiable analyte plasma concentration within the uniform dosing interval τ)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

Cmax,ss of clarythromycin (maximum concentration of the analyte in plasma at steady state)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

tz,ss of clarythromycin (time of last measurable concentration of the analyte in plasma within the dosing interval τ at steady state)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

tmax,ss of clarythromycin (time from last dosing to the maximum concentration of the analyte in plasma at steady state on day 4)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

CL/F,ss of clarythromycin (apparent clearance of the analyte in the plasma at steady state after extravascular multiple dose administration)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

Cmin,ss of clarythromycin (minimum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

tmin,ss of clarythromycin (time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval τ)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

Cpre,ss of clarythromycin (predose concentration of the analyte in plasma at steady state immediately before administration of the next dose)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

MRTpo,ss of clarythromycin (mean residence time of the analyte in the body at steady state after oral administration)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

Vz/F,ss of clarythromycin (apparent volume of distribution during the terminal phase λz at steady state following an extravascular administration)

Time frame: Before and 30 min, 55 min, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 11, 13, 25 hours after multiple dosing of clarythromycin on day 1 of visit 4 and 5

Ae0-24 of dabigatran (amount of analyte eliminated in urine from the time interval 0-24h)

Time frame: Day 1 to 2 of visits 2, 3 and 5

fe0-24 of dabigatran (fraction of administered drug excreted unchanged in urine from time point 0-24h)

Time frame: Day 1 to 2 of visits 2, 3 and 5

CLR, 0-24 of dabigatran (renal clearance of the analyte in plasma from the time point 0 until the time point 24h )

Time frame: Day 1 to 2 of visits 2, 3 and 5

Changes in thrombin time (TT)

Time frame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours after administration of study drug on day 1 of visits 2, 3 and 5

Changes in ecarin clotting time (ECT)

Time frame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours after administration of study drug on day 1 of visits 2, 3 and 5

Occurrence and intensity of adverse events

Time frame: up to 21 days

Assessment of tolerability by investigator

Time frame: Day 21

Changes from baseline in physical examination

Time frame: Baseline, day 21

Changes in vital signs (blood pressure, pulse rate)

Time frame: up to day 21

Changes in 12-lead electrocardiogram (ECG)

Time frame: up to day 21

Changes in clinical laboratory tests

Time frame: up to day 21