Safety, Pharmacokinetics, and Pharmacodynamics of BIRT 2584 XX Administered as Multiple Doses and Safety and Pharmacokinetics of BIRT 2584 XX Administered With and Without Food as Single Dose to Healthy Male Volunteers

Boehringer Ingelheim74 enrolled

Overview

The study comprised two parts. The objective of the first study period was to assess the safety and pharmacokinetics of 500 mg of BIRT 2584 XX tablets administered with and without food in male healthy volunteers and to determine the relative bioavailability of the BIRT 2584 XX tablet formulation compared by historical comparison to BIRT 2584 XX powder in PEG 400 (U05-2074) (part 1). The second and major phase of the trial was aimed at evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of BIRT 2584 XX (100 mg, 250 mg, and 500 mg bid on the first 2 days and qd on the following 12 days, or 750 mg qd for 28 days) in healthy male subjects (part 2)

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Healthy

Interventions

Eligibility

Sex: MALEMin age: 18 YearsMax age: 63 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy male subjects as determined by results of the screening * Signed written informed consent in accordance with Good Clinical Practice (GCP) and local legislation * Age ≥ 18 and ≤ 63 years * BMI ≥ 18.5 and ≤ 29.9 kg/m2 Exclusion Criteria: * Any finding during the medical examination (including blood pressure, pulse rate, and electrocardiogram) deviating from normal and of clinical relevance * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunologic, hematological, oncological, or hormonal disorders * Surgery of gastrointestinal tract (except appendectomy) * Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders * Relevant history of orthostatic hypotension, fainting spells, or blackouts * Chronic or relevant acute infections * History of allergy/hypersensitivity (including drug allergy) considered relevant to the trial as judged by the investigator * Intake of drugs with a long half-life (greater than 24 hours) (less than 1 month prior to administration or during the trial) * Use of any drugs, which might influence the results of the trial (less than 10 days prior to study drug administration or expected during the trial) * Participation in another trial with an investigational drug (less than 2 months prior to administration or expected during trial) * Smoker (more than 10 cigarettes/day or more than 3 cigars/day or more than 3 pipes/day) * Alcohol abuse (more than 60 g of ethanol per day) * Drug abuse * Blood donation or loss greater than 400 mL (less than 1 month prior to administration or expected during the trial) * Clinically relevant laboratory abnormalities

Outcomes

Primary Outcomes

Number of subjects with abnormal findings in physical examination

Time frame: up to 45 days

Number of subjects with abnormal changes in laboratory parameters

Time frame: up to 45 days

Number of subjects with clinically significant changes in vital signs

Pulse rate, systolic, and diastolic blood pressure

Time frame: up to 45 days

Number of subjects with adverse events

Time frame: up to 59 days

Number of subjects with clinically significant changes in 12-lead ECG

Time frame: up to 45 days

Secondary Outcomes

AUC0-inf (area under the concentration-time curve of BIRT 2584 XX in plasma over the time interval from 0 to infinity)

bioavailability/food effect part

Time frame: up to 72 hours

Cmax (maximum concentration of BIRT 2584 XX in plasma)

bioavailability/food effect part

Time frame: up to 72 hours

tmax (time from dosing to maximum concentration of BIRT 2584 XX and BI 610100, its major metabolite in humans)

bioavailability/food effect part

Time frame: up to 72 hours

Cmax (maximum concentration of BIRT 2584 XX and BI 610100 in plasma)

multiple rising dose part

Time frame: up to 42 days

tmax (time from dosing to maximum concentration of BIRT 2584 XX and BI 610100)

multiple rising dose part

Time frame: up to 42 days

AUC0-12 (area under the concentration-time curve of BIRT 2584 XX and BI 610100 in plasma over the time interval from 0 to 12 hours after the first dose

multiple rising dose part

Time frame: up to 14 hours after first drug administration

AUCtau,l (area under the concentration-time curve of BIRT 2584 XX and BI 610100 in plasma over a uniform dose interval tau after administration of the last dose)

multiple rising dose part

Time frame: up to 42 days

Cmin,ss (minimum concentration of BIRT 2584 XX and BI 610100 in plasma at steady state over a uniform dosing interval tau)

multiple rising dose part

Time frame: up to 42 days

AUCtau,ss (area under the concentration-time curve of BIRT 2584 XX and BI 610100 in plasma at steady state over a uniform dosing interval tau)

multiple rising dose part

Time frame: up to 42 days

λz,ss (terminal rate constant of BIRT 2584 XX and BI 610100 in plasma at steady state)

multiple rising dose part

Time frame: up to 42 days

t1/2,ss (terminal half-life of BIRT 2584 XX and BI 610100 in plasma at steady state)

multiple rising dose part

Time frame: up to 42 days

MRTpo,ss (mean residence time of BIRT 2584 XX and BI 610100 in the body at steady state after po administration)

multiple rising dose part

Time frame: up to 42 days

CL/F,ss (apparent clearance of BIRT 2584 XX from plasma at steady state after extravascular multiple dose administration)

multiple rising dose part

Time frame: up to 42 days

Vz/F,ss (apparent volume of distribution of BIRT XX 2584 during the terminal phase λz at steady state following extravascular administration)

multiple rising dose part

Time frame: up to 42 days

Aet1-t2,ss (amount of BIRT 2584 XX and BI 610100 that is eliminated in urine at steady state from the time point t1 to time point t2)

multiple rising dose part

Time frame: up to 30 days

fet1-t2,ss (fraction of BIRT 2584 XX and BI 610100 eliminated in urine at steady state from time point t1 to the time point t2)

multiple rising dose part

Time frame: up to 30 days

Accumulation ratio of the analyte in plasma at steady state at the end of dosing expressed as a ratio of Cmax after the last dose to Cmax after the first dose (RA,Cmax)

multiple rising dose part

Time frame: up to 42 days

Accumulation ratio of the analyte in plasma at steady state at the end of dosing expressed as a ratio of AUCtau after the last dose to AUCtau after the first dose (RA,AUC)

multiple rising dose part

Time frame: up to 42 days

Assessment of receptor occupancy

determined by a competitive binding assay using anti-Lymphocyte function associated antigen-1 (LFA-1) antibody fragment as competitor

Time frame: up to 42 days

Assessment of ex vivo suppression of superantigen (SEB)-induced Interleukin (IL)-2 production

Time frame: up to 42 days

Total number of white blood cells and leukocyte differential cell count

Time frame: up to 42 days