Investigation How CG5503 is Taken up and Excreted From the Body After 2 Minutes Intravenous Infusion With and Without Oral Co-administration of Charcoal

Investigation of the Pharmacokinetic Properties of CG5503 After 2 Minutes Intravenous Infusion With and Without Oral Coadministration of Charcoal in a Randomised, Open, Single Dose, 2-way Crossover, Phase I Study in 12 Healthy Male Volunteers

This was a Phase I study in 12 healthy male participants to compare the pharmacokinetic properties of CG5503 (how it is taken up and excreted from the body) after 2 minutes intravenous (i.v.) infusion with and without oral co-administration of charcoal to investigate a potential gastrointestinal secretion of CG5503.

During the course of the study each participant received two infusions of 40 mg CG5503 without (treatment A) and with (treatment B) oral co-administration of charcoal. In treatment B, eight doses of 5 grams charcoal powder were co-administered orally at defined time points. The wash out phases were to be at least 4 to 14 days between the treatment periods.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetic
• Intervention / Treatment: Drug: 4 ml CG5503; Drug: 5 g charcoal powder

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52099
    • Department of Clinical Pharmacology Grünenthal GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male Caucasian participants aged 18 - 65 years.
• Body mass index (BMI) between 20 and 30 kilograms/square meter inclusive.
• Participants must be in good health as determined by medical history, physical examination, 12-lead electrocardiogram, vital signs, and clinical laboratory parameters (serum/urine biochemistry, serology and haematology). Minor deviations of laboratory values from the normal range may be accepted, if judged by the investigator to have no clinical relevance and if not considered to interfere with the study objectives.
• Negative human immunodeficiency virus (HIV)-1/-2 antibodies, hepatitis B surface (HBs)-antigen, hepatitis B core (HBc)-antibodies, hepatitis C virus (HCV)-antibodies at the screening examination.
• Participants giving written consent to participate within this trial.

Exclusion Criteria:

• Use of any medication within four weeks prior to commencement of the study (self-medication or prescription), if not on a stable basis.
• Diseases and functional disorders of the gastrointestinal tract, liver, cardiovascular system or kidneys.
• Malignancy.
• History of orthostatic hypotension.
• Resting pulse rate equal to or below 45 beats/min or equal to or above 100 beats/min.
• Systolic blood pressure equal to or below 100 mmHg or equal to or above 160 mmHg.
• Diastolic blood pressure equal to or below 50 mmHg or equal to or above 95 mmHg.
• Clinically relevant deviations in laboratory parameters.
• Drug allergy.
• Bronchial asthma.
• Participation in another clinical study in the last three months before starting this study (exception: characterization of metabolizer status).
• Blood donation (more than 100 milliliter) in the last three months before the start of the study.
• Evidence of alcohol or drug abuse.
• Positive drug abuse screening test.
• Extremely unbalanced diet (in the opinion of the investigator).
• Excessive consumption of food or beverages containing caffeine (more than five cups of coffee per day or other equivalent amounts of caffeine).
• Consumption of grapefruit juice two weeks before the start of the study.
• Known or suspected of not being able to comply with the study protocol.
• Not able to communicate meaningfully with the investigator and staff.
• Neurotic personality, psychiatric illness, or suicide risk.
• History of seizures or at risk (i.e. head trauma, epilepsy in family anamnesis, unclear loss of consciousness).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment A: 4 ml CG5503; 4 ml of the CG5503 i.v. infusion solution corresponding to 40 mg CG5503 (tapentadol hydrochloride) was administered as a 2 minutes infusion.	Drug: 4 ml CG5503; 4 ml of the CG5503 infusion solution corresponding to 40 mg CG5503 (tapentadol hydrochloride).
EXPERIMENTAL: Treatment B: 4 ml CG5503; 5 g charcoal powder; 4 ml of the CG5503 i.v. infusion solution corresponding to 40 mg CG5503 (tapentadol hydrochloride) with oral co-administration of charcoal (5 g charcoal were co-administered orally at 1, 0.5 hours and 10 minutes before the start of CG5503 infusion and 0.5, 1, 1.5, 2 and 4 hours thereafter)	Drug: 4 ml CG5503; 4 ml of the CG5503 infusion solution corresponding to 40 mg CG5503 (tapentadol hydrochloride).; Drug: 5 g charcoal powder; Oral administration of 5 g charcoal powder suspended in 100 ml tap water.; Other Names: Tradename: Kohle-Pulvis Pulver

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameter Serum: area under the concentration-time curve extrapolated to infinity (AUC0-inf) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC0-inf was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: area under the concentration-time curve extrapolated to infinity (AUC0-inf) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. The AUC0-inf was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: area under the concentration-time curve extrapolated to infinity (AUC0-inf) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC0-inf was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: area under the concentration-time curve extrapolated to infinity (AUC0-inf) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC0-inf was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: area under the concentration-time curve from 0 to time t (AUC0-t) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC0-t was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: area under the concentration-time curve from 0 to time t (AUC0-t) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. The AUC0-t was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: area under the concentration-time curve from 0 to time t (AUC0-t) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC0-t was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: area under the concentration-time curve from 0 to time t (AUC0-t) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC0-t was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: maximum concentration (Cmax) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Cmax was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: maximum concentration (Cmax) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. tubes. The Cmax was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: maximum concentration (Cmax) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Cmax was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: maximum concentration (Cmax) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Cmax was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: time to maximum concentration (tmax) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The tmax was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: time to maximum concentration (tmax) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. The tmax was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: time to maximum concentration (tmax) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The tmax was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: time to maximum concentration (tmax) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The tmax was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameter Serum: extrapolated AUC expressed as a percentage of total AUC0-inf (AUC%extr) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC%extr was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: extrapolated AUC expressed as a percentage of total AUC0-inf (AUC%extr) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. The AUC%extr was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: extrapolated AUC expressed as a percentage of total AUC0-inf (AUC%extr) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC%extr was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: extrapolated AUC expressed as a percentage of total AUC0-inf (AUC%extr) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The AUC%extr was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: apparent terminal elimination rate constant (λz) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The λz was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: apparent terminal elimination rate constant (λz) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. The λz was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: apparent terminal elimination rate constant (λz) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The λz was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: apparent terminal elimination rate constant (λz) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The λz was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: the apparent half-life associated with the terminal elimination phase (t1/2,z) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The t½z was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: the apparent half-life associated with the terminal elimination phase (t1/2,z) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. The t½z was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: the apparent half-life associated with the terminal elimination phase (t1/2,z) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The t½z was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: the apparent half-life associated with the terminal elimination phase (t1/2,z) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The t½z was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: total serum or blood clearance of drug after intravenous administration (CL) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The CL was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: total clearance of drug after intravenous administration (CL) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. The CL was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: total serum or blood clearance of drug after intravenous administration (CL) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The CL was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: total serum or blood clearance of drug after intravenous administration (CL) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The CL was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: the apparent volume of distribution associated with terminal phase after intravenous administration (Vz) for CG5503 base	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Vz was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Saliva: the apparent volume of distribution associated with terminal phase after intravenous administration (Vz) for CG5503 base	16 PK saliva samples were obtained from each participant. Saliva concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. Participants were asked to donate saliva as much as possible in approximately 0.5 minutes. The Vz was calculated based on saliva concentration-time data (using the actual saliva sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: the apparent volume of distribution associated with terminal phase after intravenous administration (Vz) for CG5503-glucuronide	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Vz was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Serum: the apparent volume of distribution associated with terminal phase after intravenous administration (Vz) for CG5503-sulphate	26 PK blood samples were obtained from each participant. Serum concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Vz was calculated based on serum concentration-time data (using the actual blood sampling times).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Urine: renal excretion (Ae % of dose) for CG5503 base	12 PK urine samples were obtained from each participant. Urine concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Ae (% of dose) was calculated based on urine concentration-time data (using the actual urine sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Urine: renal excretion (Ae % of dose) for CG5503-glucuronide	12 PK urine samples were obtained from each participant. Urine concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Ae (% of dose) was calculated based on urine concentration-time data (using the actual urine sampling time intervals).	Pre-dose and up to 23 hours post-dose
Pharmacokinetic parameter Urine: renal excretion (Ae % of dose) for CG5503-sulphate	12 PK urine samples were obtained from each participant. Urine concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays. The Ae (% of dose) was calculated based on urine concentration-time data (using the actual urine sampling time intervals).	Pre-dose and up to 23 hours post-dose

Collaborators and Investigators

• Sponsor: Grünenthal GmbH

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2004
• Primary Completion (ACTUAL): April 1, 2004
• Study Completion (ACTUAL): April 1, 2004

Study Registration Dates

• First Submitted: May 14, 2019
• First Submitted That Met QC Criteria: May 14, 2019
• First Posted (ACTUAL): May 16, 2019

Study Record Updates

• Last Update Posted (ACTUAL): May 16, 2019
• Last Update Submitted That Met QC Criteria: May 14, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Protective Agents; Antidotes; Charcoal
• Other Study ID Numbers: HP5503/11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No