Phenotyping of High Dose Rifampicin (PHENORIF)

• ClinicalTrials.gov Identifier: NCT04525235
• Recruitment Status: Completed
• First Posted: August 25, 2020
• Last Update Posted: August 17, 2021
• Sponsor: Radboud University Medical Center
• Information provided by (Responsible Party): Radboud University Medical Center

Study Description

Brief Summary:

Higher doses of rifampicin as a means of more efficient use of this pivotal TB drug has shown promising results and might become standard in future. This means that higher doses of rifampicin will be co-administered with many other drugs taken by TB patients, including anti-retroviral, anti-diabetic, cardiovascular and other drugs. Therefore, in this study the aim is to quantitatively assess the drug interaction potential of high dose rifampicin (~40 mg/kg daily dose, the currently available maximum tolerated dose) with respect to five major human drug-metabolizing CYP enzymes and P-gp in comparison to the conventional dose of 10 mg/kg daily in pulmonary TB patients. A phenotyping approach with single administration of several selective substrates for multiple enzymes will be used, in order to prevent multiple drug-drug interaction studies.

Condition or disease	Intervention/treatment	Phase
Tuberculosis	Combination Product: phenotyping cocktail; Drug: rifampicin	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: each participants will receive phenotyping probe drugs with the standard dose of rifampicin and with a high dose rifampicin in a fixed oreder
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: The Effect of High Dose Rifampicin on the Activity of Cytochrome P450 Enzymes and P-glycoprotein in Patients With Pulmonary Tuberculosis: a Cocktail Phenotyping Study
• Actual Study Start Date: January 7, 2021
• Actual Primary Completion Date: August 12, 2021
• Actual Study Completion Date: August 12, 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Rifampicin standard dose; rifampicin standard dose + phenotyping cocktail	Combination Product: phenotyping cocktail; A single dose of a cocktail of phenotyping probe drugs (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam and digoxin) will be administered together with standard dose rifampicin and 40 mg/kg rifampicin, respectively. Blood samples will be taken to assess phenotyping metrics of the cocktail agents and rifampicin pharmacokinetic parameters. The effect of high and standard dose rifampicin on the phenotyping metrics of the cocktail agents will be compared by using the bioequivalence approach; Other Names: digoxin; caffeine; tolbutamide; midazolam; dextromethorphan; omeprazole; Drug: rifampicin; A single dose of a cocktail of phenotyping probe drugs (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam and digoxin) will be administered together with standard dose rifampicin and 40 mg/kg rifampicin, respectively. Blood samples will be taken to assess phenotyping metrics of the cocktail agents and rifampicin pharmacokinetic parameters. The effect of high and standard dose rifampicin on the phenotyping metrics of the cocktail agents will be compared by using the bioequivalence approach
Experimental: Rifampicin high dose; rifampicin high dose + phenotyping cocktail	Combination Product: phenotyping cocktail; A single dose of a cocktail of phenotyping probe drugs (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam and digoxin) will be administered together with standard dose rifampicin and 40 mg/kg rifampicin, respectively. Blood samples will be taken to assess phenotyping metrics of the cocktail agents and rifampicin pharmacokinetic parameters. The effect of high and standard dose rifampicin on the phenotyping metrics of the cocktail agents will be compared by using the bioequivalence approach; Other Names: digoxin; caffeine; tolbutamide; midazolam; dextromethorphan; omeprazole; Drug: rifampicin; A single dose of a cocktail of phenotyping probe drugs (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam and digoxin) will be administered together with standard dose rifampicin and 40 mg/kg rifampicin, respectively. Blood samples will be taken to assess phenotyping metrics of the cocktail agents and rifampicin pharmacokinetic parameters. The effect of high and standard dose rifampicin on the phenotyping metrics of the cocktail agents will be compared by using the bioequivalence approach

Outcome Measures

Primary Outcome Measures :

1. area under the curve [ Time Frame: 24 hours ]
   area under the curve of probe drugs

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• The participant is able and willing to provide written, informed consent prior to all trial-related procedures.
• The participant is aged between 18 and 65 years, inclusive.
• The participant is a diagnosed pulmonary TB patient.
• The participant is currently being treated with a daily dose of 10 mg/kg rifampicin, i.e. 450 mg daily for patients with a body weight below 55 kg and 600 mg daily for participants with a body weight above 55 kg. This is in correspondence with the local South African TB treatment programme. Furthermore, the participant has to be in the continuation phase of the treatment regimen (i.e. month 3 to 6), has demonstrated reasonable treatment compliance (≥80% of doses) and tolerates treatment well.
• The participant has a body weight (in light clothing and with no shoes) between 40 and 85 kg, inclusive.
• The participant is and stays non-pregnant (based on a negative serum pregnancy test,) and non-lactating (female participants of childbearing potential only).

Exclusion Criteria:

• The patient is in poor general condition where any change in treatment cannot be accepted per discretion of the Investigator.
• The participant has active Hepatitis B.
• The participant has active Hepatitis C.
• The participant is receiving antiretroviral therapy (ART).
• There is evidence showing the participant has clinically significant metabolic, gastrointestinal, or other abnormalities than could possibly alter the PK of rifampicin and/or the probe drugs.
• The participant has a history of or current clinically relevant cardiovascular disorder such as:
• heart failure, atrioventricular (AV) block, arrhythmia, tachyarrhythmia or status after myocardial infarction.
• family history of sudden death of unknown or cardiac-related cause, or of prolonged QTc interval.
• The participant has clinically relevant abnormalities in the ECG such as atrioventricular (AV) block, prolongation of the QRS complex over 100 milliseconds, or of a QTc interval over 450 milliseconds on the screening ECG.
• The participant has abnormal alanine aminotransferase (ALT) and/or aspartate transferase (AST) levels > 3 times the upper limit of the laboratory reference range at screening.
• The participant has a known or suspected, current drug or amphetamine abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the patient.
• The participant used any drugs or substances known to be strong inhibitors or inducers of cytochrome P450 enzymes and/or P-glycoprotein (P-gp) within 2 weeks prior to day 1 (i.e. 1 month before administration of the phenotyping probes on day 15) of the study (including carbamazepine, barbiturates, St. John's Wort, clarithromycin, itraconazole, fluconazole, quinidine, ketoconazole, erythromycin). Exceptions may be made for participants who have received 3 days or less of one of these drugs or substances, if there has been a wash-out period equivalent to at least 5 half-lives of that drug or substance before day 1 of the study.
• The participant uses any of the phenotyping probe drugs (i.e. midazolam, caffeine, dextromethorphan, tolbutamide, omeprazole and digoxin) as part of standard medical treatment.
• The participant has as history of allergy to any of the phenotyping probe drugs (i.e. midazolam, caffeine, dextromethorphan, tolbutamide, omeprazole and digoxin).

Contacts and Locations

Locations

South Africa

TASK

Cape Town, South Africa

UCT lung institute

Cape Town, South Africa

Sponsors and Collaborators

Radboud University Medical Center

More Information

• Responsible Party: Radboud University Medical Center
• ClinicalTrials.gov Identifier: NCT04525235
• Other Study ID Numbers: PHENORIF
• First Posted: August 25, 2020
• Last Update Posted: August 17, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Tolbutamide; Rifampin; Digoxin; Midazolam; Dextromethorphan; Caffeine; Omeprazole; Adjuvants, Anesthesia; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Ulcer Agents; Gastrointestinal Agents