Pharmacokinetic Study of Minocycline in Patients With Pulmonary Nontuberculous Mycobacterial Disease (Mino-PK)

Antimycobacterial treatment of M. avium complex pulmonary disease (MAC-PD) has suboptimal cure rates and is challenging due to frequent adverse drug reactions and drug-drug interactions. Hence, there is an urgent need for improved treatment regimens with effective and tolerable antibiotics.

Minocycline is a well-tolerated, orally administered tetracycline-type antibiotic with in vitro activity against MAC, but pharmacokinetic data in the target population is lacking. Moreover, rifampicin, a strong inducer of cytochrome P450 enzymes involved in drug metabolism and of various drug transporters, is part of the current first-line MAC-PD treatment regimen and has a substantial interaction with doxycycline, a related tetracycline.

Pharmacokinetic data in the target population will allow us to propose an appropriate dose of minocycline when co-administered with or without rifampicin

Mino-PK is an open label, one-arm, two-period, fixed-order pharmacokinetic study that will assess exposure to minocycline in MAC-PD patients with and without concurrent use of rifampicin. Subjects will receive two 5-day dosing periods of minocycline; the first without and second with concurrent use of rifampicin. Minocycline plasma concentrations will be determined after both dosing periods.

Study Overview

• Status: Terminated
• Conditions: Mycobacterium Avium Complex Pulmonary Disease
• Intervention / Treatment: Drug: Minocycline

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 2020 guideline (ATS/ERS/ESCMID/IDSA) diagnostic criteria for nontuberculous mycobacterial pulmonary disease are met, i.e. the patient is symptomatic, has nodules, bronchiectasis or fibro-cavitary lesions seen on (HR)CT scan of the lungs and ≥2 positive sputum cultures or one positive bronchoalveolar lavage culture of the same M. avium complex species.
• At least one of the positive cultures must be done in the last 4 months before inclusion.
• The subject is eligible to start the guideline-recommended rifampicin-based regimen according to the treating physician.
• Age ≥ 18 years.
• Signed and dated patient informed consent.

Exclusion Criteria:

• A relevant medical history or current condition that might interfere with drug absorption, distribution, metabolism or excretion (i.e. chronic gastro-intestinal disease, renal or hepatic disease).
• Diagnosed with cystic fibrosis (as this may affect the pharmacokinetics of drugs).
• Pregnant or breastfeeding (contra-indications for minocycline) or inadequate contraceptive measures (in view of the administration of rifampicin which interacts with oral contraceptive drugs, adequate contraceptive measures are abstinence from sexual activities and barrier methods).
• Use of drugs that cause a relevant drug interaction with minocycline, i.e. oral magnesium, , bismuth, aluminium, calcium, zinc or iron containing formulations, antacid drugs and drugs besides rifampicin that are strong inducers of metabolic enzymes, including barbiturates, carbamazepin and phenytoin (as judged by the investigators).
• ALAT > 3 times the upper limit of normal (normal <45 U/l).
• ASAT > 3 times the upper limit of normal (normal <35 U/l).
• An abnormal serum creatinine level (defined as a level that is higher than the upper limit of normal, i.e. >110 umol/l).
• Active alcohol abuse.
• Hypersensitivity to minocycline or to other tetracycline antibiotics.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters of minocycline in MAC-PD patients without concurrent use of rifampicin.	The area under the curve (AUC0-24h)	Day 5 of the first minocycline dosing period
Pharmacokinetic parameters of minocycline in MAC-PD patients without concurrent use of rifampicin.	The peak plasma concentration (Cmax)	Day 5 of the first minocycline dosing period
Pharmacokinetic parameters of minocycline in MAC-PD patients without concurrent use of rifampicin.	The plasma trough concentration (Cmin)	Day 5 of the first minocycline dosing period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters of minocycline in MAC-PD patients with concurrent use of rifampicin.	The area under the curve (AUC0-24h)	Day 5 of the second minocycline dosing period
Pharmacokinetic parameters of minocycline in MAC-PD patients with concurrent use of rifampicin.	The peak plasma concentration (Cmax)	Day 5 of the second minocycline dosing period
Pharmacokinetic parameters of minocycline in MAC-PD patients with concurrent use of rifampicin.	The plasma trough concentration (Cmin)	Day 5 of the second minocycline dosing period
Pharmacokinetic parameters of rifampicin in MAC-PD patients	The peak plasma concentration (Cmax)	Day 5 of the second minocycline dosing period
Adverse Events	The number of (participants with) adverse events will be measured. Adverse events will be graded according to the 'Common Terminology Criteria for Adverse Events' (CTCAE)	Through study completion, an average of 6 weeks

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Wouter Hoefsloot, MSc, PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, Bottger EC, Brozek J, Griffith DE, Guglielmetti L, Huitt GA, Knight SL, Leitman P, Marras TK, Olivier KN, Santin M, Stout JE, Tortoli E, van Ingen J, Wagner D, Winthrop KL. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020 Jul 7;56(1):2000535. doi: 10.1183/13993003.00535-2020. Print 2020 Jul.

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2023
• Primary Completion (Actual): May 14, 2025
• Study Completion (Actual): June 11, 2025

Study Registration Dates

• First Submitted: May 4, 2023
• First Submitted That Met QC Criteria: May 15, 2023
• First Posted (Actual): May 16, 2023

Study Record Updates

• Last Update Posted (Actual): June 29, 2025
• Last Update Submitted That Met QC Criteria: June 25, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Minocycline; Rifampicin
• Additional Relevant MeSH Terms: Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections, Nontuberculous; Mycobacterium Infections; Mycobacterium avium-intracellulare Infection; Anti-Bacterial Agents; Anti-Infective Agents; Minocycline
• Other Study ID Numbers: NL69313.091.19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The pseudonymized participant data will be accessible in the Radboud Data Repository under restricted access, only if the participant has provided consent. Requests for access will be checked, by a data access committee (DAC) formed by the sponsor (i.e. PI and other research members / coordinators)

The following data will be shared:

• Final versions of data used for analysis
• Documentation/codebooks necessary for understanding the data
• The .xml file that contains the full structure of the eCRF build in Castor EDC
• Read me.txt for understanding the structure and content of the documents

• IPD Sharing Time Frame: Data will become available for 15 years after the first study report has been published.
• IPD Sharing Access Criteria: To be determined
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No