Clinical trial NCT05861258: Pharmacokinetic Study of Minocycline in Patients With Pulmonary Nontuberculous Mycobacterial Disease
Official title: Pharmacokinetic Study of Minocycline in Patients With Pulmonary Nontuberculous Mycobacterial Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Mycobacterium Avium Complex Pulmonary Disease
Keywords: Pharmacokinetics
Minocycline
Rifampicin
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2023-05-16
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A single group, two-period, fixed-order pharmacokinetic study
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Pharmacokinetic parameters of minocycline in MAC-PD patients without concurrent use of rifampicin.
timeFrame: Day 5 of the first minocycline dosing period
measure: Pharmacokinetic parameters of minocycline in MAC-PD patients without concurrent use of rifampicin.
timeFrame: Day 5 of the first minocycline dosing period
measure: Pharmacokinetic parameters of minocycline in MAC-PD patients without concurrent use of rifampicin.
timeFrame: Day 5 of the first minocycline dosing period
Secondary outcomes:
measure: Pharmacokinetic parameters of minocycline in MAC-PD patients with concurrent use of rifampicin.
timeFrame: Day 5 of the second minocycline dosing period
measure: Pharmacokinetic parameters of minocycline in MAC-PD patients with concurrent use of rifampicin.
timeFrame: Day 5 of the second minocycline dosing period
measure: Pharmacokinetic parameters of minocycline in MAC-PD patients with concurrent use of rifampicin.
timeFrame: Day 5 of the second minocycline dosing period
measure: Pharmacokinetic parameters of rifampicin in MAC-PD patients
timeFrame: Day 5 of the second minocycline dosing period
measure: Adverse Events
timeFrame: Through study completion, an average of 6 weeks
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
state: Gelderland
Study officials:
affiliation: Radboud University Medical Center
name: Wouter Hoefsloot, MSc, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.