Pharmacokinetic study of minocycline in patients with nontuberculous mycobacterial disease

NTM disease is emerging in the Netherlands, particularly among patients with
underlying (pulmonary) diseases like COPD. Current treatment regimens of NTM
disease are challenging, with frequent adverse events and poor cure rates
(50-70%) after an average treatment duration of 6-18 months. The currently
recommended treatment regimen for pulmonary disease caused by Mycobacterium
avium complex, M. xenopi, M. kansasii and M. malmoense consists of rifampicin,
combined with ethambutol, azithromycin, isoniazid and possibly clofazimine
and/or amikacine. During recent studies in the hollow fiber model, we
identified minocycline as an active drug against M. avium complex bacteria, but
there is no pharmacokinetic data available for patients with M. avium complex
disease. ln addition, it has not been established to what extent rifampicin,
frequently used in M. avium complex pulmonary disease and a strong inducer of
metabolic enzymes and drug transporters, will decrease the exposure to
minocycline. Pharmacokinetic data of minocycline in actual patients with NTM
disease will allow us to propose an appropriate dose of minocycline when
co-administered with or without rifampicin in the target population.

The primary objective is to describe the pharmacokinetics of a 5-day dosing
period of minocycline in patients with NTM disease.
The secondary objective is to evaluate the effect of rifampicin on the
pharmacokinetics of a 5-day dosing period of minocycline in patients with NTM
disease.

This is an open label, one-arm, two-period, fixed-order pharmacokinetic study
in patients with NTM disease.

Subjects will receive two oral administrations of a 5-day dosing period of 200
mg minocycline.The first dosing period is given before the start of rifampicin
(as part of the antimycobacterial therapy). The rest of the antimycobacterial
regimen (e.g. ethambutol, a macrolide, isoniazid, possibly with additional
clofazimine and amikacine) can be started prior to or simultaneous with
minocycline as part of standard care. Rifampicin will be started after the
first 5-day minocycline dosing period, when PK sampling is completed.. The
second administration of a 5-day dosing period of minocycline is given after 1
month (±1 week) of rifampicin treatment.

On the fifth day of both 5-day dosing periods, minocycline will be taken on an
empty stomach (8-hour overnight fast continued until 4 hours after
administration). Patients will be sampled at t=0 (before minocycline
administration) and at t=1, 2, 3, 4, 6, 8 and 24, hours (after minocycline
administration), to measure plasma concentrations of minocycline. Additionally,
during the second study visit samples at t = 2, 4 and 6 hours (after
minocycline and rifampicin administration) will be sampled for rifampicin
plasma concentration measurements.
On both study visits blood samples will be taken to assess kidney and liver
function; i.e. hemoglobin, serum creatinine, urea, ASAT,ALAT, γ-GT, alkaline
phosphatase and LDH measurements. Weight and BMI will be assessed on both
occasions.

Patients will receive two 5-day dosing periods of 200 mg minocycline

The potential risk of this study is small because it consists of two
short-lasting (5-day) dosing periods of the study product. Risks include:
1) the possible side effects of minocycline: angioedema, rash, urticaria
(0.1-1%) and fever, eosinophilia, neutropenia and thrombocytopenia (rare). A
typical side-effect is photosensitivity to sunlight after taking minocycline.
Patients are informed in advance about these side effects. Furthermore, they
are monitored for side effects and they can reach a doctor at any time.
2) The 5-day delay of rifampicin treatment; this is an acceptable risk in our
view, because MAC lung infections are chronic infections that typically require
at least 18 months of treatment. Hence, relatively few time is lost.
3) the frequent blood sampling can be considered a burden for patients. Where
possible, a peripheral intravenous catheter will be used for blood sampling.
4) the extra time burden for participants.