Pharmacokinetic Evaluation and Local Tolerability of Dry Powder Amikacin Via the Cyclops™
Status:
Recruiting
Trial end date:
2022-06-01
Target enrollment:
Participant gender:
Summary
Rationale: Multidrug-resistant tuberculosis (MDR-TB) is defined as tuberculosis resistant to
isoniazid and rifampicin. The incidence of MDR-TB worldwide is 3.9% for new cases and 21% for
previously treated cases. However, the incidence of previously treated cases can rise to
above 50% in eastern European countries. With increasing frequency of MDR-TB (and even
extensively drug-resistant types), morbidity and mortality due to TB fail to decline
worldwide. Amikacin, one of the drugs against MDR-TB, has the most potent effect when
reaching a high peak serum concentration and this means that high doses have to be
administered. Treatment with amikacin by inhalation would be a tremendous advantage due to
the high local dose in the lungs, obtaining high local levels without the possible toxicity
due to high serum levels. With the currently available inhalation techniques these local
levels cannot be reached easily.
In this protocol, the investigators will perform a pharmacokinetic and local tolerability
study of dry powder amikacin using the Cyclops™ in patients with drug susceptible
tuberculosis.
Objective:
- primary objective is to investigate the pharmacokinetic properties of dry powder
amikacin at different dosages and compare the peak serum values to a single i.v. dose.
- secondary objective is to assess the local tolerability of dry powder amikacin via the
Cyclops™ at different dosages.
Study design: single center, active control, ascending dose response study Study population:
8 patients with DSTB. Main study parameters/endpoints: the following pharmacokinetic
parameters: actual dose (dose minus remainder in inhaler after inhalation), AUC0-24 (area
under the curve from 0-24 h), Cmax (maximum serum concentration), Tmax (time to maximum serum
concentration).
For the local tolerability the following procedures will be done, drop of FEV1 of >15 % (lung
function measurement) and any other reported adverse event are all considered critical to
decide on proceeding into a phase 2B (and/or a phase 3) trial.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: All participants included in this study are patients with DSTB, who are admitted
at the Tuberculosis Center Beatrixoord. They will receive 3 different doses of amikacin using
the DPI with (at least) one week in between doses, they will also receive one dose of
intravenous amikacin. Before using the dry powder inhaler (DPI) they will receive
instructions and their inspiratory flow will be tested. Before each test dose an indwelling
cannula will be inserted and before and after each test dose in total 9 blood samples will be
collected. To investigate local tolerability, lung function tests will be performed and the
occurrence of adverse events will be scored.