Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, other aminoglycosides. ATC code: J01GB06

Mechanism of action

Amikacin binds to a specific receptor protein on the 30S subunit of bacterial ribosomes and interferes with an initiation complex between mRNA (messenger RNA) and the 30S subunit resulting in inhibition of protein synthesis.

Resistance

The mechanism of resistance to amikacin in mycobacteria has been linked to mutations in the rrs gene of the 16S rRNA.

Clinical experience

The efficacy of inhaled liposomal amikacin was evaluated in study INS-212, a randomised, open-label study in adult patients with non-tuberculous mycobacterial lung infections caused by MAC.
Patients who had not achieved sputum culture conversion (SCC) while being treated with Multiple Drug Regimen(s) (MDR) for at least 6 months before study entry were randomised to receive ARIKAYCE in addition to their MDR treatment or to continue with MDR alone. Patients achieving SCC, defined as 3 consecutive negative MAC sputum cultures by month 6 on treatment continued therapy for up to 12 months after achieving SCC. Those not achieving SCC by month 6 were discontinued from the study at month 8.

A total of 335 patients were randomised and dosed (ARIKAYCE liposomal 590 mg + MDR n = 223; MDR alone n = 112) (Safety population). Median duration of prior MDR treatment was 2.6 years and 2.4 years in the ARIKAYCE liposomal 590 mg + MDR and MDR alone group, respectively. Patients were stratified per smoking status (current smoker or not) and MDR use at screening (on treatment or off treatment for at least 3 months prior to screening). The primary endpoint was durable SCC defined asthe proportion of randomised patients that had achieved SCC by month 6 on treatment and had no positive solid media culture or no more than two broth media cultures by 3 months off treatment.

Sixty-five (29.0%) and 10 (8.9%) patients achieved SCC by month 6 on treatment in the ARIKAYCE liposomal 590 mg+ MDR and the MDR group, respectively (p< 0.0001). Of these, based on the primary analysis durable SCC at 3 months off treatment was achieved by 16.1% [36/224] vs. 0% [0/112]; p- value <0.0001.

In a post-hoc analysis that eliminated patients with negative cultures (solid media or broth) at study baseline and which counted any post-treatment positive culture (solid media or broth) as positive, 30/224 (13.4%) in the ARIKAYCE liposomal 590 mg + MDR group and 0/112 (0%) in the MDR group achieved durable SCC at 3 months off treatment. Respective rates at 12 months off treatment were 25/224 (11%) vs. 0/112 (0%).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Sputum concentrations
Following once daily inhalation of 590 mg inhaled liposomal amikacin in MAC patients, sputum concentrations at 1 to 4 hours post-inhalation were 1720, 884, and 1300 µg/g at 1, 3, and 6 months, respectively. High variability in amikacin concentrations was observed (CV% > 100%). After 48 to 72 hours post-inhalation, amikacin sputum concentrations decreased to approximately 5% of those at 1 to 4 hours post-inhalation.

Serum concentrations
Following daily inhalation of 590 mg ARIKAYCE in MAC patients, at steady state, the median serum AUC0-24 was 16.7 µg *hr/mL (range: 4.31 to 55.6 µg *hr/mL; n = 53) and the median serum Cmax was 1.81 µg/mL (range: 0.482 to 6.87 μg/mL; n = 53).

Distribution

Amikacin is ≤ 10% bound to serum proteins. The mean total apparent volume of distribution has been estimated to be approximately 5.0 L/kg.

Biotransformation

Amikacin is not metabolised.
Elimination

Amikacin is excreted in the urine unchanged, primarily by glomerular filtration. The median apparent terminal serum half-life of amikacin after inhalation of ARIKAYCE liposomal 590 mg ranged from approximately 3.29 to 14.0 hrs.

A population pharmacokinetic analysis for ARIKAYCE liposomal 590 mg in 53 subjects with NTM lung disease aged 20 to 84 years indicated that amikacin clearance is 34 L/h. The only clinical covariateidentified to be predictive of amikacin clearance was body weight.