Pharmacokinetics and Safety of Single and Multiple Doses of ACHN-490 Injection Administered Intravenously in Healthy Subjects

Abstract

ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects

In Vitro Activity of Plazomicin against 5,015 Gram-Negative and Gram-Positive Clinical Isolates Obtained from Patients in Canadian Hospitals as Part of the CANWARD Study, 2011-2012

“…While gentamicin and tobramycin had MIC 90 values that were 2 times and 8 times lower than that of plazomicin, respectively, the significance of this observation needs to be interpreted with caution. The anticipated dosing, maximum serum concentration achieved, and area under the concentration time curve (AUC) are much higher for plazomicin than for gentamicin and tobramycin, so directly comparing the MICs for these antimicrobials in terms of clinical relevance is difficult (13,25). The in vitro activity of plazomicin versus P. aeruginosa was similar to that for amikacin, an aminoglycoside for which the AUC appears to be more comparable (13).…”

Investigational Antimicrobial Agents of 2013

“…No serious AEs were reported in the ascending-dose studies, although two reversible cases of tinnitus were reported (60). In the UTI study, mild to moderate treatment-related adverse events were reported in 17.7% of plazomicin-treated and 27.3% of levofloxacin-treated patients.…”

New antibiotics and antimicrobial combination therapy for the treatment of gram-negative bacterial infections

“…The pharmacokinetic properties of plazomicin were tested in two randomized clinical trials in healthy individuals, revealing a linear and dose-proportional profile and good penetration into the epithelial-lining fluid. Compared to other aminoglycosides, no evidence of side-effects on renal function or audiometry tests was observed [41]. A phase 2 study showed comparable efficacy to levofloxacin in patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (88 versus 81%, respectively) [42].…”