Mechanism Of Action
ZEMDRI is an antibacterial drug [see Microbiology].
The ratio of area under the plasma concentration-time
curve to the minimum inhibitory concentration (AUC:MIC) for plazomicin has been
shown to best correlate with efficacy in animal and in vitro models of
infection against Enterobacteriaceae.
Exposure- Response Relationship For Nephrotoxicity In cUTI
Based on exposure-response analysis for nephrotoxicity,
defined as serum creatinine increases greater than or equal to 0.5 mg/dL from
baseline, using the data from two cUTI clinical trials (Trial 1 and Trial 2),
development of nephrotoxicity was associated with estimated plazomicin exposure
(i.e., the plasma trough concentration [Cmin]) in patients with CLcr greater
than 30 mL/min and less than or equal to 90 mL/min (N=243). The incidence of nephrotoxicity
was higher in patients with plazomicin Cmin greater than or equal to 3 mcg/mL
(36%, 10/28) compared to patients with plazomicin Cmin less than 3 mcg/mL (5%,
The effect of ZEMDRI on the QTc interval was evaluated in
a Phase 1 randomized, placebo and positive controlled, double-blind,
single-dose, crossover thorough QTc study in 56 healthy adult subjects. At a
single dose of 20 mg/kg (1.3 times the maximum recommended dose), ZEMDRI did
not prolong the QTc interval to any clinically relevant extent.
The pharmacokinetic (PK) parameters of plazomicin are
similar for single- and multiple-dose administration of ZEMDRI in healthy
subjects. No appreciable accumulation of plazomicin was observed following
multiple IV infusions of 15 mg/kg administered every 24 hours in subjects with
normal renal function. The AUC, maximum plasma concentration (Cmax), and Cmin
increased in proportion to the dose over the dose range of 4 to 15 mg/kg. The
plazomicin AUC, Cmax, and Cmin are summarized in Table 4.
Table 4: Pharmacokinetic Parameters (Geometric Mean
[±SD]) of Plazomicin Following Administration of ZEMDRI 15 mg/kg by 30-Minute
IV Infusion in Healthy Subjects and cUTI Patients with CLcr Greater than or
Equal to 90 mL/min
||Healthy Subjects a Geometric mean (±SD)
|cUTI Patients b Geometric mean (±SD)
||257 (± 67.0)
||73.7 (± 19.7)
||51.0 (± 26.7)
||0.3 (± 0.2)
||0.5 (± 1.2)
|a PK parameters following a single dose of 15
mg/kg; Based on non-compartmental analysis of PK data; AUC0-inf is reported;
Cmin is concentration at 24 hours.
b Day 1 PK parameters following administration of 15 mg/kg; Derived
based on population PK model; AUC0-24h is reported.
The mean (±SD) volume of distribution of plazomicin in
healthy adults and cUTI patients is 17.9 (±4.8) and 30.8 (±12.1) L,
respectively. The average binding of plazomicin to human plasma proteins is
approximately 20%. The degree of protein binding was concentrationindependent across
the range tested in vitro (5 to 100 mcg/mL).
The mean (±SD) total body clearance of plazomicin in
healthy adults and cUTI patients is 4.5 (±0.9) and 5.1 (±2.01) L/h, respectively.
The mean (±SD) half-life of plazomicin was 3.5 h (±0.5) in healthy adults with
normal renal function (n=54).
Plazomicin does not appear to be metabolized to any
Plazomicin is primarily excreted by the kidneys.
Following a single 15 mg/kg IV dose of radiolabeled plazomicin in healthy
subjects, 56% of the total administered radioactivity was recovered in urine
within 4 hours, 89.1% was recovered within 168 hours, with less than 0.2% in feces.
In total, 97.5% of the dose was recovered in the urine as unchanged plazomicin.
The mean renal clearance (±SD) of plazomicin (4.6 [±1.2] L/h) was similar to
total body clearance, suggesting that plazomicin is eliminated by the kidneys.
No clinically significant differences in the
pharmacokinetics of plazomicin were observed based on age (18 to 90 years of
age), sex, or race/ethnicity. The pharmacokinetics of plazomicin in patients
with hepatic impairment is unknown.
Patients With Renal Impairment
Following a single 7.5 mg/kg IV dose (0.5 times the
recommended dose) of ZEMDRI as a 30-minute infusion, the geometric mean
AUC0-inf of plazomicin in subjects with mild (CLcr 60 to <90 mL/min, n=6),
moderate (CLcr 30 to <60 mL/min, n=6), and severe (CLcr 15 to <30 mL/min,
n=6) renal impairment was 1.01-fold, 1.98-fold, and 4.42-fold higher,
respectively, compared to subjects with normal renal function (CLcr ≥90
mL/min, n=6) [see DOSAGE AND ADMINISTRATION and Use In Specific
Based on the population PK model, the recommended dosage
of ZEMDRI was associated with a mean (±SD) Cmin of 1.0 (±1.3) and 1.7 (±1.4)
mcg/mL in cUTI patients with mild (CLcr 60 to <90 mL/min, n=104) and
moderate (CLcr 30 to <60 mL/min, n=89) renal impairment, respectively. The
mean (±SD) area under the curve from time zero to 24 hours (AUC0-24h) was 261
(±102) and 224 (±147) mcg•h/mL
in cUTI patients with mild (CLcr 60 to <90 mL/min, n=104) and moderate (CLcr
30 to <60 mL/min, n=89) renal impairment, respectively. There were
insufficient data to calculate Cmin and AUC0-24h for patients with severe renal
impairment (CLcr 15 to <30 mL/min).
No clinically relevant trend in plazomicin exposure (Cmax
and AUC0-24h) was observed with regard to age alone. Higher Cmin in elderly
subjects (65 to 90 years of age) as compared to nonelderly adult subjects (18
to 64 years of age) was mainly attributable to age-related changes in renal
function [see DOSAGE AND ADMINISTRATION and Use In Specific
Drug Interaction Studies
Based on the results of a clinical drug-drug interaction
(DDI) study that evaluated the effect of a single dose of plazomicin (15 mg/kg)
on the single dose plasma PK of metformin, plazomicin did not affect the PK of
metformin, which is a substrate of OCT and MATE transporters.
In Vitro Studies
Plazomicin does not inhibit the following cytochrome P450
isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
Plazomicin does not induce CYP1A2, CYP2B6, and CYP3A4.
Plazomicin is not a substrate of P-gp or BCRP transporters.
Plazomicin does not inhibit the following hepatic and renal transporters in
vitro at clinically relevant concentrations: P-gp, BCRP, BSEP, MRP2, OATP1B1,
OATP1B3, OAT1, OAT3, OCT1, and OCT2. Plazomicin selectively inhibited the MATE1
and MATE2-K renal transporter in vitro with an IC50 value of 1300 and 338
Mechanism Of Action
Plazomicin is an aminoglycoside that acts by binding to
bacterial 30S ribosomal subunit, thereby inhibiting protein synthesis.
Plazomicin has concentration-dependent bactericidal activity as measured by
time kill studies. In vitro studies demonstrated a plazomicin post-antibiotic
effect ranging from 0.2 to 2.6 hours at 2X MIC against Enterobacteriaceae.
Resistance to aminoglycosides includes production of
aminoglycoside modifying enzymes (AMEs), alteration of the ribosomal target
through production of 16S rRNA methyltransferases, up-regulation of efflux
pumps and reduced permeability into bacterial cell due to loss of outer membrane
Plazomicin is not inhibited by most AMEs known to affect
gentamicin, amikacin and tobramycin, including acetyltransferases (AACs),
phosphotransferases (APHs) and nucleotidyltransferases (ANTs). Plazomicin, like
other aminoglycosides, is inactive against bacterial isolates that produce 16S
rRNA methyltransferases. Plazomicin may have reduced activity against
Enterobacteriaceae that overexpress certain efflux pumps (e.g., acrAB-tolC)
or lower expression of porins (e.g., ompF or ompK36).
Plazomicin has no in vitro activity against streptococci
(including Streptococcus pneumoniae), enterococci (including Enterococcus
faecalis, E. faecium), anaerobes, Stenotrophomonas maltophilia
and Acinetobacter spp and variable activity against Pseudomonas
Activity of plazomicin was demonstrated in vitro against
Enterobacteriaceae in the presence of certain beta-lactamases, including
extended-spectrum beta-lactamases (TEM, SHV, CTX-M, AmpC), serine
carbapenemases (KPC-2, KPC-3), and oxacillinase (OXA-48). Bacteria producing
metallo-beta-lactamases often co-express 16S rRNA methyltransferase, conferring
resistance to plazomicin.
Interaction With Other Antimicrobials
In vitro studies have demonstrated that against
Enterobacteriaceae isolates, no antagonism was observed for plazomicin in
combination with clindamycin, colistin, daptomycin, fosfomycin, levofloxacin,
linezolid, rifampin, tigecycline and vancomycin; few isolates showed synergy
with ceftazidime, meropenem and piperacillin-tazobactam. The clinical significance
of these findings is unknown.
Animal Infection Models
Plazomicin demonstrated activity in animal models of
infection (e.g., thigh infection, lung infection, and septicemia) caused by
either amikacin-non-susceptible, gentamicin-nonsusceptible, or beta-lactamase
ZEMDRI has been shown to be active against most isolates
of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE]
The following in vitro data are available, but their
clinical significance is unknown. At least 90 percent of the following bacteria
exhibit in vitro minimum inhibitory concentration (MIC) less than or equal to
the susceptible breakpoint for plazomicin against isolates of similar genus or organism
group. However, the efficacy of ZEMDRI in treating clinical infections caused
by these bacteria has not been established in adequate and well-controlled
Susceptibility Test Methods
For specific information regarding susceptibility test
interpretive criteria, and associated test methods and quality control
standards recognized by FDA for this drug, please see https://www.fda.gov/STIC
Complicated Urinary Tract Infections, Including
A total of 609 adults hospitalized with cUTI (including
pyelonephritis) were randomized in a multinational, double-blind,
noninferiority trial comparing ZEMDRI (15 mg/kg IV once daily as a 30-minute
infusion) to meropenem (1 g intravenously every 8 hours as a 30-minute
infusion) (Trial 1, NCT02486627). Switch to an oral antibacterial drug, such as
levofloxacin, was allowed after a minimum of 4 and maximum of 7 days of IV
therapy for a total of 7 to 10 days of treatment.
Efficacy was assessed in the microbiological modified
intent-to-treat (mMITT) population, which included all patients who received
study medication and had at least 1 baseline uropathogen. The mMITT population
excluded patients with organisms resistant to study drugs. Patient demographic
and baseline characteristics were balanced between treatment groups in the mMITT
population. The mMITT population consisted of 388 patients with cUTI, including
162 (41.8%) with pyelonephritis. The median age was 64 years, 52.8% were female
and 99.5% were White. The majority of the patients (99%) were from Eastern
Europe; 3 patients were from the United States. Concomitant bacteremia was
identified in 25 (13.1%) and 23 (11.7%) patients atÂ baseline in the ZEMDRI and
meropenem groups, respectively. The median treatment duration of IV study drug
was 6 days in both groups.
ZEMDRI demonstrated efficacy for composite cure at Day 5
and the Test of Cure (TOC) visit (Table 5). Composite cure at Day 5 was defined
as resolution or improvement of clinical cUTI symptoms and a microbiological
outcome of eradication (all baseline uropathogens reduced to <104 colony-forming units [CFU]/mL). Composite cure at the TOC visit (Day 17 ± 2
from the first dose of study drug) was defined as resolution of clinical cUTI
symptoms and a microbiological outcome of eradication.
Table 5: Composite Cure Rates in cUTI Patients in
Trial 1 (mMITT Population)
|Treatment Difference a (95% CI)
|Clinical cure or improvement
|Abbreviations: CI=confidence interval; TOC=test-of-cure;
CI=95% confidence interval based on Newcombe method with continuity correction.
a Treatment difference is ZEMDRI – meropenem.
Microbiological eradication rates at the TOC visit by
baseline uropathogen in the mMITT population are presented in Table 6.
Composite Cure at the TOC visit in individuals with concomitant bacteremia at
baseline was achieved in 72.0% (18/25) of patients in the ZEMDRI group and 56.5%
(13/23) of patients in the meropenem group.
Table 6: Microbiological Eradication Rate at TOC by
Baseline Pathogen in cUTI Patients in Trial 1 (mMITT Population)
There were 52 baseline Enterobacteriaceae isolates in
51/189 (27%) patients in the ZEMDRI group that were non-susceptible (defined as
intermediate or resistant) to gentamicin, or tobramycin or both. All of these
isolates were susceptible to plazomicin and all but one was susceptible to
amikacin (one isolate was intermediate to amikacin). The microbiological eradication
rate at the TOC visit in this subset was 78.9% (41/52) in the ZEMDRI group.
Note that certain resistance mechanisms can confer resistance to all
aminoglycosides, including plazomicin [see Microbiology].