ZEMDRI Solution for injection Ref.[10168] Active ingredients: Plazomicin

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 Patients

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 [C_min]) 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 C_min greater than or equal to 3 mcg/mL (36%, 10/28) compared to patients with plazomicin C_min less than 3 mcg/mL (5%, 11/215).

Cardiac Electrophysiology

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 (C_max), and C_min increased in proportion to the dose over the dose range of 4 to 15 mg/kg. The plazomicin AUC, C_max, and C_min 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:

* PK parameters following a single dose of 15 mg/kg; Based on non-compartmental analysis of PK data; AUC_0-inf is reported; C_min is concentration at 24 hours.
^† Day 1 PK parameters following administration of 15 mg/kg; Derived based on population PK model; AUC_0-24h is reported.

Distribution

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 concentration-independent across the range tested in vitro (5 to 100 mcg/mL).

Elimination

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).

Metabolism

Plazomicin does not appear to be metabolized to any appreciable extent.

Excretion

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.

Specific Populations

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 AUC_0-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 (2.2) and Use in Specific Populations (8.6)].

Based on the population PK model, the recommended dosage of ZEMDRI was associated with a mean (±SD) C_min 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 (AUC_0-24h) 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 C_min and AUC_0-24h for patients with severe renal impairment (CLcr 15 to <30 mL/min).

Geriatric Patients

No clinically relevant trend in plazomicin exposure (C_max and AUC_0-24h) was observed with regard to age alone. Higher C_min in elderly subjects (65 to 90 years of age) as compared to non-elderly adult subjects (18 to 64 years of age) was mainly attributable to age-related changes in renal function [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)].

Drug Interaction Studies

Clinical 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

Drug-Metabolizing Enzymes: 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.

Membrane Transporters: 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 mcg/mL, respectively.

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 2× MIC against Enterobacteriaceae.

Resistance

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 porins.

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 aeruginosa.

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-non-susceptible, or beta-lactamase producing Enterobacteriaceae.

Antimicrobial Activity

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 (1)].

Aerobic Bacteria:

Gram-negative Bacteria:

Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Enterobacter cloacae

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 clinical trials.

Aerobic Bacteria:

Gram-negative Bacteria:

Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Klebsiella oxytoca
Morganella morganii
Proteus vulgaris
Providencia stuartii
Serratia marcescens

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

Carcinogenesis

Long term carcinogenicity studies in animals have not been conducted with plazomicin.

Mutagenesis

Plazomicin was negative for mutagenicity in an Ames test and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes. In vivo, a mouse bone marrow micronucleus assay showed no evidence of clastogenic potential.

Impairment of Fertility

In a fertility and early embryonic development study, male and female rats received subcutaneous plazomicin at 0, 8, 25, or 50 mg/kg/day from prior to pairing through the mating and postmating period. Parental toxicity (reduced food consumption and body weight gain, and gross kidney changes) was observed at the mid and high doses. Plazomicin had no adverse effects on fertility in male rats at up to 50 mg/kg/day, resulting in an exposure (AUC) approximately 0.8-fold the human AUC at the clinical dose of 15 mg/kg once daily. In female rats, there were no effects on estrous cyclicity or reproductive performance including mating indices, fertility and fecundity indices, and copulatory intervals. At 25 and 50 mg/kg/day, female rats had fewer corpora lutea, leading to fewer uterine implantation sites and viable embryos per dam. The no observed effect level (NOEL) for fertility and reproductive performance in female rats was 8 mg/kg/day (0.1-fold human AUC).

14.1 Complicated Urinary Tract Infections, Including Pyelonephritis

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 at 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):

Abbreviations: CI=confidence interval; TOC=test-of-cure; CI=95% confidence interval based on Newcombe method with continuity correction.

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 (12.4)].