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| | FDA Approves ZEMDRI (plazomicin) for the Treatment of Patients with Complicated Urinary Tract Infections Including Pyelonephritis
On June 25, 2018, the U.S. Food and Drug Administration (FDA) approved ZEMDRI (plazomicin) for the treatment of patients 18 years of age or older with complicated urinary tract infections (cUTI) including pyelonephritis. As only limited clinical safety and efficacy data are available, reserve ZEMDRI for use in patients who have limited or no alternative treatment options.
The approved recommended dosage of ZEMDRI is 15 mg/kg every 24 hours by intravenous (IV) infusion over 30 minutes to patients with creatinine clearance ≥ 90 mL/min. The recommended duration of treatment is 4 to 7 days. Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy. Adjustment of initial dose and therapeutic drug monitoring (TDM) is recommended in patients with renal impairment (see below).
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
- MOA: ZEMDRI is an aminoglycoside antibacterial drug.
- General PK: 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 the plasma trough concentration (Cmin) increased in proportion to the dose over the dose range of 4 to 15 mg/kg. Following administration of ZEMDRI 15 mg/kg by 30 minute IV infusion in healthy subjects and cUTI patients, the geometric mean (± SD) plazomicin AUC was 257 (± 67.0) and 226 (± 113) mcg·h/mL, respectively; Cmax was 73.7 (± 19.7) and 51.0 (± 26.7) mcg/mL, respectively; and Cmin was 0.3 (± 0.2) and 0.5 (± 1.2) mcg/mL, respectively.
- 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. Protein binding of plazomicin is approximately 20%.
- Elimination: The mean (± SD) total body clearance of plazomicin 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).
- Metabolism: Plazomicin does not appear to be metabolized to any appreciable extent.
- Excretion: Plazomicin is primarily excreted by the kidneys, and 97.5% of the dose was recovered in the urine as unchanged plazomicin.
- PD: Exposure-response analysis for nephrotoxicity, defined as serum creatinine increases ≥ 0.5 mg/dL from baseline, indicated that development of nephrotoxicity was associated with estimated plazomicin exposure (i.e., Cmin) in cUTI patients with CLcr > 30 mL/min and ≤ 90 mL/min. The incidence of nephrotoxicity was higher in patients with plazomicin Cmin ≥ 3 mcg/mL compared to patients with plazomicin Cmin < 3 mcg/mL.
Use in Specific Populations
Renal Impairment Plazomicin total body clearance was significantly decreased in patients with CLcr ≥ 15 to < 60 mL/min compared to patients with CLcr ≥ 60 mL/min. The recommended initial dosage regimen of ZEMDRI in adult patients with CLcr ≥ 15 and < 90 mL/min is as follows: - CLcr ≥ 60 to < 90 mL/min: ZEMDRI 15 mg/kg every 24 hours.
- CLcr ≥ 30 to < 60 mL/min: ZEMDRI 10 mg/kg every 24 hours.
- CLcr ≥ 15 to < 30 mL/min: ZEMDRI 10 mg/kg every 48 hours.
There is insufficient information to recommend a dosage regimen in patients with CLcr < 15 mL/min or on renal replacement therapy, including hemodialysis or continuous renal replacement therapy. For patients with CLcr ≥ 15 mL/min and < 90 mL/min, TDM is recommended in order to avoid plazomicin-induced nephrotoxicity. Monitor plazomicin trough concentrations and adjust ZEMDRI dosage as described in the full prescribing information linked below.
Efficacy and Safety
Efficacy of ZEMDRI was demonstrated 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) in hospitalized adults with cUTI (including pyelonephritis). Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.
The most common adverse reactions (≥ 1% of patients treated with ZEMDRI) are decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA. |
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