Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies [Pharmacology]

Plazomicin is an aminoglycoside with activity against multidrug-resistant Enterobacteriaceae. Plazomicin is dosed on a mg/kg basis and administered by 30-min intravenous infusion every 24 h, with dose adjustments for renal impairment and body weight (BW) ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1–3). A three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration–time profiles. The base structural model included creatinine clearance (CL_CR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The range of α-, β-, and -phase half-lives for the analysis population are 0.328–1.58, 2.77–5.38, and 25.8–36.5 h, respectively. Total and renal clearance in a typical cUTI or HABP/VABP patient are 4.57 and 4.08 l/h, respectively. Starting dose adjustments for CL_CR are sufficient for minimizing variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a mg/kg basis with adjustments for CL_CR and BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renal impaired.

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