Introduction 

Multidrug–resistant (MDR) Enterobacteriaceae are the causative organisms of complicated urinary tract infections (cUTIs). Plazomicin, an aminoglycoside, has an established efficacy and safety profile. However, since geographic and ethnic differences lead to variations in pharmacokinetic (PK) parameters, it was important to find about the need for dose adjustment of plazomicin to achieve optimal efficacy and safety in Indian population. Therefore, a post hoc analysis of the Phase 2 study was conducted to compare the PK parameters of plazomicin in patients who were enrolled from India and those outside India.

Aim

To compare pharmacokinetic (PK) parameters of plazomicin among Indian versus non–Indian patients suspected with cUTI or acute pyelonephritis

Patient Profile 

Method

Study Design

• Post hoc analysis of PK data from the Phase 2 study (multicenter, double-blind, randomized, comparator-controlled study)
• Patients received either 10 or 15 mg/kg plazomicin administered as a 30–min intravenous infusion, immediately followed by a 90–min infusion of placebo once daily for up to 5 consecutive days
• Samples were collected on Day 1 (35 to 55 min and 1.5 to 3 h after the start of infusion) and on Days 2 to 5 prior to infusion

Endpoints

• Total exposure (area under the plasma time–concentration curve from time 0 to 24 h, AUC_0-24)
• Peak exposure (maximum concentration, C_max)
• Trough exposure (minimum concentration, C_min)
• Clearance (CL) between Indian and non-Indian participants

Results 

• Plazomicin 15 mg/kg dose demonstrated a higher area under the plasma time-concentration curve from time 0 to 24 h (AUC_0-24, 233.0 mg.h/L vs. 177.0 mg.h/L) and maximum concentration (C_max, 54.5 mg/L vs. 38.7 mg/L) compared to the 10 mg/kg dose, which showed greater variability
• Plazomicin 10 mg/kg dose demonstrated a mean AUC_0-24 of 163.0 mg.h/L in Indian participants compared to 185 mg.h/L in non–Indian participants; mean C_max values were higher in Indian vs. non-Indian patients (47.2 vs. 34.8 mg/L, resp.)
• At plazomicin 15 mg/kg dose, the mean AUC_0-24 was 265.0 mg.h/L for Indian participants vs. 226.0 mg.h/L for non–Indian participants; mean C_max values were 50.5 mg/L for Indian subset and 55.6 mg/L for non–Indian subset
• Dose–normalized estimated mean plazomicin AUC_0-24 values were comparable for Indian (17.2 mg.h/L) and non–Indian participants (15.7 mg.h/L)
• Dose–normalized AUC_0-24 and C_max  point estimates were 110% and 103% in Indian participants versus non–Indian participants, respectively
• The median of AUC_0-24, C_max, and C_min for Indian participants was well within the interquartile range of non–Indian participants, and there was a considerable overlap between interquartile ranges for Indian and non–Indian participants (Table S5)
• The estimated mean plazomicin AUC_0-24 values were comparable between Indian and non–Indian participants
• Mean AUC(0-∞) and C_max increased with increasing plazomicin doses from 4 to 15 mg/kg; apparent half–life remained relatively consistent across dose levels

Conclusion 

• Plazomicin exposure was comparably similar in Indian and non–Indian participants
• It was the first–of–its–kind post hoc analysis from the Phase 2 study of PK parameters to understand the variations in plazomicin exposure in Indian versus non–Indian participants
• Differences in plazomicin exposure were not clinically significant, and no dose adjustment was necessary.

Clin Pharmacol Drug Dev 2025; 14(12): 903-910