Introduction

Complicated urinary tract infections (cUTIs) affect all ages and are often linked to urinary tract abnormalities. Treatment options for multidrug resistance (MDR) Enterobacteriaceae are very limited, and drugs like colistin often cause significant side effects in critically ill patients. Due to the lack of effective therapies, optimizing antibiotic dosage is crucial to ensure adequate drug levels at the infection site.

Plazomicin, a next‑generation aminoglycoside specifically developed to overcome the resistance mechanisms that limit the efficacy of traditional aminoglycosides.

Aim 

This post hoc analysis of the Phase 2 study compared the PK parameters of plazomicin in patients who were enrolled from India and those outside India.

Patient Profile

Adults Aged 18-85 years, body weight < 100 kg with documented/suspected cUTI or acute pyelonephritis.

Methods

• Post hoc analysis of PK data from the Phase 2 study (ACHN–490-002), a multicenter, double–blind, randomized, comparator–controlled study.
• N=91 
• Indian (n=21) and non‑Indian (n=70) participants were included, with 10 or 15 mg/kg dosing in both groups. 
• Demographics (sex, height, weight) were comparable between groups, with most participants receiving 15 mg/kg. 

Plazomicin Administration

• Administered as a 30-minute intravenous infusion. 
• Followed by a 90-minute infusion of placebo once daily for up to 5 consecutive days

Study Endpoint: Comparison of pharmacokinetic (PK) parameters and exposures (AUC_0-24, C_max, C_min, and clearance) between Indian and non-Indian participants

Results 

Effect of Dose Change on PK Parameters

• Increasing the dose from 10 mg/kg to 15 mg/kg increased exposure
  1. AUC₀₋₂₄ rose from 177.0 to 233.0 mg·h/L
  2. C_max from 38.7 to 54.5 mg/L
  3. Clearance and C_min remained similar across doses

Table 1: Effect of Dose Change on PK Parameters

Parameter	10 mg/kg (GeoMean, %CV)	15 mg/kg (GeoMean, %CV)
AUC0-24 (mg·h/L)	177.0, 53.5%	233.0, 45.5%
Clearance (L/h)	4.0, 43.6%	4.4, 43.2%
Cmax (mg/L)	38.7, 63.4%	54.5, 43.2%
Cmin (mg/L)	0.5, 132.7%	0.5, 138.6%

AUC0-24, area under the plasma time–concentration curve from time 0 to 24 h; CL, clearance; Cmax, maximum concentration; Cmin, minimum concentration, CV, coefficient of variation; PK, pharmacokinetic. Data presented as geometric mean (geometric %CV).

Drug Exposures in Indian vs Non‑Indian Participants

• Indian vs non‑Indian (10 mg/kg): Mean AUC₀₋₂₄ was 163.0 vs 185.0 mg·h/L, and Cmax 47.2 vs 34.8 mg/L, showing higher variability at this dose. 
• Indian vs non‑Indian (15 mg/kg): AUC₀₋₂₄ was 265.0 vs 226.0 mg·h/L and Cmax 50.5 vs 55.6 mg/L, indicating broadly comparable exposures. 

Table 2: Effect Dose Change in Indian and Non–Indian Participants on PK Parameters

Dose	Nationality	AUC0-24 (mg·h/L)	Cmax (mg/L)	Cmin (mg/L)
10 mg/kg	Indian	163.0	47.2	0.3
10 mg/kg	Non-Indian	185.0	34.8	0.7
15 mg/kg	Indian	265.0	50.5	0.9
15 mg/kg	Non-Indian	226.0	55.6	0.4

AUC0-24, area under the plasma time–concentration curve from time 0 to 24 h; CL, clearance C_max maximum concentration Cmin minimum concentration, CV, coefficient of variation; PK, pharmacokinetic. Data presented as Geometric mean (geometric %CV).

Dose‑Normalized Comparison

• Dose‑normalized AUC₀₋₂₄ was 17.2 mg·h/L/mg/kg (Indian) vs 15.7 mg·h/L/mg/kg (non‑Indian); dose‑normalized C_max was nearly identical (3.8 vs 3.7 mg·h/L/mg/kg). 
• Median values overlapped across groups, indicating comparable PK profiles. 

Table 3: Dose-Normalized Comparison

	Indian (GeoMean)	Non-Indian (GeoMean)
AUC0-24 per mg/kg	17.2	15.7
Cmax per mg/kg	3.8	3.7
Cmin per mg/kg	0.1	0.0

AUC_0-24, area under the plasma time–concentration curve from time 0 to 24 h; C_max, maximum concentration; C_min, minimum concentration, CV, coefficient of variation; PK, pharmacokinetic. Data presented as geometric mean and arithmetic mean.

Clearance Distribution

• There was substantial overlap in the interquartile ranges of drug exposures between Indian and non‑Indian participants, except for C_min among those receiving the 10 mg/kg dose.
• The distribution of clearance values showed that the median clearance in Indian participants fell within the interquartile range of non‑Indian participants, indicating that plazomicin clearance was comparable between the two groups.

Conclusion

• This post hoc evaluation of plazomicin pharmacokinetics showed that overall drug exposure was comparable between Indian and non‑Indian participants with documented or suspected cUTI or acute pyelonephritis.
• Dose‑normalized AUC₀_–₂₄ and C_max values confirmed that plazomicin exposure remained similar across both groups, indicating no clinically relevant differences related to geographic origin.

Reference

Gupte V, Sawant S, Mohanasundaram S, Malabade R, Warrier A, Sivakumar MN, Singh YP, Bhattacharya P, Chawla R, Gogtay J. Plazomicin Pharmacokinetics in Indian Complicated Urinary Tract Infections Patients: A Subgroup Analysis from a Phase 2 Study. Clin Pharmacol Drug Dev. 2025 Dec;14(12):903-910. doi: 10.1002/cpdd.1616. Epub 2025 Oct 19. PMID: 41109976