Population pharmacokinetic model and dosing optimization of vancomycin in hematologic malignancies with neutropenia and augmented renal clearance

Abstract

Aim: Data on the pharmacokinetics (PK) and area under the curve (AUC)-based dosing strategy of vancomycin (VCM) in hematologic malignancies are limited. According to our preliminary narrative review, only a few population PK analyses in hematologic malignancies have been performed. Therefore, we aimed to develop a population PK model, investigate the factors influencing VCM PK, and propose an optimal dosing regimen for hematologic malignancies.

Methods: A retrospective study was conducted in patients with underlying hematologic malignancies treated with VCM. A total of 148 patients were enrolled for population PK modeling. Simulation analyses were performed to identify dosing regimens achieving a target exposure of AUC_0-24 of 400-600 mg h/L at the steady-state.

Results: The VCM PK data were best described with a one-compartment model. Significant covariates included creatinine clearance (Ccr), diagnosis of acute myeloid leukemia (AML) and neutropenia on VCM clearance (CL), and body weight (WT) on the volume of distribution (Vd). The typical values of CL and Vd were 3.09 L/h (normalized to Ccr value of 90 mL/min) and 122 L/70 kg, respectively. Concerning the effect on VCM dosing, AML patients required 15% higher doses than non-AML patients, independently of renal function. In contrast, for neutropenic patients, only those with augmented renal clearance (ARC, Ccr value ≥ 130 mL/min) required a 10% dose increase compared to non-neutropenic patients.

Conclusion: AML patients with neutropenia and ARC represent a critical population with a higher risk of VCM underexposure. Thus, individualized dosing adjustment and therapeutic drug monitoring are strongly recommended.

Keywords: Augmented renal clearance; Dosing regimen; Hematologic malignancies; Neutropenia; Population pharmacokinetic model; Vancomycin.