Vancomycin population pharmacokinetics and dosing recommendations in haematologic malignancy with augmented renal clearance children

Abstract

What is known and objectives Augmented renal clearance (ARC) is characterized by enhanced renal clearance, which leads to insufficient vancomycin exposure and treatment failure. In haematologic malignancy patients, determination of optimal vancomycin dosage is essential because of high stake of life‐threatening bacterial infection and increased clearance. The aim of this study was to describe vancomycin pharmacokinetic parameters in haematologic malignancy with augmented renal clearance children and define the appropriate dosing regimen to achieve an AUC0‐24h/MIC ≥400. Methods Hematologic malignancy with ARC children was enrolled in this retrospective study. The vancomycin PPK model was established by non‐linear mixed‐effects modelling programme. Goodness‐of‐fit (GOF) plots, non‐parametric bootstrap, normalized prediction distribution error (NPDE) and visual predictive checks (VPCs) were carried out for internal evaluation of the final model. Monte Carlo simulation method was used to stimulate the optimal dosage regimens. Results Fifty‐three patients with 106 samples were included. A one‐compartment model with first‐order elimination was developed, and the final model was as follows: CL (L/h) = 6.32×（WT/70）0.75 × e0.0467; V(L) = 39.6×(WT/70), where WT denotes weight (kg). The internal validation of the model showed a good prediction performance. Monte Carlo simulation results showed that when MIC was 0.5 mg/L or 1 mg/L, the recommended doses to achieve a target of AUC0‐24h/MIC ≥400 were 25 to 40 and 50 to 75 mg/kg/d, respectively. With decreasing weight, the recommended dosage to achieve an AUC0‐24h/MIC ≥400 increased. What is new and conclusion A one‐compartment vancomycin PPK model was established in haematologic malignancy with augmented renal clearance children with weight with allometric scaling as a significant covariate. When MIC was 1 mg/L, current recommended paediatric dosages were insufficient in haematologic malignancy with augmented renal clearance children and should be increased.

Population Pharmacokinetics Modeling of Vancomycin Among Chinese Infants With Normal and Augmented Renal Function

“…Among the pediatric population with normal renal function, WT and SCR are the main determinants for the vancomycin CL, which was in accordance with the model based on the whole population data. However, among the ARC group, only WT was included as a covariate, which agreed with the findings of Lv et al in 2020, who demonstrated that body weight with allometric scaling was the only significant determinant on CL and V in the group of Chinese hematologic malignancy children with eGFR ≥130 ml/min/1.73 m 2 ( 7 ), and Yamamoto et al in 2009 observed that the clearance of vancomycin was linearly correlated to CLCR in patients with renal insufficiency (CLCR < 85 ml/min/1.73 m 2 ), but there was no linear relationship when CLCR was ≥85 ml/min/1.73 m 2 ( 20 ).…”

“…Age, WT, height (HT), alanine transferase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN), SCR, Cystatin C (CYSC), albumin (ALB), total protein (TP), daily dosage (DD), and concomitant medication were retrospectively collected from the electronic medical records of the hospital information system. eGFR was calculated by the modified Schwartz formula ( 7 ):…”

Population Pharmacokinetic Study of Cefathiamidine in Infants With Augmented Renal Clearance

“…We summarized eight pharmacokinetic models of renally eliminated drugs in pediatric patients with ARC, as shown in Supplementary Tables S1, S2. Importantly, clinicians need to be aware of the risk of conventional dosing in patients with ARC because these patients have elevated significant higher CL than the general population without ARC for renally cleared drugs (Udy et al, 2015;Lv et al, 2020). Age and ARC had effects on the pharmacokinetic parameters of renally excreted drugs (Avedissian et al, 2017;Chen et al, 2018;Béranger et al, 2019).…”

“…ARC was defined based on estimated glomerular filtration rate (eGFR) ≥ 130 ml/ min/1.73 m 2 in pediatric patients (Béranger et al, 2018;Béranger et al, 2019;Lv et al, 2020). ARC is strongly associated with subtherapeutic concentrations of antibiotics such as β-lactams and vancomycin, which leads to underexposure and, as a consequence, to increased treatment failure (Udy et al, 2012;Carlier et al, 2013;Udy et al, 2015;Lv et al, 2020). ARC is likely to influence the pharmacokinetic (PK) parameters of cefathiamidine owing to an enhanced eGFR, which results in enhanced drug clearance.…”

Pharmacokinetics of Antibiotics in Pediatric Intensive Care: Fostering Variability to Attain Precision Medicine

“…Several studies have also reported subtherapeutic vancomycin exposure in critically ill children with ARC [52,56,64,[111][112][113][114][115]. Increased loading or initial doses have been recommended to achieve early therapeutic exposure.…”