Population pharmacokinetics of amikacin in patients with haematological malignancies

e An increase in vancomycin dose has been proposed in adults with malignant hematological disease. As pediatric data are limited, our aim was to evaluate the population pharmacokinetics of vancomycin in order to define the appropriate dosing regimen in children with malignant hematological disease. Vancomycin concentrations were collected prospectively during therapeutic monitoring. Population pharmacokinetic analysis was performed using NONMEM software. Seventy children (age range, 0.3 to 17.7 years) were included. With the current recommended dosing regimen of 40 to 60 mg/kg/day, 53 children (76%) had subtherapeutic steady-state trough concentrations (C ss/min of <10 mg/liter). A one-compartment model with first-order elimination was developed. Systematic covariate analysis identified that weight significantly influenced clearance (CL) and volume of distribution (V) with power functions of 0.677 for CL and 0.838 for V. Vancomycin CL also significantly increased with increases in creatinine clearance and seemed to be higher in children with malignant hematological disease than in the general pediatric population. The model was validated internally. Its predictive performance was further confirmed in an external validation by Bayesian estimation. A patient-tailored dosing regimen was developed based on the final pharmacokinetic model and showed that a higher proportion of patients reached the target C ss/min than with the traditional mg/kg-basis dose (60% versus 49%) and that the risks associated with underdosing or overdosing were reduced. This is the first population pharmacokinetic study of vancomycin in children with malignant hematological disease. An optimized dosing regimen, taking into account patient weight, creatinine clearance, and susceptibility of the pathogens involved, could routinely be used to individualize vancomycin therapy in this vulnerable population.

Section: Discussionsupporting

confidence: 62%

mentioning

confidence: 99%

Population Pharmacokinetics and Dosing Optimization of Vancomycin in Children with Malignant Hematological Disease

Zhao

Zhang

Fakhoury

et al. 2014

“…According to previous criteria, a total of 348 treatments corresponding to 274 patients were available. Owing to intraindividual physiopathological changes, if the time period between two successive treatments in the same patient was more than 1 month we considered each as an individual course of VAN for population analysis, according to our previous experience for this kind of patient (37). Two hundred twenty-four patients received only one course of VAN therapy, and the remaining 50 patients received from two to six courses.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Vancomycin in Patients with Hematological Malignancies

Buelga

Gatta

Herrera

et al. 2005

107

103

This study determines vancomycin (VAN) population pharmacokinetics (PK) in adult patients with hematological malignancies. VAN serum concentration data (n ‫؍‬ 1,004) from therapeutic drug monitoring were collected retrospectively from 215 patients. A one-compartment PK model was selected. VAN pharmacokinetics population parameters were generated using the NONMEM program. A graphic approach and stepwise generalized additive modeling were used to elucidate the preliminary relationships between PK parameters and clinical covariates analyzed. Covariate selection revealed that total body weight (TBW) affected V, whereas renal function, estimated by creatinine clearance, and a diagnosis of acute myeloblastic leukemia (AML) influenced VAN clearance. We propose one general and two AML-specific models. The former was defined by CL (liters/h) ‫؍‬ 1.08 ؋ CL CR(Cockcroft and Gault) (liters/h); CV CL ‫؍‬ 28.16% and V (liters) ‫؍‬ 0.98 ؋ TBW; CV V ‫؍‬ 37.15%. AML models confirmed this structure but with a higher clearance coefficient (1.17). The a priori performance of the models was evaluated in another 59 patients, and clinical suitability was confirmed. The models were fairly accurate, with more than 33% of the measured concentrations being within ؎20% of the predicted value. This therapeutic precision is twofold higher than that of a noncustomized population model (16.1%). The corresponding standardized prediction errors included zero and a standard deviation close to unity. The models could be used to estimate appropriate VAN dosage guidelines, which are not clearly defined for this high-risk population. Their simple structure should allow easy implementation in clinical software and application in dosage individualization using the Bayesian approach.

“…Indeed, major changes in patients' extracellular fluid content and glomerular filtration rate were shown to account for most of the pharmacokinetic variability of hydrophilic antibiotics, including ceftazidime, in critically ill patients (16). Consistently, altered pharmacokinetic behavior also of vancomycin (2,7,11), amikacin (17,22), and teicoplanin (12,15) was documented in hematological patients, and higher dosages were advocated for ensuring therapeutic concentrations.…”

mentioning

confidence: 94%

Ceftazidime in Acute Myeloid Leukemia Patients with Febrile Neutropenia: Helpfulness of Continuous Intravenous Infusion in Maximizing Pharmacodynamic Exposure

Pea

Viale

Damiani

et al. 2005

The pharmacokinetic-pharmacodynamic profile of a fixed 6-g daily continuous intravenous infusion of ceftazidime was assessed in 20 febrile neutropenic patients with acute myeloid leukemia. Mean steady-state ceftazidime concentrations averaging 40 mg/liter from day 2 on ensured maximized pharmacodynamic exposure (values close to four to five times the MIC breakpoint against Pseudomonas aeruginosa). However, large intra-and interindividual pharmacokinetic variability was documented throughout the study period.