title: Population pharmacokinetics and dosing optimization of vancomycin in children with malignant hematological disease.
abstract: 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 (Css/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 Css/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.
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France Clinical Investigation Center CIC1426, INSERM, Paris, France wei.zhao@rdb.aphp.fr evelyne.jacqz-aigrain@rdb.aphp.fr.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: Daolun
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: May
authors.initials: M
authors.lastname: Fakhoury
authors.affiliation: Department of Pediatric Hemato-Oncology, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: Mony
authors.initials: M
authors.lastname: Fahd
authors.affiliation: Department of Pediatric Hemato-Oncology, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Duquesne
authors.affiliation: Department of Pharmacy, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Storme
authors.affiliation: Department of Pediatric Hemato-Oncology, Hôpital Robert Debré, APHP, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France Clinical Investigation Center CIC1426, INSERM, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France wei.zhao@rdb.aphp.fr evelyne.jacqz-aigrain@rdb.aphp.fr.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D019337:Hematologic Neoplasms / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D015233:Models, Statistical; D057285:Precision Medicine; D014640:Vancomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D003404:Creatinine