title: A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients.
abstract: The role of pharmacokinetic-guided dosing of factor concentrates in hemophilia is currently a subject of debate and focuses on long-term prophylactic treatment. Few data are available on its impact in the perioperative period. In this study, a population pharmacokinetic model for currently registered factor VIII concentrates was developed for severe and moderate adult and pediatric hemophilia A patients (FVIII levels <0.05 IUmL-1) undergoing elective, minor or major surgery. Retrospective data were collected on FVIII treatment, including timing and dosing, time point of FVIII sampling and all FVIII plasma concentrations achieved (trough, peak and steady state), brand of concentrate, as well as patients' and surgical characteristics. Population pharmacokinetic modeling was performed using non-linear mixed-effects modeling. Population pharmacokinetic parameters were estimated in 75 adults undergoing 140 surgeries (median age: 48 years; median weight: 80 kg) and 44 children undergoing 58 surgeries (median age: 4.3 years; median weight: 18.5 kg). Pharmacokinetic profiles were best described by a two-compartment model. Typical values for clearance, intercompartment clearance, central and peripheral volume were 0.15 L/h/68 kg, 0.16 L/h/68 kg, 2.81 L/68 kg and 1.90 L/68 kg. Interpatient variability in clearance and central volume was 37% and 27%. Clearance decreased with increasing age (P<0.01) and increased in cases with blood group O (26%; P<0.01). In addition, a minor decrease in clearance was observed when a major surgical procedure was performed (7%; P<0.01). The developed population model describes the perioperative pharmacokinetics of various FVIII concentrates, allowing individualization of perioperative FVIII therapy for severe and moderate hemophilia A patients by Bayesian adaptive dosing.
authors.affiliation: Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children's Hospital Rotterdam.
authors.forename: Hendrika
authors.initials: H
authors.lastname: Hazendonk
authors.affiliation: Department of Pediatric Hematology, Academic Medical Center, Amsterdam.
authors.forename: Karin
authors.initials: K
authors.lastname: Fijnvandraat
authors.affiliation: Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children's Hospital Rotterdam.
authors.forename: Janske
authors.initials: J
authors.lastname: Lock
authors.affiliation: Netherlands Hemophilia Patient Organization (NVHP), Nijkerk.
authors.forename: Mariëtte
authors.initials: M
authors.lastname: Driessens
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University Medical Center.
authors.forename: Felix
authors.initials: F
authors.lastname: van der Meer
authors.affiliation: University of Groningen, Department of Hematology, University Medical Center Groningen.
authors.forename: Karina
authors.initials: K
authors.lastname: Meijer
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam.
authors.forename: Marieke
authors.initials: M
authors.lastname: Kruip
authors.affiliation: Department of Hematology, Radboud university medical center, Sophia Children's Hospital Rotterdam.
authors.forename: Britta Laros-van
authors.initials: BL
authors.lastname: Gorkom
authors.affiliation: Department of Pediatric Hematology, Academic Medical Center, Amsterdam.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Peters
authors.affiliation: Intensive Care and Department of Pediatric Intensive Care, Erasmus University Medical Center - Sophia Children's Hospital Rotterdam Department of Pharmacology, Radboud university medical center, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: de Wildt
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam.
authors.forename: Frank
authors.initials: F
authors.lastname: Leebeek
authors.affiliation: Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children's Hospital Rotterdam.
authors.forename: Marjon
authors.initials: M
authors.lastname: Cnossen
authors.affiliation: Hospital Pharmacy-Clinical Pharmacology, Academic Medical Center Amsterdam, The Netherlands r.mathot@amc.uva.nl.
authors.forename: Ron
authors.initials: R
authors.lastname: Mathôt
mesh_terms: D000017:ABO Blood-Group System; D000367:Age Factors; D001789:Blood Group Antigens; D001835:Body Weight; D002675:Child, Preschool; D054796:Drug Dosage Calculations; D005169:Factor VIII / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D008962:Models, Theoretical; D019990:Perioperative Care / Q000379:methods*; D012189:Retrospective Studies
chemical_list: D000017:ABO Blood-Group System; D001789:Blood Group Antigens; D005169:Factor VIII