TY - JOUR
T1 - Population Pharmacokinetics of Clotting Factor Concentrates and Desmopressin in Hemophilia
AU - Preijers, Tim
AU - Schütte, Lisette M.
AU - Kruip, Marieke J. H. A.
AU - Cnossen, Marjon H.
AU - Leebeek, Frank W. G.
AU - van Hest, Reinier M.
AU - Mathôt, Ron A. A.
N1 - Funding Information: TP, LS, and RH have no conflicts of interest that are directly relevant to the content of this review. RM has received grants from governmental and societal research institutes such as NWO, ZonMW, and Innovation Fund and unrestricted investigator research grants from Baxter/Baxalta/Shire/Takeda, Bayer, CSL Behring, and Sobi. He has served as an advisor for Bayer, CSL Behring, Merck Sharp & Dohme, and Baxter/Baxalta/Shire/Takeda. All grants and fees were paid to the institution. MC has received grants from governmental research institutes such as Dutch Research Institute (NWO), ZonMW, Innovation Fund, and NWO-NWA and unrestricted investigator-initiated research grants as well as educational and travel funding from the following companies over the years: Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a member on steering boards of Roche and Bayer. All grants, awards, and fees received went to the institution. FWGL received unrestricted search grants of CS: Behring, Takeda, and UniQure. He is also a consultant for CSL Behring, Takeda, and UniQure of which fees go to the institution. He received travel support from Sobi. He is a DSMB member for a study conducted by Roche. MK reports grants from Daiichi Sankyo, Boehringer Ingelheim, Pfizer, and Sobi, and grants and fees from Bayer, all outside the submitted work and payments to the Department of Hematology of Erasmus MC. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL −1) and some patients with moderate hemophilia (0.01–0.05 IU mL −1) administer clotting factor concentrates prophylactically. Desmopressin (d-amino d-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or d-amino d-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.
AB - Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL −1) and some patients with moderate hemophilia (0.01–0.05 IU mL −1) administer clotting factor concentrates prophylactically. Desmopressin (d-amino d-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or d-amino d-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.
UR - http://www.scopus.com/inward/record.url?scp=85091091648&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s40262-020-00936-5
DO - https://doi.org/10.1007/s40262-020-00936-5
M3 - Review article
C2 - 32936401
SN - 0312-5963
VL - 60
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 1
ER -