Review Articles: Focus on Pharmacodynamic Drug MonitoringStrategies for Individualized Dosing of Clotting Factor Concentrates and Desmopressin in Hemophilia A and BPreijers, Tim PharmD, MSc*; Schütte, Lisette M. MD, MSc†; Kruip, Marieke J. H. A. MD, PhD†; Cnossen, Marjon H. MD, PhD‡; Leebeek, Frank W. G. MD, PhD†; van Hest, Reinier M. PharmD, PhD*; Mathôt, Ron A. A. PharmD, PhD*Author Information *Department of Hospital Pharmacy-Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; †Department of Hematology, Erasmus University Medical Center; and ‡Department of Pediatric Hematology, Erasmus University Medical Center- Sophia, Children's Hospital Rotterdam, Rotterdam, the Netherlands. Correspondence: Ron A. A. Mathôt, PharmD, PhD, Hospital Pharmacy-Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, P.O. Box 22660, 1100 DD Amsterdam, the Netherlands (e-mail: [email protected]). T. Preijers and L. M. Schütte performed the literature search, analyzed the data, and wrote the manuscript. R. M. van Hest and R. A. A. Mathôt supervised the study and gave critical guidance during the analysis. M. H. Cnossen, F. W. G. Leebeek, and M. J. H. A. Kruip critically reviewed the manuscript and provided additional comments. All authors approved the final version of the manuscript. L. M. Schütte reports other from CSL Behring, outside the submitted work. M. J. H. A. Kruip reports grants from Daiichi Sankyo, grants from Boehringer Ingelheim, grants from Pfizer, and grants and personal fees from Bayer, outside the submitted work. M. H. Cnossen reports grants and other from Bayer, other from Roche, grants from NovoNordisk, grants from CSL Behring, and other from Drug trials/Baxalta-Shire, Roche, outside the submitted work. F. W. G. Leebeek reports grants from CSL Behring, grants from Shire, other from uniQure, other from Shire, and personal fees from Roche, outside the submitted work. R. A. A. Mathôt reports grants from Bayer, grants from Shire, grants from Merck Sharpe Dome, grants from CSL Behring, other from Bayer, and other from Shire, outside the submitted work. The remaining authors declare no conflict of interest. T. Preijers and L. M. Schütte both are first authors. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com). Therapeutic Drug Monitoring: April 2019 - Volume 41 - Issue 2 - p 192-212 doi: 10.1097/FTD.0000000000000625 Buy SDC Metrics Abstract Hemophilia A and hemophilia B are hereditary bleeding disorders, caused by a deficiency of clotting factor VIII or clotting factor IX, respectively. To treat and prevent bleedings, patients can administer clotting factor concentrates (hemophilia A and B) or desmopressin (hemophilia A). Both clotting factor concentrates and desmopressin are currently dosed according to the patients' body weight. However, clotting factor concentrates exhibit considerable pharmacokinetic (PK) variability. Therefore, several alternative dosing strategies to individualize dosing of clotting factor concentrates and desmopressin in hemophilia A and B have been proposed. In this study, a review of the existing literature on the individualization of dosing based on PK guidance was performed. In total, 79 articles were included. The methods to individualize dosing were divided into 3 categories: (1) methods using clinical parameters, (2) empirical individual PK-guided methods, and (3) maximum a posteriori (MAP) Bayesian estimation methods. The clinical parameter mainly used to individualize dosing is bleeding phenotype. Dosing based on bleeding phenotype may decrease clotting factor consumption. However, with this method, it is not possible to individualize on-demand dosing during bleeding events or in the perioperative setting. Empirical individual PK-guided methods can be used both for prevention and treatment of bleedings. These methods include dose individualization using a nomogram and individualized in vivo recovery. In the perioperative setting, adjustment of the rate of continuous infusion can be applied to obtain a specific target level. The final category, MAP Bayesian estimation methods, relies on the availability of a population PK model. In total, 22 population PK models describing clotting factor concentrate or desmopressin dosing are currently available in literature. MAP Bayesian estimates can be used to calculate the individualized doses required to achieve or maintain a target level in every setting. The application of PK-guided and pharmacodynamic-guided dosing of clotting factor concentrates and desmopressin seems promising, although further investigation is warranted. Prospective studies analyzing its potential benefit are on the way. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.