Lars L. F. G. Valke, Michael E. Cloesmeijer, Hassan Mansouritorghabeh, Wideke Barteling, Nicole M. A. Blijlevens, Marjon H. Cnossen, Ron A. A. Mathôt, Saskia E. M. Schols, Waander L. van Heerde
{"title":"血友病 A 的药代动力学-药效学建模：服用 VWF/FVIII 浓缩液后凝血酶和凝血酶原的生成与因子 VIII 活性的关系","authors":"Lars L. F. G. Valke, Michael E. Cloesmeijer, Hassan Mansouritorghabeh, Wideke Barteling, Nicole M. A. Blijlevens, Marjon H. Cnossen, Ron A. A. Mathôt, Saskia E. M. Schols, Waander L. van Heerde","doi":"10.1007/s13318-024-00876-6","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic–pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P<sup>®</sup>). The predictive performance of the previously developed pharmacokinetic–pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC<sub>50</sub> and <i>E</i><sub>max</sub> values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":"81 1","pages":""},"PeriodicalIF":1.9000,"publicationDate":"2024-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetic–Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate\",\"authors\":\"Lars L. F. G. Valke, Michael E. Cloesmeijer, Hassan Mansouritorghabeh, Wideke Barteling, Nicole M. A. Blijlevens, Marjon H. Cnossen, Ron A. A. Mathôt, Saskia E. M. Schols, Waander L. van Heerde\",\"doi\":\"10.1007/s13318-024-00876-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Background</h3><p>Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay.</p><h3 data-test=\\\"abstract-sub-heading\\\">Objective</h3><p>The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic–pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p>Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P<sup>®</sup>). The predictive performance of the previously developed pharmacokinetic–pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed.</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC<sub>50</sub> and <i>E</i><sub>max</sub> values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%).</p><h3 data-test=\\\"abstract-sub-heading\\\">Conclusion</h3><p>Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. 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Pharmacokinetic–Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate
Background
Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay.
Objective
The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic–pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters.
Methods
Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P®). The predictive performance of the previously developed pharmacokinetic–pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed.
Results
The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC50 and Emax values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%).
Conclusion
Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.
期刊介绍：
Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences.
Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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