Abstract
Background: To account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK-guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance. Aim: Explore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens. Methods: We analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI-CLOT randomized controlled trial. Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration-time curves were constructed by nonlinear mixed-effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen. Results: In 45/50 included patients, actual potency was higher than its label potency. The median potency difference was 6.0% (range -9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentration-time curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose. Conclusion: It is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK-guided dosing, trough levels may deviate ±20% from calculations based on label dose.
| Original language | English |
|---|---|
| Pages (from-to) | 610-618 |
| Number of pages | 9 |
| Journal | Haemophilia |
| Volume | 28 |
| Issue number | 4 |
| Early online date | 8 May 2022 |
| DOIs | |
| Publication status | Published - Jul 2022 |
Bibliographical note
Funding Information:This report is a substudy of the OPTI-CLOT trial, which was funded by a governmental grant from NWO-ZonMw (project number 836011011) and co-financed by an unrestricted investigator-initiated research grant from Baxter/Shire/Baxalta/Takeda (grant number GHOL 6238). We write on behalf of the international multicentre OPTI-CLOT and to WiN studies that aim to implement pharmacokinetic (PK)-pharmacodynamic (PD)-guided dosing of desmopressin, factor concentrates, and other alternative drugs for the treatment of bleeding disorders using population PK-(PD) models. A complete list of the members of the OPTI-CLOT research programme is in the appendix. We are grateful to all patients and family members who participated in this trial. We also thank all haemophilia treatment teams, nurses, and research coordinators for their indispensable assistance. Furthermore, we thank I. van Vliet for trial support, and J. M. Heijdra and L. M. Schütte for their help and assistance during the trial period. The SYMPHONY NWO-NWA consortium which aims to orchestrate personalized treatment in patients with bleeding disorders, is a unique collaboration between patients, health care professionals and translational & fundamental researchers specialized in inherited bleeding disorders, as well as experts from multiple disciplines. It aims to identify best treatment choice for each individual based on bleeding phenotype. In order to achieve this goal, work packages (WPs) have been organized according to three themes, for example, Diagnostics (WPs 3&4), Treatment (WPs 5–9) and Fundamental Research (WPs 10–12). This research received funding from the Netherlands Organization for Scientific Research (NWO) in the framework of the NWA-ORC Call grant agreement NWA.1160.18.038. Principal investigator: Dr. M.H. Cnossen. Project manager: Dr. S.H. Reitsma. Beneficiaries of the SYMPHONY consortium: Erasmus MC and Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, project leadership and coordination; Sanquin Diagnostics; Sanquin Research; Amsterdam University Medical Centers; University Medical Center Groningen; University Medical Center Utrecht; Leiden University Medical Center; Radboud University Medical Center; Netherlands Society of Hemophilia Patients (NVHP); Netherlands Society for Thrombosis and Hemostasis (NVTH); Bayer B.V., CSL Behring B.V., Swedish Orphan Biovitrum (Belgium) BVBA/SPRL.
Funding Information:
MC has received grants from governmental and societal research institutes such as NWO, ZonMW, Innovation fund, from private funds, institutional grants and unrestricted investigator research grants/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 go to the institution.
Funding Information:
This report is a substudy of the OPTI‐CLOT trial, which was funded by a governmental grant from NWO‐ZonMw (project number 836011011) and co‐financed by an unrestricted investigator‐initiated research grant from Baxter/Shire/Baxalta/Takeda (grant number GHOL 6238). We write on behalf of the international multicentre OPTI‐CLOT and to WiN studies that aim to implement pharmacokinetic (PK)‐pharmacodynamic (PD)‐guided dosing of desmopressin, factor concentrates, and other alternative drugs for the treatment of bleeding disorders using population PK‐(PD) models. A complete list of the members of the OPTI‐CLOT research programme is in the appendix. We are grateful to all patients and family members who participated in this trial. We also thank all haemophilia treatment teams, nurses, and research coordinators for their indispensable assistance. Furthermore, we thank I. van Vliet for trial support, and J. M. Heijdra and L. M. Schütte for their help and assistance during the trial period.
Funding Information:
The SYMPHONY NWO‐NWA consortium which aims to orchestrate personalized treatment in patients with bleeding disorders, is a unique collaboration between patients, health care professionals and translational & fundamental researchers specialized in inherited bleeding disorders, as well as experts from multiple disciplines. It aims to identify best treatment choice for each individual based on bleeding phenotype. In order to achieve this goal, work packages (WPs) have been organized according to three themes, for example, Diagnostics (WPs 3&4), Treatment (WPs 5–9) and Fundamental Research (WPs 10–12). This research received funding from the Netherlands Organization for Scientific Research (NWO) in the framework of the NWA‐ORC Call grant agreement NWA.1160.18.038. Principal investigator: Dr. M.H. Cnossen. Project manager: Dr. S.H. Reitsma.
Funding Information:
RM has received 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.
Publisher Copyright:
© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.