Abstract
Original language | English |
---|---|
Pages (from-to) | 706-718 |
Number of pages | 13 |
Journal | CPT: pharmacometrics & systems pharmacology |
Volume | 12 |
Issue number | 5 |
Early online date | 2023 |
DOIs | |
Publication status | Published - May 2023 |
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In: CPT: pharmacometrics & systems pharmacology, Vol. 12, No. 5, 05.2023, p. 706-718.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Relationship between factor VIII levels and bleeding for rFVIII-SingleChain in severe hemophilia A
T2 - A repeated time-to-event analysis
AU - Bukkems, Laura H.
AU - Jönsson, Siv
AU - the OPTI-CLOT studies and the SYMPHONY consortium
AU - Cnossen, Marjon H.
AU - Karlsson, Mats O.
AU - Mathôt, Ron A. A.
N1 - Funding Information: The authors would like to thank CSL Behring, especially Nathalie Jansen and Charles Liss, for providing the clinical trial data for this study. This study was performed as part of the OPTI-CLOT international multicenter research consortium, “Patient tailOred PharmacokineTIc-guided dosing of CLOTting factor concentrates and desmopressin in bleeding disorders,” which is currently WP6 within the SYMPHONY consortium. L.H.B. is funded by the Innovatiefonds, OPTI-CLOT TARGET study (Bayer, Sobi, NovoNordisk, and CSL Behring have funded this investigator-initiated study) and the SYMPHONY NWO-NWA consortium. The SYMPHONY consortium aims to orchestrate personalized treatment in patients with bleeding disorders, and is a unique collaboration among patients, healthcare professionals, and translational and 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 have been organized according to three themes, for example, Diagnostics (workpackage 3 and 4); Treatment (workpackages 5–9), and Fundamental Research (workpackages 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 coordinator: Dr. S.H. Reitsma. Beneficiaries of the SYMPHONY consortium: Erasmus University Medical Center-Sophia Children's Hospital, 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: The authors would like to thank CSL Behring, especially Nathalie Jansen and Charles Liss, for providing the clinical trial data for this study. This study was performed as part of the OPTI‐CLOT international multicenter research consortium, “Patient tailOred PharmacokineTIc‐guided dosing of CLOTting factor concentrates and desmopressin in bleeding disorders,” which is currently WP6 within the SYMPHONY consortium. L.H.B. is funded by the Innovatiefonds, OPTI‐CLOT TARGET study (Bayer, Sobi, NovoNordisk, and CSL Behring have funded this investigator‐initiated study) and the SYMPHONY NWO‐NWA consortium. The SYMPHONY consortium aims to orchestrate personalized treatment in patients with bleeding disorders, and is a unique collaboration among patients, healthcare professionals, and translational and 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 have been organized according to three themes, for example, Diagnostics (workpackage 3 and 4); Treatment (workpackages 5–9), and Fundamental Research (workpackages 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 coordinator: Dr. S.H. Reitsma. Beneficiaries of the SYMPHONY consortium: Erasmus University Medical Center‐Sophia Children's Hospital, 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. Publisher Copyright: © 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2023/5
Y1 - 2023/5
N2 - Publications on the exposure-effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII-SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII-SingleChain prophylaxis from three clinical trials were combined. The published rFVIII-SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one-stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow-up and a FVIII level of 8.9 IU/dL (95% confidence interval: 6.9–10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre-study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3 IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0–17) or one (90% PI: 0–11) bleeds per year, respectively. In conclusion, the developed PK-RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII-SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81-8973 (octocog alfa) and BAY 94-9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.
AB - Publications on the exposure-effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII-SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII-SingleChain prophylaxis from three clinical trials were combined. The published rFVIII-SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one-stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow-up and a FVIII level of 8.9 IU/dL (95% confidence interval: 6.9–10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre-study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3 IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0–17) or one (90% PI: 0–11) bleeds per year, respectively. In conclusion, the developed PK-RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII-SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81-8973 (octocog alfa) and BAY 94-9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.
UR - http://www.scopus.com/inward/record.url?scp=85151066797&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/psp4.12938
DO - https://doi.org/10.1002/psp4.12938
M3 - Article
C2 - 36965157
SN - 2163-8306
VL - 12
SP - 706
EP - 718
JO - CPT: pharmacometrics & systems pharmacology
JF - CPT: pharmacometrics & systems pharmacology
IS - 5
ER -