Relationship between factor VIII levels and bleeding for rFVIII‐SingleChain in severe hemophilia A: A repeated time‐to‐event analysis
Abstract 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‐SingleC...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-05-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12938 |
| _version_ | 1797823641432358912 |
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| author | Laura H. Bukkems Siv Jönsson Marjon H. Cnossen Mats O. Karlsson Ron A. A. Mathôt the OPTI‐CLOT studies and the SYMPHONY consortium |
| author_facet | Laura H. Bukkems Siv Jönsson Marjon H. Cnossen Mats O. Karlsson Ron A. A. Mathôt the OPTI‐CLOT studies and the SYMPHONY consortium |
| author_sort | Laura H. Bukkems |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-13T10:26:54Z |
| format | Article |
| id | doaj.art-7eec7fdf7ae047a5bdab05ee3fb2e3b5 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-03-13T10:26:54Z |
| publishDate | 2023-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-7eec7fdf7ae047a5bdab05ee3fb2e3b52023-05-19T06:03:15ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-05-0112570671810.1002/psp4.12938Relationship between factor VIII levels and bleeding for rFVIII‐SingleChain in severe hemophilia A: A repeated time‐to‐event analysisLaura H. Bukkems0Siv Jönsson1Marjon H. Cnossen2Mats O. Karlsson3Ron A. A. Mathôt4the OPTI‐CLOT studies and the SYMPHONY consortiumHospital Pharmacy‐Clinical Pharmacology Amsterdam University Medical Center Amsterdam The NetherlandsDepartment of Pharmacy Uppsala University Uppsala SwedenDepartment of Pediatric Hematology Erasmus University Medical Center ‐ Sophia Children's Hospital Rotterdam Rotterdam The NetherlandsDepartment of Pharmacy Uppsala University Uppsala SwedenHospital Pharmacy‐Clinical Pharmacology Amsterdam University Medical Center Amsterdam The NetherlandsAbstract 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.https://doi.org/10.1002/psp4.12938 |
| spellingShingle | Laura H. Bukkems Siv Jönsson Marjon H. Cnossen Mats O. Karlsson Ron A. A. Mathôt the OPTI‐CLOT studies and the SYMPHONY consortium Relationship between factor VIII levels and bleeding for rFVIII‐SingleChain in severe hemophilia A: A repeated time‐to‐event analysis CPT: Pharmacometrics & Systems Pharmacology |
| title | Relationship between factor VIII levels and bleeding for rFVIII‐SingleChain in severe hemophilia A: A repeated time‐to‐event analysis |
| title_full | Relationship between factor VIII levels and bleeding for rFVIII‐SingleChain in severe hemophilia A: A repeated time‐to‐event analysis |
| title_fullStr | Relationship between factor VIII levels and bleeding for rFVIII‐SingleChain in severe hemophilia A: A repeated time‐to‐event analysis |
| title_full_unstemmed | Relationship between factor VIII levels and bleeding for rFVIII‐SingleChain in severe hemophilia A: A repeated time‐to‐event analysis |
| title_short | Relationship between factor VIII levels and bleeding for rFVIII‐SingleChain in severe hemophilia A: A repeated time‐to‐event analysis |
| title_sort | relationship between factor viii levels and bleeding for rfviii singlechain in severe hemophilia a a repeated time to event analysis |
| url | https://doi.org/10.1002/psp4.12938 |
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