A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A
| Autor: | Koichiro Yoneyama, Christophe Schmitt, Naoki Kotani, Takehiko Kawanishi, Gallia G. Levy, Ryu Kasai, Satofumi Iida, Midori Shima |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent Population Urology Hemorrhage 030204 cardiovascular system & hematology Antibodies Monoclonal Humanized Hemophilia A Models Biological 03 medical and health sciences Young Adult 0302 clinical medicine Pharmacotherapy Rare Diseases Pharmacokinetics Antibodies Bispecific medicine Humans Pharmacology (medical) Dosing Original Research Article education Pharmacology Emicizumab education.field_of_study Factor VIII Dose-Response Relationship Drug business.industry Clinical trial Dose–response relationship 030220 oncology & carcinogenesis Monoclonal business |
| Zdroj: | Clinical Pharmacokinetics |
| ISSN: | 1179-1926 |
| Popis: | Background Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I–I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Methods Using the phase I–I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. Results The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥ 45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. Conclusions A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process. Electronic supplementary material The online version of this article (10.1007/s40262-017-0616-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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