1. Development and Validation of a Population-Pharmacokinetic Model for Rurioctacog Alfa Pegol (Adynovate®): A Report on Behalf of the WAPPS-Hemo Investigators Ad Hoc Subgroup
- Author
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Andrea N. Edginton, Anjali Sharathkumar, Fernando F. Corrales-Medina, Christina Ashburner, Samuel Sarmiento, Pierre Chelle, Azusa Nagao, Stacy E. Croteau, Santiago Bonanad, Meera Chitlur, Juan Eduardo Megías-Vericat, Jennifer Lissick, Huyen Tran, Vinod Balasa, Cindy H. T. Yeung, Young Shil Park, Alfonso Iorio, and Tung Wynn
- Subjects
Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,PROPHYLACTIC TREATMENT ,medicine.medical_specialty ,Population ,RECOMBINANT FACTOR-VIII ,030204 cardiovascular system & hematology ,030226 pharmacology & pharmacy ,Recombinant factor viii ,PARAMETERS ,Cross-validation ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,hemic and lymphatic diseases ,Internal medicine ,Covariate ,Medicine ,Pharmacology (medical) ,SEVERE HEMOPHILIA-A ,education ,FULL-LENGTH ,COAGULATION-FACTOR VIII ,Pharmacology ,education.field_of_study ,HALF-LIFE ,business.industry ,PROFILES ,PK Parameters ,QUANTIFICATION ,Clinical trial ,Regimen ,BAX 855 ,business - Abstract
Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design. Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date. The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay – 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations. The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.
- Published
- 2019