Pierre Chelle1, Cindy H T Yeung2, Stacy E Croteau3, Jennifer Lissick4, Vinod Balasa5, Christina Ashburner5, Young Shil Park6, Santiago Bonanad7, Juan Eduardo Megías-Vericat7, Azusa Nagao8, Tung Wynn9, Fernando Corrales-Medina10, Huyen Tran11, Anjali Sharathkumar12, Meera Chitlur13, Samuel Sarmiento14, Andrea Edginton1, Alfonso Iorio15,16. 1. School of Pharmacy, University of Waterloo, Waterloo, ON, Canada. 2. Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. 3. Boston Children's Hospital/Harvard Medical School, Boston, MA, USA. 4. Children's Minnesota, Minneapolis, MN, USA. 5. Valley Children's Healthcare, Madera, CA, USA. 6. Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea. 7. Hospital Universitari i Politècnic La Fe, Valencia, Spain. 8. Ogikubo Hospital, Tokyo, Japan. 9. University of Florida, Gainesville, FL, USA. 10. University of Miami Hemophilia Treatment Center, Miami, FL, USA. 11. Ronald Sawers Haemophilia Treatment Centre, Melbourne, VIC, Australia. 12. University of Iowa Carver College of Medicine, Stead Family Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, IA, USA. 13. Children's Hospital of Michigan, Detroit, MI, USA. 14. Integral Solutions SD S.A.S, Bogotá, Colombia. 15. Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. iorioa@mcmaster.ca. 16. McMaster Bayer Endowed Chair for Clinical Epidemiology of Congenital Bleeding Disorders, Department of Medicine, McMaster University, Hamilton, ON, Canada. iorioa@mcmaster.ca.
Abstract
BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND AND OBJECTIVE: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 hemophiliapatients and are subsequently used for personalized dose regimen design. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 Apatients.
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