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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

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.

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Acknowledgements

The authors gratefully acknowledge the following centers that contributed to this study by providing their data on the WAPPS-Hemo platform: Boston Children’s Hospital, Boston, MA, USA; St. Michael’s Hospital, Toronto, ON, Canada; SickKids Hospital, Toronto, ON, Canada; Center for Bleeding and Clotting, Minneapolis, MN, USA; Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA; St. Jude Children’s Research Hospital, Memphis, TN, USA; Hospital University and Politechnic La Fe, Valancia, Spain; Valley Children’s Healthcare, Madera, CA, USA; Center for Inherited Blood Disorders, Orange, NJ, USA; Rady Children’s Hospital, San Diego, CA, USA; Universitätsklinikum Bonn, Bonn, Germany; Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Ogikubo Hospital, Tokyo, Japan; Royal Adelaide Hospital, Adelaide, SA, Australia; St. Jude Affiliate Clinic at Novant Health Hemby Children’s Hospital, Charlotte, NC, USA; The Women’s and Children’s Hospital, Adelaide, SA, Australia; University of Florida, Gainesville, FL, USA; Zurich University Hospital, Zurich, Switzerland; University of Miami Hemophilia Treatment Center, Miami, FL, USA; Bloodworks Northwest, Seattle, WA, USA; Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea; Universitaets-Kinderklinik Wien, Vienna, Austria; The Maine Hemophilia and Thrombosis Center, Scarborough, ME, USA; Ronald Sawers Haemophilia Treatment Centre, Melbourne, VIC, Australia; St. Paul’s Hospital, Vancouver, BC, Canada; University Children’s Hospital, Hemophilia Center, Berne, Switzerland; University of Iowa Children’s Hospital, Iowa City, IA, USA; Children’s Minnesota, Minneapolis, MN, USA; Children’s Hospital of Michigan, Detroit, MI, USA; Integral Solutions SD S.A.S, Bogota, Columbia; Northwest Ohio Hemophilia Treatment Center, Toldeo, OH, USA.

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Correspondence to Alfonso Iorio.

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Funding

No sources of funding were received for the preparation of this article or conduct of this study.

Conflict of Interest

PC, CHTY, JL, CA, YSP, TW, HT and AI declared they had no conflict of interest or that their conflict of interest was not relevant to this publication. SEC has served as a consultant for Shire. VB served on the Speakers bureau for Shire. SB has received grants from Baxalta and Takeda for studies about PK-tailored therapy in patients with severe hemophilia A using a specific tool (myPKFiT), has lectured and has been part of medical and commercial advisory boards organized by Takeda and Baxalta in the past, and has chaired meetings about rurioctocog. JEMV has received research support from Shire and Grifols and speaker, support consulting fees from Bayer, CSL Behring, Grifols, NovoNordisk, Pfizer, Shire, Sobi, Takeda. AN received honoraria from Shire/Baxalta, Bioverative, Bayer and Chugai. FCM served on Octapharma, Shire, Kendrion, Genentech advisory boards. AS served on Shire, Biogen and CSL Behring advisory boards. MC received honoraria from NovoNordisk, Shire, Genentech, Baxalta, Bayer, BPL, Octapharma. ANE has received speaking fees from Bayer.

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Chelle, P., Yeung, C.H.T., Croteau, S.E. et al. 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. Clin Pharmacokinet 59, 245–256 (2020). https://doi.org/10.1007/s40262-019-00809-6

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