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J.A. Abrantes et al.
individualization, a pre-defined FVIII activity target would not be required, in contrast to the current implementation of PK-based dosing. Instead, the full model would be employed using a Bayesian approach, with the estimation of the individual bleeding hazard in addition to the indi- vidual PK parameters. Thus, the individualized dose and dosing interval would be selected not only based on the individual pharmacokinetics, but also the individual bleeding risk. This implementation warrants further study; namely, to understand which information is required to allow a precise estimation of the individual bleeding risk and which target to aim for in the dose cal- culation.47
In conclusion, we have developed an integrated popula- tion PK and repeated time-to-categorical bleed model based on data from patients with severe hemophilia A fol-
lowing prophylactic treatment. This combined model characterizes the relationship between the dose of a recombinant FVIII product, plasma FVIII activity, the bleeding outcome, as well as severity and the correlation with covariates. In the future, this model may be used for dose-tailoring using covariate, PK and/or bleeding infor- mation. Such an application requires a detailed theoretical assessment as well as robust data on bleeding and other factors, such as lifestyle or comorbidities, with the final goal of suggesting a more effective individualized FVIII dose.
Acknowledgments
The authors would like to thank Gunnar Yngman for skillful assistance during the implementation of the full random effects modeling approach.
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