Population Pharmacokinetic Analysis of Recombinant Factor VIII Fc Fusion Protein in Subjects with Severe Hemophilia A Across All Ages
Srividya Neelakantan (1), Lei Diao (2), and Ivan Nestorov (3)
(1) Bioverativ, Waltham, USA, (2) Johnson & Johnson, Shanghai, China, and (3) Biogen Inc, Cambridge, USA.
Objectives: To develop a population pharmacokinetic (PK) model that characterizes the PK of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with severe Hemophilia A across all ages and to identify factors that determine the PK variability.
Methods: The FVIII activity data from 3 clinical studies, measured by one-stage clotting assay, was used as marker for rFVIIIFc PK. Mixed-effects modelling with maximal likelihood parameter estimation methods were used to evaluate the population characteristics of rFVIIIFc. Since the proportion of observations below the lower limit of quantification (BLQ) was greater than 10%, the M3 method was used to account for the BLQ values. The effect of covariates was evaluated using a forward inclusion, backward elimination process. Diagnostic plots, standard errors of model parameters, evaluation of shrinkage, and visual predictive checks were used to guide model building and assess goodness-of-fit.
Results: The final population PK model for rFVIIIFc was a two compartment model with covariates weight (WT) and von Willebrand Factor (VWF) on CL; WT on V1. The population estimates of CL for this model was 1.59 dL/h (95% CI 1.53 – 1.65 dL/h); while the V1 was 32.2 dL (95% CI 31.3 –33.1 dL), the intercompartmental clearance Q was 1.01 dL/h (95% CI 0.44 – 1.58 dL/h), and V2 was 4.89 dL (95% CI 3.70– 6.08 dL). Weight was identified as a major covariate of both the clearance and volume terms. The single allometric exponent that describes the relationship between weight and the clearances is 0.690, while the exponent for the volume terms is 0.932. Consistent with the mechanistic understanding of rFVIIIFc clearance, VWF explained additional 6% inter-individual variability in rFVIIIFc clearance in adults and adolescents ≥ 12 years of age. The negative exponent on VWF (-0.408) indicates that the higher the measured level of VWF, the lower the rFVIIIFc clearance. It should be noted that VWF data was not available in children <12 years of age and therefore, the relationship between VWF and rFVIIIFc clearance could not be ascertained in this population.
Conclusion: The kinetics of rFVIIIFc activity displays a two-compartmental behavior. The covariate for FVIII activity identified was Weight and VWF on Clearance; Weight was identified as a major covariate on the volume of distribution.
References:
[1] Mahlangu, J., et al., Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood, 2013. 123(3): p. 317-325.
[2] Powell, J.S., et al., Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood, 2012. 119(13): p. 3031-7
[3] Jae Eun Ahn, M.O.K., Adrian Dunne and Thomas M. Ludden, Likelihood based approaches to handling data below the quantification limit using NONMEM VI J Pharmacokin Pharmacodyn, 2008. 35(4): p. 401-21.