Allometry of Factor VIII and Informed Scaling of Next-Generation Therapeutic Proteins

Abstract

Allometric scaling has been applied to the pharmacokinetics (PK) of factor VIII (FVIII), but published relationships are based on relatively small subsets of available data. Numerous next generation forms of FVIII are being developed (e.g. Fc fusion, PEGylated, and liposomal formulations) and traditional pharmacokinetic scaling of these products would not incorporate the wealth of existing knowledge for current FVIII therapy in humans. We conducted a meta-analysis and developed allometric relationships of FVIII from over 100 PK studies collected from literature. Normalized Wajima curves were used to relate mean FVIII profiles between species. An ‘informed scaling’ approach was derived for predicting first-in-human PK parameters and demonstrated with a case study for an Fc fusion FVIII. NCA values for FVIII PK were well described by the allometric equations CL=6.59·W0.85 and Vss=65.0·W0.97. A subset of studies characterized by two compartment modeling showed strong linearity in scaling of total clearance and central volume, but more variability in distributional clearance and peripheral volume. Wajima curves for FVIII superimposed across species and the disposition of Fc fusion FVIII in humans was well predicted by ‘informed scaling.’ This approach might be generally applicable for predicting human PK of next generational therapeutics.

BAY 94‐9027, a PEGylated recombinant factor VIII, exhibits a prolonged half‐life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies

“…For example, lower mean t ½ values have been reported for Eloctate ® (Bioverativ, Cambridge, MA) and Adynovate ® (Shire, Westlake Village, CA) in children compared with adolescents and adults . This may be explained by the nonlinear relationship between CL and body weight (or lean body weight); this is described by allometric scaling and has been reported previously for other FVIII concentrates . Body weight‐based dosing assumes a linear increase in CL in relation to body weight leading to overcorrection of CL and lower exposure in children than adults.…”

Soy Phosphatidylinositol Containing Nanoparticle Prolongs Hemostatic Activity of B-Domain Deleted Factor VIII in Hemophilia A Mice

“…Simulations were conducted to predict PK profiles of free and PI–BDD FVIII in humans after a 50‐IU/kg dose using a previously reported “informed scaling” approach . The “informed scaling” approach utilizes relative changes caused by PI in mice and the known behavior of the free protein in humans to predict human PK of PI–BDD FVIII.…”

“…This method combines allometry‐based scaling of PK parameters with normalized Wajima curves from preclinical species to generate human concentration–time profiles. The suitability of this method to scale PK of modified FVIII products has been previously demonstrated . Briefly, parameter estimates of V ss and CL in mice were obtained by fitting of a 1 compartment, linear clearance model to PK data.…”

“…Estimates for V ss and CL of the free protein in humans were obtained from literature . Predictions of V ss and CL of PI–BDD FVIII in humans were generated using the following equation:with P as the parameter of interest. Concentration–time profiles for free and PI–BDD FVIII were obtained by multiplying t ′ and C ′ of the normalized Wajima curves with human parameters of MRT and C ss of the respective protein form.…”

Nonlinear pharmacokinetics of factor VIII and its phosphatidylinositol lipidic complex in hemophilia A mice

“…Thus predicted parameter values in humans can be calculated according to the equation: where P is the parameter of interest for free FVIII or FVIII–PI in humans and mice . V ss and CL in humans were mean values for all collected literature profiles described by a two‐compartment model: CL = 218 ml/h and V ss = 4230 ml for a body weight of 70.2 kg . At lower doses the PK of FVIII in mice approaches a first‐order linear system, thus MRT (= V ss / CL ) and C ss (= Dose/ V ss ) values were calculated for 40 IU/kg doses from observed values of CL and V ss (free FVIII mice, FVIII–PI mice, free FVIII humans) or from predicted values (FVIII–PI humans).…”