Single Dose Pharmacokinetics of a Recombinant FVIIa In Factor VIII KO Mice, Rats, and Cynomolgus Monkeys

Abstract 4655

The purpose of these PK studies was to assess the pharmacokinetic profile of Baxter's rFVIIa in comparison with a commercially available rFVIIa after a single intravenous bolus injection at a target dose of 0.6 mg/kg BW in mice and rats and 2.7 mg/kg BW in cynomolgus monkeys. The AUC0-t last (the area under the concentration vs. time curve from 0 to the last measured time point) was evaluated as primary endpoint. Secondary endpoints were terminal half-life (HL), mean residence time (MRT) and total clearance standardized per kg body mass (Cl) for FVIIa protein and clotting activity. In cynomolgus monkeys only FVIIa clotting activity was evaluated.

Blood was sampled at baseline and each of the time points after a single intravenous bolus injection of Baxter's rFVIIa or the commercially available rFVIIa. The citrated plasma samples were analyzed for FVIIa activity and FVII protein (antigen).

A serial sacrifice design was used for the PK in mice. Ten FVIII ko mice (B6;129S4-F8^tm1Kaz; 5m/5f) per time point were bled by cardiac puncture under anesthesia for blood sampling 5 – 200 minutes after a single intravenous bolus injection.

A single animals design was used for the single dose PK in Sprague Dawley rats (5m/5f) and cynomolgus monkeys (2m/2f). In rats and cynomolgus monkeys blood samples for citrated plasma were drawn before administration (for analysis of baseline FVIIa levels) and 5 – 270 minutes (rats) or 5 minutes to 15 hours (cynomolgus monkeys) after administration.

Plasma samples were analyzed for FVIIa protein (antigen) using a FVII ELISA calibrated for FVIIa measurement and for FVIIa activity using a FVIIa clotting assay.

In all three species bioequivalence of Baxter's rFVIIa and the reference item could be shown for the primary endpoint (AUC0-tlast) for FVIIa activity and antigen (the latter was only tested in mice and rats). Additionally, secondary endpoints of FVIIa activity (terminal half-life, mean residence time and total clearance) were similar for Baxter's rFVIIa and the reference item.

In mice, HL was 0.64 h, MRT was 0.80 h and Cl was 245 ml/kg/h for Baxter's new rFVIIa. Values for the secondary endpoints in rats were 1.17 h for HL, 1.29 h for MRT and 102.6 mL/kg/h for Cl. In cynomolgus monkeys, HL was 2.00 h, MRT was 2.45 h and Cl was 33.6 mL/kg/h.

In summary, the pharmacokinetic profiles of Baxter's rFVIIa and the commercially available rFVIIa were similar in all species studied.