Absorption, Metabolism, Distribution, and Excretion of Longer Acting rFVIII (BAX 855) Following Intravenous Administration to Rats

Abstract 4358

Baxter and Nektar have developed BAX 855, a PEGylated variant of Baxter’s rFVIII product based on the ADVATE™ manufacturing process using Nektar’s polymer technology. The absorption, metabolism, distribution and excretion (ADME) of radiolabeled PEG-rFVIII was investigated after single dose i.v. injection to male and female rats. Radiolabeled BAX 855 was synthesized by conjugation of rFVIII with tritiated [3H] PEG polymer, where several hydrogens [1H] were replaced by tritium atoms [3H] on the PEG backbone.

The animals designated for the collection of excreta and animals designated for the collection of blood received a single intravenous 1 mg/kg dose of [3H] PEG-rFVIII at a dose volume of 0.68 mL/kg. The animals designated for whole body autoradiography (WBA) were administered a single intravenous 2 mg/kg dose at 1.36 mL/kg. The radioactivity dose for 1 mg/kg was 122 μ Ci/kg and 2 mg/kg for 251 μ Ci/kg. With a specific activity of 2088 IU/mg, these single doses correspond to an FVIII activity dose of 2088 and 4176 IU/kg, respectively. Urine and feces were collected for 1008 hours post-dose and selected tissues were collected for metabolite profiling. Blood was collected at specified times during 1008 hours post-dose. Blood, plasma, urine, and feces were analyzed for total radioactivity. Rats designated for WBA were killed at specified times during 168 hours post-dose and rats designated for tissue excision were killed at specified times during 1008 hours post-dose. In addition, selected plasma, urine, feces, kidney, liver and lung samples were profiled for the parent compound and its metabolites.

Radioactivity was eliminated from blood and plasma with half-lives (t_1/2) of 827 and 655 hours, respectively, in males, and 306 and 276 hours, respectively, in females. The distribution of drug-derived radioactivity was extensive in both males and females, with radioactivity quantifiable in blood and plasma and all matrices analyzed. The maximum concentrations (C_max) of radioactivity for tissues were observed at the 1-, 8-, 24-, and 168-hour collections. The highest maximum concentrations of radioactivity were observed in the plasma, blood, mesenteric lymph nodes, spleen, liver, adrenal glands, and kidneys in both males and females. Radioactivity in the spleen analyzed by WBA presented a mottled appearance with most of the radioactivity in the red pulp. Elimination of radioactivity occurred primarily via urine. At 1008 hours post-dose, urine, feces, and daily cage rinse corresponded to 51.9, 38.4 and 4.01% of the dose administered to males, and 55.7, 45.0 and 3.53% of the dose administered to females. The mean overall recoveries in males and females were 97.4 and 107%, respectively.

In conclusion, the results of this study show that radio-labeled PEG-rFVIII was distributed to tissues analyzed without binding to the cellular blood components and radioactivity was excreted quantitatively within 6 weeks via urine and feces.