Phor21-βCG(ala) (NSC 731443) is a 36-amino acid peptide comprised of a lytic agent (Phor21) that is conjugated to a modified 15-amino acid segment of the β-chain of chorionic gonadotropin. Phor21-βCG(ala) has been shown to selectively kill cancer cells, including metastatic cells, by destroying cell membranes that express functional luteinizing hormone/chorionic gonadotropin receptors. The present studies investigated the stability of Phor21-βCG(ala) in vitro in plasma and the pharmacokinetics of Phor21-βCG(ala) in male C57BL/6 mice and male Fisher rats. An LC/MS/MS method was developed and used for the quantitation of Phor21-β CG(ala) in biological samples. When incubated with mouse, rat, dog, or human plasma at 37° C for 6 hours, Phor21-β CG(ala) was most stable in mouse and dog plasma (13-15% degradation) and least stable in rat plasma (69% degradation). No degradation of Phor21-β CG(ala) was observed in mouse, rat, dog, or human plasma maintained frozen (-20° C) for 7 days. Following administration of single iv doses of Phor21-βCG(ala), the Cmax (2 min) in plasma was 8.94 and 88.2 μg/mL for mice given 2.4 or 24 mg/m2 (0.8 or 8 mg/kg), respectively, and 37.3 μ g/mL for rats given 36 mg/m2 (6 mg/kg). Mean plasma concentrations of Phor21-βCG(ala) declined to ≤ 1.0 μ g/mL within 1 hour after dosing mice with 2.4 mg/m2; within 4 hours for mice given 24 mg/m2; and within 2 hours for rats given 36 mg/m2. The terminal half-life of Phor21-βCG(ala) in plasma was longer in mice (5.0 hours) than in rats (2.3 hours). This difference in half-life was correlated with a smaller volume of distribution of Phor21-βCG(ala) in mice (0.51-0.86 L/m2) than in rats (3.93 L/m2) and a slower rate of clearance of Phor21-βCG(ala) in mice (0.47-0.94 L/hr/m2) than in rats (2.43 L/hr/m2). For both mice and rats, the concentrations of Phor21-βCG(ala) in RBCs at the early times after dosing were approximately 10-fold lower than the corresponding concentrations in plasma, indicating a low affinity of Phor21-βCG(ala) for RBCs. These results suggest that Phor21-β CG(ala) is relatively stable in plasma and undergoes wide extravascular distribution in mice and rats. (Supported by NCI Contract N01-CM-07110 in support of Dr. Hansel’s RAID application).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]