O.106 Pharmakokinetics, safety, tolerability, and pharmacodynamics of the isatoribine oral prodrug ANA975 in a multidose phase 1 healthy volunteer study

Abstract

N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-β-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human β-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 μM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol · g−1 after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol · g−1 (P < 0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by β-glucuronidase. In this respect, a considerably higher β-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by β-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity.