Preclinical study of the systemic toxicity and pharmacokinetics of 5-iodo-2-deoxypyrimidinone-2 '-deoxyribose as a radiosensitizing prodrug in two, non-rodent animal species: Implications for phase I study design

We have demonstrated previously an improved therapeutic index for oral 5-io do-2-deoxypyrimidinone-2'-deoxyribose (IPdR) compared with oral and continu ous infusion of 5-iodo-2'-deoxyuridine (IUdR) as a radiosensitizing agent u sing three different human tumor xenografts in athymic mice. IPdR is a prod rug that is efficiently converted to IUdR by a hepatic aldehyde oxidase, re sulting in high IPdR and IUdR plasma levels in mice for greater than or equ al to 1 h after p.o. IPdR, Athymic mice tolerated oral IPdR at up to 1500 m g/kg/day given four times per day for 6-14 days without significant systemi c toxicities. In anticipation of an investigational new drug application fo r the first clinical Phase I and pharmacology study of oral IPdR in humans, we studied the drug pharmacokinetics and host toxicities in two non-rodent , animal species. For the IPdR systemic toxicity and toxicology study, twenty-four male or fe male ferrets were randomly assigned to four IPdR dosage groups receiving 0, 15, 150, and 1500 mg/kg/day by oral gavage x 14 days prior to sacrifice on study day 15, All ferrets survived the 14-day treatment. Ferrets receiving 1500 mg/kg/day showed observable systemic toxicities with diarrhea, emesis , weight loss, and decreased motor activity beginning at days 5-8 of the 14 -day schedule. Overall, both male and female ferrets receiving IPdR at 1500 mg/kg/day experienced significant weight loss (9 and 19%, respectively) co mpared with controls after the 14-day treatment, No weight loss or other sy stemic toxicities were observed in other IPdR dosage groups, Grossly, no an atomical lesions were noted at complete necropsy, although liver weights we re increased in both male and female ferrets in the two higher IPdR dosage groups. Histologically, IPdR-treated animals showed dose-dependent microsco pic changes in liver consisting of minimal to moderate cytoplasmic vacuolat ion of hepatocytes, which either occurred in the periportal area (high dosa ge group) or diffusely throughout the liver (lower dosage groups). Female f errets in the highest IPdR dose group also showed decreased kidney and uter us weights at autopsy without any associated histological changes. No histo logical changes were found in central nervous system tissues. No significan t abnormalities in blood cell counts, liver function tests, kidney function tests, or urinalysis were noted. Hepatic aldehyde oxidase activity was dec reased to approximately 50 and 30% of control ferrets in the two higher IPd R dosage groups, respectively, after the 14-day treatment period, The % IUd R-DNA incorporation in ferret bone marrow at the completion of IPdR treatme nt was less than or equal to 0.05% in the two lower dosage groups and congr uent to 2% in the 1500 mg/kg/day dosage group. The % IUdR-DNA in normal liv er was less than or equal to 0.05% in all IPdR dosage groups, In a pharmacokinetic study in four Rhesus monkeys, we determined the plasma concentrations of IPdR after a single i.v. bolus of 50 mg/kg over 20 min, Using a two-compartment model to fit the plasma pharmacokinetic data, we fo und that IPdR was cleared in these non-human primates in a biexponential ma nner with an initial rapid distributive phase (mean T(1/2)alpha = 6.5 min), followed by an elimination phase with a mean T(1/2)beta of 63 min. The mea n maximum plasma concentration of IPdR was 124 +/- 43 mu M with a mean tota l body clearance of 1.75 +/- 0.95 I/h/kg. IPdR was below detection (<0.5 mu M) in the cerebrospinal fluid. We conclude that there are dose-limiting systemic toxicities to a 14-day sc hedule of p.o. IPdR at 1500 mg/kg/day in ferrets that were not found previo usly in athymic mice. However, no significant hematological, biochemical, o r histopathological changes were found. Hepatic aldehyde oxidase activity w as reduced in a dose-dependent in ferret liver, suggesting partial enzyme s aturation by this IPdR schedule. The plasma pharmacokinetic profile in Rhes us monkeys showing biexponential clearance is similar to our published data in athymic mice. These data are being applied to the design of an initial clinical Phase I study of p.o. IPdR as a radiosensitizer.