title: 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.
abstract: We have demonstrated previously an improved therapeutic index for oral 5-iodo-2-deoxypyrimidinone-2'-deoxyribose (IPdR) compared with oral and continuous infusion of 5-iodo-2'-deoxyuridine (IUdR) as a radiosensitizing agent using three different human tumor xenografts in athymic mice. IPdR is a prodrug that is efficiently converted to IUdR by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for > or =1 h after p.o. IPdR. Athymic mice tolerated oral IPdR at up to 1500 mg/kg/day given four times per day for 6-14 days without significant systemic toxicities. In anticipation of an investigational new drug application for 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 female 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) compared with controls after the 14-day treatment. No weight loss or other systemic toxicities were observed in other IPdR dosage groups. Grossly, no anatomical lesions were noted at complete necropsy, although liver weights were increased in both male and female ferrets in the two higher IPdR dosage groups. Histologically, IPdR-treated animals showed dose-dependent microscopic changes in liver consisting of minimal to moderate cytoplasmic vacuolation of hepatocytes, which either occurred in the periportal area (high dosage group) or diffusely throughout the liver (lower dosage groups). Female ferrets in the highest IPdR dose group also showed decreased kidney and uterus weights at autopsy without any associated histological changes. No histological changes were found in central nervous system tissues. No significant abnormalities in blood cell counts, liver function tests, kidney function tests, or urinalysis were noted. Hepatic aldehyde oxidase activity was decreased to approximately 50 and 30% of control ferrets in the two higher IPdR dosage groups, respectively, after the 14-day treatment period. The % IUdR-DNA incorporation in ferret bone marrow at the completion of IPdR treatment was < or =0.05% in the two lower dosage groups and approximately 2% in the 1500 mg/kg/day dosage group. The % IUdR-DNA in normal liver was < or =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 found that IPdR was cleared in these non-human primates in a biexponential manner with an initial rapid distributive phase (mean T1/2alpha = 6.5 min), followed by an elimination phase with a mean T1/2 of 63 min. The mean maximum plasma concentration of IPdR was 124+/-43 microM with a mean total body clearance of 1.75+/-0.95 l/h/kg. IPdR was below detection (<0.5 microM) in the cerebrospinal fluid. We conclude that there are dose-limiting systemic toxicities to a 14-day schedule of p.o. IPdR at 1500 mg/kg/day in ferrets that were not found previously in athymic mice. However, no significant hematological, biochemical, or histopathological changes were found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent in ferret liver, suggesting partial enzyme saturation by this IPdR schedule. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance is similar to our published data in athymic mice. These data are being applied
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University and University Hospitals of Cleveland/Ireland Cancer Center, Ohio 44106-6068, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kinsella
authors.forename: J E
authors.initials: JE
authors.lastname: Schupp
authors.forename: T W
authors.initials: TW
authors.lastname: Davis
authors.forename: S E
authors.initials: SE
authors.lastname: Berry
authors.forename: H S
authors.initials: HS
authors.lastname: Hwang
authors.forename: K
authors.initials: K
authors.lastname: Warren
authors.forename: F
authors.initials: F
authors.lastname: Balis
authors.forename: J
authors.initials: J
authors.lastname: Barnett
authors.forename: H
authors.initials: H
authors.lastname: Sands
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005289:Ferrets; D006403:Hematologic Tests; D007065:Idoxuridine / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics / Q000633:toxicity; D011741:Pyrimidine Nucleosides / Q000493:pharmacokinetics* / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D014556:Urine / Q000737:chemistry
chemical_list: D011355:Prodrugs; D011741:Pyrimidine Nucleosides; D011838:Radiation-Sensitizing Agents; C045889:ropidoxuridine; D004247:DNA; D000445:Aldehyde Oxidoreductases; D007065:Idoxuridine