title: Clinical pharmacology of hepatic arterial infusions of 5-bromo-2'-deoxyuridine.
abstract: This investigation was undertaken to determine the pharmacokinetic parameters relevant to hepatic arterial (HA) infusion of 5-bromo-2'-deoxyuridine (BrdUrd) and to ascertain the maximum tolerated dose and related toxicities of BrdUrd administered as a 14-day HA infusion. In the pharmacokinetic study, 6 patients received a 2-h i.v. infusion (to steady-state) of BrdUrd at each of 5 escalating dose rates (10 to 160 mg/kg/day) with simultaneous blood sampling for BrdUrd levels from HA and hepatic venous catheters. Dose dependent HA and hepatic venous drug levels, total body clearance, hepatic extraction, and estimated regional exposure advantage were determined. The total body clearance of BrdUrd was high and dose rate dependent, falling from 3340 ml/min with a 10-mg/kg/day infusion to 2180 ml/min at a 160-mg/kg/day dose rate. Hepatic extraction was high and dose rate dependent as well, declining from 80% extraction at 10 mg/kg/day to 68% at 160 mg/kg/day. The calculated estimate for the exposure advantage achievable with HA as compared with i.v. infusion reflects the dose rate dependence of total body clearance and hepatic extraction and decreases from a 70-fold advantage at 10 mg/kg/day to a 30-fold advantage at 160 mg/kg/day. In the Phase I study aimed at determining the maximum tolerated dose, successive groups of 3 patients were administered continuous HA infusions for 14 days at escalated BrdUrd dose rates (5, 10, 15, 25, and 35 mg/kg/day) in order to ascertain dose-limiting toxicity. The maximum tolerated dose of BrdUrd for a 14-day continuous HA infusion was found to be 35 mg/kg/day with reversible thrombocytopenia as the sole dose-limiting toxicity. Skin and other toxicities were infrequent, minor, reversible, and non-dose dependent. No hepatic toxicity was detected despite direct drug infusion into the liver. The high total body clearance and hepatic extraction of BrdUrd substantiate its administration via the hepatic artery as a means to achieve higher exposure with intrahepatic tumors than can be obtained by systemic administration. Despite higher hepatic exposures, no hepatic toxicity was noted, and readily reversible systemic toxicity (thrombocytopenia) was dose limiting for the 14-day continuous HA infusion. Thus, HA infusion of the potent radiosensitizer BrdUrd is both pharmacokinetically rational and well tolerated.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109.
authors.forename: W D
authors.initials: WD
authors.lastname: Ensminger
authors.forename: S C
authors.initials: SC
authors.lastname: Walker
authors.forename: P L
authors.initials: PL
authors.lastname: Stetson
authors.forename: J G
authors.initials: JG
authors.lastname: Wagner
authors.forename: J A
authors.initials: JA
authors.lastname: Knol
authors.forename: T S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: J C
authors.initials: JC
authors.lastname: Andrews
mesh_terms: D000328:Adult; D000368:Aged; D001973:Bromodeoxyuridine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005706:Gallbladder Neoplasms / Q000097:blood / Q000188:drug therapy*; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008433:Mathematics; D008875:Middle Aged
chemical_list: D001973:Bromodeoxyuridine