title: Phase I and pharmacokinetic study of intraperitoneal ormaplatin.
abstract: Ormaplatin is a cisplatin analog which has demonstrated activity against cisplatin-resistant tumors in preclinical studies. We delivered 28 cycles to 14 patients in a phase I trial of intraperitoneal ormaplatin given every 28 days. The maximum tolerated dose was 88.4 mg/m2 and acute dose-limiting toxicity was abdominal pain. Other toxicities include nausea, emisis, fever, and severe neuropathy seen in 1 patient at a cumulative dose of 399 mg/m2. No objective responses were observed. Hematologic toxicity was mild. The dose recommended for future trials of intraperitoneal ormaplatin is 66.5 mg/m2. Pharmacokinetic analysis performed at a dose of 66.5 mg/m2 demonstrated that the initial phase of elimination from the peritoneal cavity follows first-order kinetics with k = 0.69 hr-1 and half-life of 1.4 hr. Plasma pharmacokinetic behavior is best described by biexponential model with k1 = 0.369 hr-1, k2 = 0.107 hr-1, and first half-life of 2.9 hr and second half-life of 8.4 hr. Pharmacologic advantage, calculated by ratio of peritoneal to plasma AUC, is 17.1. If site-specific activity is demonstrated, then the intraperitoneal route of administration of ormaplatin at 66.5 mg/m2 may be beneficial.
authors.affiliation: Division of Gynecologic Oncology, University of California, San Diego 92103-8433.
authors.forename: S C
authors.initials: SC
authors.lastname: Plaxe
authors.forename: P S
authors.initials: PS
authors.lastname: Braly
authors.forename: J L
authors.initials: JL
authors.lastname: Freddo
authors.forename: E
authors.initials: E
authors.lastname: McClay
authors.forename: R D
authors.initials: RD
authors.lastname: Christen
authors.forename: S
authors.initials: S
authors.lastname: Kirmani
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: D
authors.initials: D
authors.lastname: Heath
authors.forename: S B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002408:Catheters, Indwelling; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C049777:ormaplatin