Phase I and pharmacokinetic study of intraperitoneal ormaplatin.
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.
Plaxe
S C
SC
Division of Gynecologic Oncology, University of California, San Diego 92103-8433.
Braly
P S
PS
Freddo
J L
JL
McClay
E
E
Christen
R D
RD
Kirmani
S
S
Kim
S
S
Heath
D
D
Howell
S B
SB
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*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C049777:ormaplatin