title: Phase-I study of intraperitoneal mitoxantrone--clinical and pharmacokinetic evaluation.
abstract: Mitoxantrone, a recent anthracenedione derivative is a potentially useful drug for direct intraperitoneal (i.p.) application because of its high tissue-binding and therapeutic index. We have carried out studies to establish maximum tolerated doses as well as pharmacokinetic studies with i.p. mitoxantrone in 21 patients (5 male, 16 female) with gastrointestinal (9), ovarian (6), unknown (2) and other (4) primary cancers and peritoneal carcinomatosis. Increasing doses (10-40 mg/m2) were given i.p. every 4 weeks. Five partial remissions (2-8+ months) and 7 stable disease courses (2-6+ months) were achieved. A reduction or disappearance of ascites was seen in an additional 3 patients. Severe toxicity (leukopenia) was observed in 4 patients only after 35 mg/m2 and 40 mg/m2 i.p. Pharmacokinetic analysis using high-performance liquid chromatography yielded the following data: The mean ratio of area under curve peritoneal fluid to serum was 1,108. The peritoneal clearance ranged from 2 ml/min to 9,617 ml/min and the disappearance half-life from 0.6-28.9 h. Mean urinary excretion within 24 h was 0.42% of the i.p. dose. These data indicate that mitoxantrone is sequestered in the intraperitoneal tissue compartment and only slowly released. Based on the outcome of this phase-I study we recommend phase-II studies at a dose of 30 mg/m2 i.p., repeated every 3-4 weeks.
authors.forename: B
authors.initials: B
authors.lastname: Blöchl-Daum
authors.forename: H G
authors.initials: HG
authors.lastname: Eichler
authors.forename: H
authors.initials: H
authors.lastname: Rainer
authors.forename: R
authors.initials: R
authors.lastname: Jakesz
authors.forename: H
authors.initials: H
authors.lastname: Salzer
authors.forename: G
authors.initials: G
authors.lastname: Steger
authors.forename: J
authors.initials: J
authors.lastname: Schüller
authors.forename: E
authors.initials: E
authors.lastname: Günther
authors.forename: P
authors.initials: P
authors.lastname: Proksch
authors.forename: G
authors.initials: G
authors.lastname: Ehninger
mesh_terms: D004341:Drug Evaluation; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D008942:Mitoxantrone / Q000008:administration & dosage* / Q000009:adverse effects; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy*
chemical_list: D008942:Mitoxantrone