A Phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor.
OBJECTIVE
The purpose of this study was to assess the feasibility and characterize the pharmacokinetics of squalamine administered as a continuous i.v. infusion daily for 5 days every 3 weeks.


METHODS
Patients with advanced solid malignancies were treated with escalating doses of squalamine as a 5-day continuous i.v. infusion every 3 weeks. Doses were initially escalated in 100% increments from a starting dose of 6 mg/m(2)/day, with a single patient treated at each dose level until moderate toxicity was observed, at which time additional patients were treated.


RESULTS
Thirty-three patients were treated with 73 courses of squalamine at 13 dose levels ranging from 6 to 700 mg/m(2)/day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal dose-limiting toxicity of squalamine. At 700 mg/m(2)/day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m(2)/day, one of seven patients experienced dose-limiting grade 4 hyperbilirubinemia and grade 3 neurosensory changes, which resolved soon after treatment. Squalamine pharmacokinetics were dose-proportional. At 500 mg/m(2)/day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of squalamine were 2.67 liters/h/m(2) (85%), 9.46 h (81%), and 36.84 liters/m(2) (124%), respectively, and steady-state concentrations [20.08 micro g/ml (13%)] were well above those that inhibit angiogenesis in preclinical models.


CONCLUSIONS
At the recommended Phase II dose of 500 mg/m(2)/day, squalamine is well tolerated and results in plasma concentrations at least an order of magnitude higher than those required for prominent antiangiogenic effects in preclinical studies.
Hao
Desirée
D
Institute for Drug Development, Cancer Therapy and Research Center and The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Hammond
Lisa A
LA
Eckhardt
S Gail
SG
Patnaik
Amita
A
Takimoto
Chris H
CH
Schwartz
Garry H
GH
Goetz
Andrew D
AD
Tolcher
Anthony W
AW
McCreery
Heather A
HA
Mamun
Khalid
K
Williams
Jon I
JI
Holroyd
Kenneth J
KJ
Rowinsky
Eric K
EK
D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002777:Cholestanols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D013261:Sterols / Q000737:chemistry*; D013997:Time Factors
D020533:Angiogenesis Inhibitors; D002777:Cholestanols; D013261:Sterols; C079655:squalamine