Phase I clinical and pharmacologic trial of intravenous estramustine phosphate.
OBJECTIVE
To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP).


METHODS
A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m(2). Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment.


RESULTS
The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m(2), and cumulative fatigue developed after multiple cycles at 2,500 mg/m(2). Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 micromol/L after IV EMP doses greater-than-or-equal 2,000 mg/m(2).


CONCLUSIONS
High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.
Hudes
Gary
G
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. g_hudes@fccc.edu
Haas
Naomi
N
Yeslow
Gwen
G
Gillon
Thomas
T
Gunnarsson
Per Olov
PO
Ellman
Marianne
M
Nordle
Orjan
O
Eriksson
Brigitta
B
Miller
Langdon
L
Cisar
Laura
L
Kopreski
Michael
M
Viaro
Donatella
D
Hartley-Asp
Beryl
B
D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004961:Estramustine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D005221:Fatigue / Q000139:chemically induced; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010146:Pain / Q000139:chemically induced; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013927:Thrombosis / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
D018931:Antineoplastic Agents, Hormonal; D004961:Estramustine