Phase I pharmacokinetics and limited sampling strategies for the bioreductive alkylating drug EO9. EORTC Early Clinical Trials Group.
EO9 is a synthetic indoloquinone which was designed to undergo redox cycling and formation of alkylating intermediates under bioreductive conditions. As part of a phase I clinical trial, EO9 plasma disposition was evaluated in 20 patients receiving 2.7-15 mg/m2i.v. weekly for 3 weeks. Pharmacokinetic studies were performed with the first and third dose of therapy and nine blood samples were obtained over 30 min postinfusion. Plasma EO9 was detected using HPLC UV and the disposition described by a two-compartment model. Wide variability in EO9 pharmacokinetics was observed. EO9 was rapidly eliminated from plasma with a median systemic clearance of 3.5 l/min/m2 (range 1.2-9.8), apparent volume of distribution of 6.2 l/m2 (1.0-34.9) and t 1/2 beta of 10.1 min (2.2-63.0). Substantial intrapatient variability was observed for all pharmacokinetic parameters. Linear regression and Bayesian methods were developed and validated for estimation of EO9 plasma AUC using up to three samples postinfusion. The use of two or three plasma samples provided precise estimation with acceptable prediction bias. In addition, a Bayesian algorithm offered more robust estimation of AUC and is preferable to linear regression models for future EO9 population pharmacokinetic analysis.
McLeod
H L
HL
CRC Department of Medical Oncology, University of Glasgow, U.K.
Graham
M A
MA
Aamdal
S
S
Setanoians
A
A
Groot
Y
Y
Lund
B
B
D000328:Adult; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001388:Aziridines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001499:Bayes Theorem; D005260:Female; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012044:Regression Analysis
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; C060817:apaziquone