Nontoxic suramin as a chemosensitizer in patients: dosing nomogram development.
OBJECTIVE
We reported that suramin produced chemosensitization at nontoxic doses. This benefit was lost at the approximately 10-fold higher, maximally tolerated doses (MTD). The aim of the current study was to identify in patients the chemosensitizing suramin dose that delivers 10-50 microM plasma concentrations over 48 h.


METHODS
Nonsmall cell lung cancer patients were given suramin, paclitaxel, and carboplatin, every 3 weeks. The starting chemosensitizing suramin dose was estimated based on previous results on MTD suramin in patients, and adjusted by using real-time pharmacokinetic monitoring. A dosing nomogram was developed by using population-based pharmacokinetic analysis of phase I results (15 patients, 85 treatment cycles), and evaluated in phase II patients (19 females, 28 males, 196 treatment cycles).


RESULTS
The chemosensitizing suramin dose showed a terminal half-life of 202 h and a total body clearance of 0.029 L h(-1) m(-2) (higher than the 0.013 L h(-1) m(-2) value for MTD of suramin). The dosing nomogram, incorporating body surface area as the major covariate of intersubject variability and the time elapsed since the previous dose (to account for the residual concentrations due to the slow elimination), delivered the target concentrations in >95% of treatments.


CONCLUSIONS
The present study identified and validated a dosing nomogram and schedule to deliver low and nontoxic suramin concentrations that produce chemosensitization in preclinical models.
Chen
Danny
D
College of Pharmacy, The Ohio State University, 496 West 12th Avenue, Columbus, Ohio 43210, USA.
Song
Sae Heum
SH
Wientjes
M Guillaume
MG
Yeh
Teng Kuang
TK
Zhao
Liang
L
Villalona-Calero
Miguel
M
Otterson
Gregory A
GA
Jensen
Rhonda
R
Grever
Michael
M
Murgo
Anthony J
AJ
Au
Jessie L-S
JL
D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism*; D016190:Carboplatin / Q000493:pharmacokinetics / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008954:Models, Biological; D049451:Nomograms; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000627:therapeutic use; D011485:Protein Binding; D015203:Reproducibility of Results; D013498:Suramin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D001798:Blood Proteins; D013498:Suramin; D016190:Carboplatin; D017239:Paclitaxel