Journal of Clinical Oncology, Vol 15, 1481-1491, Copyright © 1997 by American Society of Clinical Oncology
Phase I pharmacokinetic study of multicycle high-dose carboplatin followed by peripheral-blood stem-cell infusion in patients with cancer
MJ Johansen, T Madden, RC Mehra, JG Wood, G Rondon, V Browne, RA Newman and RE Champlin
Department of Pharmacy, University of Texas M.D. Anderson Cancer Center, Houston, USA.
PURPOSE: To examine the feasibility of escalating carboplatin area under
the concentration-time curve (AUC), using dose predictions based on
individual estimates of drug clearance, in a phase I trial of multicycle
carboplatin, paclitaxel, and cyclophosphamide chemotherapy with
peripheral-blood stem-cell (PBSC) replacement. PATIENTS AND METHODS:
Forty-four patients (37 breast, seven ovarian) received 165 courses.
Initial target carboplatin AUC was 10 mg/ml x min, with interpatient
escalation in increments of 25%. Initial carboplatin dose estimates used
creatinine clearance (CrCl) to estimate carboplatin clearance. Subsequent
clearance and dose estimates were determined using a model incorporating
Bayesian estimation and two measured carboplatin plasma ultrafiltrate
concentrations. RESULTS: Median clearance was 80.5 mL/min/m2 (range, 41.6
to 131.8). Carboplatin doses up to 2,440 mg/m2 per course were administered
without major extramedullary toxicity. Doses varied 2.6-fold at each
exposure level. Using the Bayesian model, AUC was predicted with a mean
accuracy of 101.2% (83% using CrCl). Ninety-six of 117 courses were within
25% of the target AUC. This model was less biased (0.15 v -2.35 mg/mL x
min) and more precise (2.76 v 3.52) in predicting AUC compared with one
using CrCl. Hematologic recovery was not prolonged with increasing
exposure. The carboplatin maximum-tolerated systemic exposure (MTSE) was
13.3 mg/mL x min (level five). The dose-limiting toxicity was cardiac
toxicity, which occurred at dose levels six and seven. CONCLUSION: Results
demonstrate that (1) CrCl is a poor estimator of carboplatin clearance in
this population, and (2) the use of a model incorporating limited sampling
and Bayesian estimation improves the precision of carboplatin clearance
estimation and is suitable for targeting carboplatin exposure in an
ambulatory setting.
