Phase I pharmacokinetic study of multicycle high-dose carboplatin followed by peripheral-blood stem-cell infusion in patients with cancer.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Johansen
M J
MJ
Department of Pharmacy, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Madden
T
T
Mehra
R C
RC
Wood
J G
JG
Rondon
G
G
Browne
V
V
Newman
R A
RA
Champlin
R E
RE
D000553:Ambulatory Care; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D001943:Breast Neoplasms / Q000097:blood*; D016190:Carboplatin / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D010051:Ovarian Neoplasms / Q000097:blood*; D017239:Paclitaxel / Q000493:pharmacokinetics
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D003520:Cyclophosphamide; D016190:Carboplatin; D017239:Paclitaxel