Evaluating Oxaliplatin Exposure in Adults with Advanced Colorectal Cancer: Development and Validation of Methods with Enhanced Bioanalytical Specificity and Clinical Applicability.

内容摘要

The clinical efficacy and adverse effects of oxaliplatin [Pt(DACH)(oxalato)] (DACH = 1R,2R-cyclohexanediamine) may depend upon systemic drug exposure quantified as the area under the plasma concentration versus time curve (AUC). Most previous oxaliplatin pharmacokinetic studies measured total platinum exposure without separating intact oxaliplatin [Pt(DACH)oxalato] from its inactive biotransformation products, and estimated AUC using intensive sampling methods unsuitable for routine clinical application. In the current study, we aimed to (1) evaluate systemic exposure to intact oxaliplatin and (2) develop and validate enhanced methods for estimating oxaliplatin AUC in adults with advanced colorectal cancer. Two oxaliplatin clinical pharmacokinetic datasets were analyzed. The first dataset included 19 patients and 38 treatment cycles from our previous clinical trial (ATCRN12611000738921). The second dataset included ten patients from an independent published clinical study. In both datasets, oxaliplatin 85 or 130 mg/m2 was given by constant-rate intravenous infusion over 2&#xa0;h. Reference AUCs for intact oxaliplatin and total unbound platinum were estimated by the trapezoidal rule using between 9 and 13 predefined concentration timepoints. End of infusion plasma concentrations were used to estimate AUC by equation-based methods. The accuracy of AUC estimations from end of infusion plasma concentrations was assessed in correlation plots and from their relative mean prediction error (MPE%) and relative root mean square prediction error (RMSE%). Intact oxaliplatin plasma concentration had almost reached steady state (>&#xa0;95%) and most systemic exposure (70%) had already occurred by the end of infusion. Intact oxaliplatin accounted for 77% of the AUC of total unbound platinum. Intact oxaliplatin AUCs were dose-proportional, moderately variable between individuals (%CV&#xa0;=&#xa0;18%), and linearly related to end of infusion plasma concentrations (y&#xa0;=&#xa0;2.231x, R2&#xa0;=&#xa0;0.72). Validation studies showed acceptable levels of bias (MPE% < 15%) and imprecision (RMSE% < 20%) for estimating intact oxaliplatin AUC from the end of infusion plasma concentration multiplied by the infusion duration. Intact oxaliplatin was the major pharmacologically active platinum species present in the systemic circulation of adults with advanced colorectal cancer in this study. Intact oxaliplatin AUC estimation from the end of infusion plasma concentration multiplied by the infusion duration offers a clinically practicable and potentially reliable method with enhanced bioanalytical specificity for evaluating oxaliplatin systemic exposure.