Bayesian estimation of doxorubicin pharmacokinetic parameters

Summary

Doxorubicin was given by brief i.v. infusion (doses ranging from 25 to 72 mg/m²) to 28 patients for 2–7 successive courses of chemotherapy (68 courses studied in all). A Bayesian approach was developed to determine the individual pharmacokinetic parameters of doxorubicin. Statistical characteristics of the population pharmacokinetic parameters were first evaluated for 19 patients and a total of 30 courses, which, when combined with 4 individual plasma concentrations of drug, led to a Bayesian estimation of individual pharmacokinetic parameters for the remaining 38 courses. The estimated parameters for the elimination phase (A₃/V₁ andt1/2 elimination) and the residual plasma level at 48 h as computed by Bayesian estimation on this reduced sub-optimal sampling protocol were compared with a maximal likelihood estimation of these parameters. No statistically significant differences were found. Performance of the developed methodology was evaluated by computing bias and precision. The mean errors were −0.0315×10⁻⁴ l⁻¹ for A₃/V₁, 0.0839 h fort1/2 elimination, and −0.22 ng/ml forc _{(48 h)}. The precision of the prediction of these three parameters (0.304×10⁻⁵ l⁻¹, 3.34 h, and 0.659 ng/ml, respectively) remained lower than the interindividual standard deviation (1.42×10⁻⁴ l⁻¹, 14.9 h, and 4.54 ng/ml, respectively). This procedure enables the estimation of individual pharmacokinetic parameters for doxorubicin at minimal cost and minimal disturbance of the patient.