EVALUATION OF THE LINEARITY OF DOCETAXEL PHARMACOKINETICS

The taxanes, paclitaxel and docetaxel, have favorable response rates i n patients with breast, gynecologic, and lung cancers and have demonst rated activity against a variety of malignancies. In human trials, pac litaxel pharmacokinetics are nonlinear and are best fit by a three-com partment model with nonlinear distribution into the second compartment as well as nonlinear elimination. This finding is important for patie nts receiving paclitaxel at high doses or as a short infusion, as it r esults in disproportionately high peak concentrations and delayed elim ination. The presence of nonlinear processes in docetaxel pharmacokine tics has not previously been examined. Therefore, plasma concentration data obtained from 53 patients receiving docetaxel at 55-115 mg/m(2) over 1-24 h as part of phase I studies were modeled using the nonlinea r three-compartment model found most suitable for paclitaxel and the r esults were compared with those obtained using the linear version. Doc etaxel disposition was best described by the three-compartment nonline ar model in 28 of 53 data sets (53%). However, the difference in curve fit observed between the two models was modest (did not improve Akaik e criteria) and unlikely to be of relevance. This study suggests that nonlinear processes in docetaxel pharmacokinetics may exist, but, unli ke the case of paclitaxel, they are not likely to have a significant i mpact at the dose and administration schedule used in routine clinical practice (60-100 mg/m(2) given over 1 h by infusion). The presence of nonlinear docetaxel pharmacokinetics at doses above 115 mg/m(2) will have to be determined in case of further dose escalation.