Pharmacokinetic models for the saturable distribution of paclitaxel

Paclitaxel pharmacokinetics are nonlinear with saturable metabolism and sat urable distribution to the tissues. The saturable distribution has in previ ous pharmacokinetic modeling been described as a saturable transport proces s, whereas the present study was undertaken to investigate alternative expl anations. Using a sparse sampling scheme (on average 3.3 samples per profil e), 101 plasma concentration-time profiles in 22 female patients with metas tatic cancer of the breast or ovary were monitored. It was found that the o bserved data could be equally well described by saturable tissue binding as well as by capacity-limited tissue transport. The data were better describ ed by a model where equilibrium was achieved with drug in the central rathe r than in the peripheral compartment. Models where the binding was assumed to be an instantaneous or a noninstantaneous process were tried, but the da ta did not allow resolution between these two possibilities. The value at w hich the saturable transport was half-maximal was 0.55 mu M. The K-d values of the binding models were 0.06 to 0.12 mu M. These are close to the value s reported as a threshold for drug toxicity of paclitaxel, suggesting a pos sible connection between the binding sites involved in the pharmacokinetics and the mechanism responsible for the toxicity. For all models, a saturabl e elimination of paclitaxel was included using the Michaelis-Menten model. K-m for the elimination ranged in the different models from 2.5 to 5.6 mu M .