Pharmacologic sensitivity of paclitaxel to its delivery vehicles drives distinct clinical outcomes of paclitaxel formulations

Abstract

Paclitaxel, an effective antitumor agent, is formulated in various vehicles serving as carriers to deliver the hydrophobic paclitaxel to tissue. The approved formulations in the U.S. are paclitaxel formulated in Cremophor EL (currently known as Kolliphor EL) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Despite having the same active ingredient (paclitaxel), different formulations produce distinct products with unique efficacy and safety profiles. A semimechanistic model was developed to describe the pharmacologic sensitivity of paclitaxel under different formulations. Circulating paclitaxel concentration data from patients treated with nab-paclitaxel or Cremophor EL-paclitaxel were analyzed in NONMEM using a semimechanistic model with simultaneous disposition of paclitaxel-carrier complexes and the total paclitaxel released from the complexes. The key factors driving paclitaxel exposure in circulation and peripheral tissues were explored via sensitivity analysis. The rapid decline of total paclitaxel concentration following intravenous administration of nab-paclitaxel and Cremophor EL-paclitaxel was attributed to rapid tissue distribution of the paclitaxel-carrier complexes, with minor contribution of free and protein-bound paclitaxel. Distribution of nab-paclitaxel to peripheral tissue was 4-fold faster and 10-fold more extensive than that of Cremophor EL-paclitaxel micelles, resulting in distinct tissue paclitaxel profiles. Sensitivity analyses showed the plasma paclitaxel-time profile was insensitive to the rapid rates of tissue distribution and decomposition of paclitaxel-carrier complexes but that the tissue distribution profile of paclitaxel was highly sensitive. Tissue distribution of paclitaxel is carrier complex system-dependent. Different delivery systems result in distinct tissue paclitaxel profiles but similar paclitaxel concentration-time profiles in plasma or blood, rendering the paclitaxel plasma profile a poor surrogate for its clinical outcome.