Physiologically-based modeling and interspecies prediction of paclitaxel pharmacokinetics

Abstract

The objective was to develop a physiologically-based pharmacokinetic (PBPK) model to characterize the whole-body disposition of paclitaxel (formulated in Cremophor EL and ethanol—Taxol^®) in mice and to evaluate the utility of this model for predicting pharmacokinetics in other species. Published studies that reported paclitaxel plasma and tissue concentration–time data following single intravenous bolus administration of Taxol^® to mice were used; and the PBPK model included plasma, liver, lungs, kidneys, spleen, heart, gastrointestinal tract, and remainder compartments. The final model resulted in a good description of the experimental plasma and tissues data in mice, where all tissues were represented by a single compartment, except the remainder that included two sub-compartments. The predictive performance of the PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of paclitaxel in rats and humans. The relationship between species body weights (mice, rats, rabbits, and humans) and plasma clearance was determined by power-based regression, and resulting allometric exponent was 0.86. The model demonstrated reasonable predictions of plasma and tissue paclitaxel concentration–time profiles in rats and plasma profiles in humans. The proposed PBPK model represents an important basis that can be further utilized for characterization of novel formulations of paclitaxel.

Appendix

The following equations were used to describe the model structure for paclitaxel disposition following IV administration of Taxol:

Plasma (pl):

$V_{pl} \frac{{dC_{pl} }}{{d_{t} }} = Inf + Q_{CO} (\frac{{C_{lu} }}{{Kp_{lu} }} - C_{pl} )$

Gastrointestinal tract (gi), spleen (sp), kidneys (kd), heart (hr):

$V_{ti} \frac{{dC_{ti} }}{{d_{t} }} = Q_{ti} (C_{pl} - \frac{{C_{ti} }}{{Kp_{ti} }})$

Liver (li):

$V_{li} \frac{{dC_{li} }}{{d_{t} }} = Q_{ha} C_{pl} + Q_{sp} \frac{{C_{sp} }}{{Kp_{sp} }} + Q_{gi} \frac{{C_{gi} }}{{Kp_{gi} }} - Q_{li} \frac{{C_{li} }}{{Kp_{li} }} - CL_{li} f_{u}^{pl} \frac{{C_{li} }}{{Kp_{li} }}$

Lung (lu):

$V_{lu} \frac{{dC_{lu} }}{{d_{t} }} = Q_{li} \frac{{C_{li} }}{{Kp_{li} }} + Q_{kd} \frac{{C_{kd} }}{{Kp_{kd} }} + Q_{hr} \frac{{C_{hr} }}{{Kp_{hr} }} + Q_{rm} C_{rm,vas} - Q_{CO} \frac{{C_{lu} }}{{Kp_{lu} }}$

Remainder (rm):

$\begin{aligned} V_{rm,vas} \frac{{dC_{rm,vas} }}{{d_{t} }} & = Q_{rm} \left( {C_{pl} - C_{rm,vas} } \right) - PS_{rm} \left( {f_{u}^{pl} C_{rm,vas} - f_{u}^{rm} C_{rm,exv} } \right) \\ V_{rm,exv} \frac{{dC_{rm,exv} }}{{d_{t} }} & = PS_{rm} \left( {f_{u}^{pl} C_{rm,vas} - f_{u}^{rm} C_{rm,exv} } \right) \\ \end{aligned}$

Where Inf is the infusion rate (in simulation for humans), Q_ti is tissue plasma flow, and V_ti is tissue volume (V_rm,vas and V_rm,exv are the volumes of the vascular and extravascular subcompartments). The initial condition for plasma equation was set to $\frac{Dose}{{V_{pl} }}$ for modeling animal data (drug was injected as an IV bolus), and was set to zero for simulating human studies in which the drug was administered as an IV infusion. The initial conditions for all other equations were set to zero.