Methods, devices, and reagents for monitoring paclitaxel concentration in plasma for pharmacokinetic-guided dosing of paclitaxel

Abstract

Methods, devices, and compositions for assaying therapeutic agents. In one aspect, methods, devices, and compositions for assaying paclitaxel to provide therapeutic drug monitoring guided therapy of paclitaxel.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . A method for assaying paclitaxel in a liquid sample, comprising:
 (a) applying a liquid sample comprising paclitaxel to a lateral flow assay device, the device comprising
 (i) a sample receiving zone for receiving the liquid sample; 
 (ii) a detection reagent zone in liquid communication with the sample receiving zone and downstream in flow direction from the sample receiving zone, 
 wherein the detection reagent zone comprises a detection reagent deposited thereon, 
 wherein the detection reagent is a paclitaxel antibody, or fragment or derivative thereof, that binds paclitaxel, labeled with a detectable reporting group, and 
 wherein the paclitaxel antibody, or fragment or derivative thereof, has a K on  from about 10 4  to about 10 7 , and a K off  from about 10 −3  to about 10 −7 ; and 
 (iii) a capture zone in liquid communication with the detection reagent zone and downstream in flow direction from the detection reagent zone, 
 wherein the capture zone comprises first and second capture reagents immobilized thereon, 
 wherein the first capture reagent is a paclitaxel material capable of binding the detection reagent (test line), 
 wherein the second capture reagent is an antibody capable of binding the detection reagent (control line), 
 wherein the first capture reagent is positioned at a first distance downstream in flow direction from the upstream end of the capture zone, 
 wherein the second capture reagent is positioned at a second distance downstream in flow direction from the upstream end of the capture zone, 
 wherein the second distance is greater than the first distance, and 
 wherein the ratio of the first distance to the second distance is from about 0.0 to about 0.4, when the K on  is greater than about 2.0×10 5  and the K off  is less than about 1.0×10 −3 , and 
 wherein the ratio of the first distance to the second distance is from about 0.2 to about 1.0, when the K on  is greater than about 2.0×10 4  and the K off  is less than about 2.0×10 −4 ; and 
   (b) allowing the sample to flow from the sample receiving zone through the detection reagent zone to provide detection reagent with paclitaxel;   (c) allowing the detection reagent with paclitaxel to flow through the capture zone,   whereby the first capture reagent (test line) competes with the analyte (paclitaxel) for binding with the detection reagent, and   whereby the second capture reagent (control line) binds excess detection reagent; and   (d) observing the amount of detection reagent bound to the first capture reagent (test line) relative to the second capture reagent (control line).   
     
     
         2 . The method of  claim 1  further comprising determining the quantity of paclitaxel in the sample by quantitating the amount of detection reagent bound at control line and test line. 
     
     
         3 . The method of  claim 2 , wherein quantitating the amount of detection reagent bound to the capture reagents comprises optical density measurement. 
     
     
         4 . The method of  claim 1 , wherein the detectable reporting group is colloidal gold. 
     
     
         5 . The method of  claim 1 , wherein the paclitaxel antibody is 3C6. 
     
     
         6 . The method of  claim 1 , wherein the paclitaxel antibody is 8A10. 
     
     
         7 . The method of  claim 1 , wherein the paclitaxel material is a paclitaxel antigen that competes with paclitaxel for binding to the detection reagent. 
     
     
         8 . The method of  claim 1 , wherein the paclitaxel material is a paclitaxel protein conjugate. 
     
     
         9 . The method of  claim 1 , wherein the distance between the sample receiving zone and the first capture reagent is varied to optimize paclitaxel detection sensitivity. 
     
     
         10 . The method of  claim 1 , wherein the distance between the sample receiving zone and the first capture reagent is minimized to optimize paclitaxel detection sensitivity. 
     
     
         11 . The method of  claim 1  further comprising observing the amount of excess detection reagent bound to the second capture reagent (control line). 
     
     
         12 . The method of  claim 1  further comprising determining the quantity of paclitaxel in the sample by quantitating the amount of excess detection reagent bound to the second capture reagent. 
     
     
         13 . The method of  claim 1  further comprising a third capture zone intermediate the first and second capture zones, wherein the third capture zone comprises a paclitaxel material capable of binding the detection reagent. 
     
     
         14 . The method of  claim 13 , comprising determining the quantity of paclitaxel in the sample by quantitating the amount of detection reagent bound to the third capture reagent. 
     
     
         15 . The method of  claim 13 , wherein quantitating the amount of detection reagent bound to the third capture reagent comprises optical density measurement. 
     
     
         16 . The method of  claim 1 , wherein first and second antibodies are used, and wherein the first has a K on  greater than 10 4  and the second has a K off  less than 10 −3 . 
     
     
         17 . The method of  claim 1 , wherein two or three lines can be used to generate multiple readings on the same sample, allowing for increased reproducibility and expanded dynamic range. 
     
     
         18 . A method for monitoring the efficacy of a paclitaxel therapy in a patient diagnosed with cancer, comprising:
 (a) treating a cancer patient with paclitaxel at a first point in time;   (b) determining a first concentration of paclitaxel in the patient at a first point in time, wherein determining the concentration comprises the method of  claim 1 ;   (c) treating the patient with paclitaxel at a second point in time;   (d) determining a second concentration of paclitaxel drug in the patient at a second point in time, wherein determining the concentration comprises the methods of  claim 1 ; and   (e) comparing the first and second concentrations of paclitaxel in the patient to determine the efficacy of the cancer treatment.   
     
     
         19 . A method for PK-guided dosing of paclitaxel therapy in a patient diagnosed with cancer, comprising:
 (a) treating the cancer patient with paclitaxel at a first point in time;   (b) determining one or more pharmacokinetic parameters of paclitaxel in the patient at a first point in time, wherein determining the one or more pharmacokinetic parameters comprises measuring the concentration of paclitaxel by the method of  claim 1 ;   (c) treating the patient with paclitaxel at a second point in time using the PK information from the first dosing;   (d) determining one or more pharmacokinetic parameters of paclitaxel in the patient at a second point in time, wherein determining the one or more pharmacokinetic parameters comprises measuring the concentration of paclitaxel by the method of  claim 1 ; and   (e) comparing one or more pharmacokinetic parameters of paclitaxel in the subject at the first point in time with the levels at the second point in time to confirm that optimal dosing was achieved.   
     
     
         20 . The method of  claim 19 , wherein the pharmacokinetic parameters are selected from the group consisting of time to maximum concentration (T max ), concentration maximum (C max ), area under the curve (AUC), clearance (CL), volume of distribution (V d ), apparent volume of distribution during the terminal phase (V Z ), apparent volume of distribution during steady state (V ss ), and combinations thereof.