Formulation-dependent differences in paclitaxel distribution to anatomical sites relevant to chemotherapy-induced peripheral neuropathy

Abstract

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event observed in patients receiving paclitaxel, associated with initial pathological changes in the peripheral nervous system, i.e., distal nerves and dorsal root ganglia (DRG). The prevalence of CIPN in patients receiving paclitaxel formulated i) in polyethylated castor oil with ethanol (CreEL-PTX), ii) as albumin-bound (nab-PTX), and iii) in XR17 micelles (micellar-PTX), is unexpectedly varying. We hypothesize that the discrepancy in CIPN prevalence could be governed by differences in the extent of paclitaxel distribution across blood-to-tissue barriers at the CIPN-sites, caused by the specific formulation.

Methods: The recently developed Combinatory Mapping Approach for CIPN was used to determine the unbound tissue-to-plasma concentration ratio K_p,uu,tissue, after a 4-h infusion of 4 mg/kg CreEL-PTX, 4 mg/kg nab-PTX or 1 mg/kg micellar-PTX in male and female Sprague Dawley rats. K_p,uu,tissue was determined in conventional (DRG, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN-sites.

Results: Based on our data, the Cremophor-free paclitaxel formulations were associated with a higher distribution of paclitaxel to CIPN-sites than CreEL-PTX, e.g., K_p,uu,DRG of 0.70 and 0.60 for nab-PTX and micellar-PTX, respectively, in comparison to 0.27 for CreEL-PTX (p < 0.01). In addition, the fraction of unbound paclitaxel in plasma was on average 1.6-fold higher in nab- and micellar PTX arms and equal to 0.061 and 0.065, respectively, compared to 0.039 for the CreEL-PTX treatment arm (p < 0.0001).

Discussion: In the case of similar unbound paclitaxel concentration in the plasma of patients and assumed species-independent extent of paclitaxel transport across the barriers, nab- and micellar-PTX formulations can lead to higher paclitaxel exposure at CIPN-sites in comparison to CreEL-PTX.

Keywords: CreEL-paclitaxel; blood-brain barrier; blood-dorsal root ganglion barrier; blood-nerve barrier; chemotherapy-induced peripheral neuropathy (CIPN); micellar-paclitaxel; nab-paclitaxel.

FIGURE 1

Total and unbound plasma pharmacokinetics of paclitaxel after a 4-h intravenous infusion of 4 mg/kg CreEL-PTX (N = 8, black), 4 mg/kg nab-PTX (N = 7, magenta) and 1 mg/kg micellar-PTX (N = 6, green) formulations. Semilogarithmic plot showing total (A) and unbound (B) paclitaxel plasma concentrations (ng/mL) over time. Data presented as mean ± SD.

FIGURE 2

Unbound paclitaxel tissue distribution after administration of CreEL-PTX (N = 8, black), nab-PTX (N = 7, magenta) and micellar-PTX (N = 6, green) formulations. Semilogarithmic scatter plots of mean ± SD values of unbound paclitaxel tissue-to-plasma concentration ratios in the brain (Br), spinal cord (SC), skeletal muscle (SM), sciatic nerve (SN) and dorsal root ganglia (DRG). The dotted line indicates a K_p,uu,tissue of unity. The standard deviations were calculated using the error propagation method (Loryan et al., 2017). The comparisons were performed using one-way ANOVA followed by Tukey’s multiple comparisons within each tissue separately. Significance levels were <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****).

FIGURE 3

Total paclitaxel tissue distribution after administration of a 4-h intravenous infusion of 4 mg/kg CreEL-PTX (N = 5 males (M), 3 females (F), black), 4 mg/kg nab-PTX (N = 3M, 4F, magenta) and 1 mg/kg micellar-PTX (N = 4M, 2F, green) formulations. Semilogarithmic scatter dot plot of total paclitaxel tissue-to-plasma concentration ratios in male (filled symbols) and female (open symbols) rats in the brain (Br), spinal cord (SC), skeletal muscle (SM), sciatic nerve (SN) and dorsal root ganglia (DRG). Data presented as mean ± SD. K_p,tissue comparison between treatment arms was performed using a two-way ANOVA test followed by Tukey’s multiple comparisons. Significance levels are depicted as follows: <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****).

FIGURE 4

The impact of dexamethasone premedication on total plasma exposure and the extent of total and unbound paclitaxel distribution after a 4-h IV infusion of 4 mg/kg CreEL-PTX alone (n = 8, black), with 0.15 mg/kg DEX (n = 4, blue) and with 0.3 mg/kg DEX (n = 4, red) premedication. (A) semilogarithmic plot represents total paclitaxel plasma concentration (ng/mL) over time, (B) semilogarithmic scatter dot plot of total paclitaxel tissue-to-plasma concentration ratios in male rats, and (C) semilogarithmic scatter plot of mean ± SD values of unbound paclitaxel tissue-to-plasma concentration ratios in brain (Br), spinal cord (SC), skeletal muscle (SM), sciatic nerve (SN) and dorsal root ganglia (DRG). Data are presented as mean ± SD. K_p,tissue comparison between treatment arms was performed using a two-way ANOVA test followed by Tukey’s multiple comparisons. The dotted line in C indicates a K_p,uu,tissue of unity. The standard deviation was calculated using the error propagation method (Loryan et al., 2017). For K_p,uu,tissue comparison was performed using a one-way ANOVA test followed by Tukey’s multiple comparisons within each tissue separately. Significance levels are depicted as follows: <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****). Abbreviation: DEX - dexamethasone.