Grade 3 PN was reported in 20%of patients previously treated with anthracycline. In trials where ixabepilone was administered in combination with capecitabine, Chondroitin the incidence of PN was common, generally grade 1/2, and reversible. In study 046, 67% of patients had PN, with grades 3 and 4 sensory symptoms reported in 21% and 1% of patients, respectively. Incidence of painful neuropathy was 6%. Severe motor neuropathy was reported in 5% of patients, and no grade 4 event was reported. In study 048, 66% of patients in the combination group had treatment related PN, 65% had sensory neuropathy, and 9% had motor neuropathy. Factors affecting neuropathy Risk factors A risk factor analysis was done investigating the association of various covariates with cumulative dose to onset of grade 3/4 PN for 1,540 ixabepilone treated patients Glycyrrhetin across several clinical studies. In this analysis, the majority of these covariates were not significantly associated with the development of grade 3/4 neuropathy.
Prior taxane was paradoxically associated with a decreased risk of severe neuropathy, maybe because of a selection bias where patients who had persistent grade 2 or higher neuropathy from prior therapy were excluded. However, the analysis showed that preexisting neuropathy significantly correlated with a greater risk of grade 3/4 neuropathy. Celecoxib this finding is consistent with the individual results from 046 and 048 studies: the rates of grade 3/4 PN for patients with and without baseline neuropathy in 046 were 27% and 22%, respectively, and in 048, were 32% and 22%, respectively. In an earlier analysis that included 945 patients, diabetes mellitus was found to be a significant risk factor, however, this analysis did not identify diabetes as a significant risk factor. Additional analysis showed no influence of baseline hepatic dysfunction on the development of PN. However, since subjects with grade 2 or higher levels of alanine aminotransferase, aspartate aminotransferase, or bilirubin at baseline were excluded from the trials, impact of baseline HSP hepatic impairment on PN cannot be fully evaluated. Dose per cycle The incidence of PN is also correlated with the dose of ixabepilone administered per treatment cycle and the duration of infusion.
In several clinical studies where ixabepilone was given at a dose of 40 mg/m2 every 3 weeks infused over 3 h, grade 3/4 PN was observed in 15% to 24% of patients. In clinical trials where a higher dose of ixabepilone was infused for 1 h, 17% to 38% of patients showed evidence of severe neuropathy, when infused for 3 h, 11% to 33% of patients had severe PN. In a clinical trial testing with a lower dose of 32 mg/m2 infused for 3 h, the incidence of grade 3/4 PN was reduced. Lower incidences of PN were also observed when ixabepilone was administered at 6 mg/m2/day on days 1 through 5 of a 3 week cycle.In the pivotal studies where ixabepilone was either used as monotherapy, or in combination with capecitabine, PN was found to be reversible. In study 081, 13 of the 17 patients with grade 3/4 neuropathy had documented resolution to baseline or grade 1 in a median time of 5.4 weeks and 14 had an improvement in a median time of 4.6 weeks, 47 patients with grade 2 PN had documented resolution in a median time of 4.0 weeks.