Analysis of accumulation of paclitaxel and ixabepilone in the dorsal root ganglia of mice following intravenous compound administrations showed that at equineurotoxic doses, Nattokinase there was 10 fold more paclitaxel bound to neuronal microtubule than ixabepilone in peripheral neurons. The pathophysiological consequence of the higher deposit of tubulin bound drug in peripheral neurons by paclitaxel is currently uncertain, but could be responsible for affecting the duration of neuropathic symptoms and time to resolution following treatment cessation. In this report, we present data on the incidence and characteristics of PN induced by ixabepilone treatment and evaluate potential risk factors for its development.The drug screening libraries database of phase II/III clinical trials, involving more than 2,000 patients receiving ixabepilone either as monotherapy or in combination with capecitabine, was searched to obtain incidences of PN.
The majority of patients with MBC included into this report received ixabepilone either as monotherapy in several phase II studies or in combination with capecitabine in two large phase III studies and one phase II study. The remaining patients either received alternate ixabepilone doses for MBC or received it as treatment for non small cell lung cancer. Daunorubicin patients were considered eligible if they did not have baseline PN grade 1. PN was graded by investigators using the NCI CTC version 2.0 or 3.0, and the worst grade on treatment was reported, assessments were done prior to each cycle and every 4 weeks after completion of treatment until resolution occurred. Assessments included deep tendonreflexes, sensory function, motor strength, and other neurologic findings, including autonomic function. Neuropathy was followed in all patients in the three pivotal studies of ixabepilone beyond the point that treatment was discontinued to assess for reversibility.
Improvement of PN was defined as the time from onset of worst grade to a reduction by at least 1 grade, and resolution was defined as time from onset of worst grade neuropathy to grade 1 or baseline level. Median time to resolution of PN was estimated using the Kaplan Meier product limit method. A Cox regression analysis was performed on a dataset of 1,540 patients to identify the potential risk high throughput chemical screening factors for grade 3/4 PN. This analysis included patients with MBC and lung cancer. Patients with MBC were treated with either combination therapy or ixabepilone monotherapy in multiple clinical studies across different dose schedules. Results Incidence PN, predominantly sensory, has been consistently observed across clinical studies of ixabepilone in patients with early and metastatic disease. In the neoadjuvant setting, the rate for all grades of peripheral sensory neuropathy was 15%, when administered for 4 cycles. Across the three monotherapy studies in MBC, incidence of sensory neuropathy was 64%, motor neuropathy was less common and was usually reported in patients with peripheral sensory neuropathy. Painful neuropathy was reported in 6% of patients. Incidences of grade 3/4 sensory PN in monotherapy studies ranged from 0% in taxane naive patients to 14% in taxane, anthracyclines, and capecitabine resistant patients depending on dose, schedule, and setting of administration.