Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities of certain drugs are unclear. At their maximal tolerated doses (MTD), the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a two week MTD-dosing regimen followed by a determination of drug pharmacokinetics, tissue distribution and multiple functional measures of peripheral nerve toxicity for four weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity produced biologically was consistently more severe with paclitaxel. Overall, our results argued that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity.

Clinical Pharmacokinetics of Paclitaxel Monotherapy: An Updated Literature Review

“…Accumulation of paclitaxel in the peripheral nervous system has been associated with its toxicity. In mice, paclitaxel accumulates in the dorsal root ganglia and sciatic nerve following both single and multiple doses [115]. Paclitaxel was still detectable up to 72 h after a single dose, which was significantly after the drug could be detected in the systemic circulation.…”

Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse

“…This finding suggests that sensitization occurs during the first cycle of paclitaxel treatment. The observed sensitization may be due to the accumulation of paclitaxel in the periphery, as detectable concentrations of paclitaxel have been measured in the dorsal root ganglia and the sciatic nerve up to 26 days post-paclitaxel dosing (Wozniak et al, 2016). …”

Microtubule-Targeting Agents Eribulin and Paclitaxel Differentially Affect Neuronal Cell Bodies in Chemotherapy-Induced Peripheral Neuropathy

“…In other words, might the apparent reduction in eribulin-mediated neuropathic events be the result of reduced exposure of peripheral neurons to eribulin as compared to paclitaxel? In this regard, recent work demonstrates that eribulin actually has greater penetration and retention in dorsal root ganglia and axons of peripheral neurons than does paclitaxel (Wozniak et al 2016). …”