# Comparative acute toxicity of intravenous paclitaxel and sirolimus in rats

## TL;DR

This study compares the toxicity of sirolimus and paclitaxel in rats, finding both drugs have similar tolerability and potential benefits for cardiovascular applications.

## Contribution

The study provides new evidence that sirolimus is a viable alternative to paclitaxel for endovascular applications based on similar tolerability profiles.

## Key findings

- Both sirolimus and paclitaxel caused reduced thymus weights and decreased white blood cell counts.
- Sirolimus induced prolonged body weight reduction in male rats, potentially beneficial for cardiovascular patients.
- Both drugs showed acceptable tolerability, with no major safety concerns for sirolimus as an endovascular alternative.

## Abstract

•Intravenous sirolimus and paclitaxel led to reduced thymus weights, accompanied by decreased white blood cell counts, consistent with their known mechanisms of action.•Both drugs demonstrated similar and acceptable tolerability profiles, with no evidence to contraindicate sirolimus as an alternative to paclitaxel for high-dose endovascular applications.•Sirolimus induced a prolonged reduction in body weight in male rats, a known metabolic effect that may offer potential benefits for patients with cardiovascular diseases.

Intravenous sirolimus and paclitaxel led to reduced thymus weights, accompanied by decreased white blood cell counts, consistent with their known mechanisms of action.

Both drugs demonstrated similar and acceptable tolerability profiles, with no evidence to contraindicate sirolimus as an alternative to paclitaxel for high-dose endovascular applications.

Sirolimus induced a prolonged reduction in body weight in male rats, a known metabolic effect that may offer potential benefits for patients with cardiovascular diseases.

In view of the exploration of sirolimus (rapamycin) as balloon coating for peripheral intravasal treatment and the reports on unfavorable tolerance of daily low-dose sirolimus, the aim of the study was to investigate potential toxicological effects of a single intravascular dose of sirolimus in comparison to paclitaxel and vehicle in the rat.

Rats were treated intravenously with a single dose of 20 mg/kg sirolimus or paclitaxel dissolved in identical vehicle and sacrificed 5- or 14-days post treatment. Vehicle (Cremophor EL/Ethanol diluted with saline) treated rats served as a control. Potential effects on survival, hematology, organ weights, organ histology were analyzed.

Single dose i.v. injection of sirolimus, paclitaxel and vehicle induced temporary sedation after treatment. One animal treated with paclitaxel died, probably due to solvent toxicity. Sirolimus, paclitaxel and the vehicle control were tolerated. Animals treated with sirolimus or paclitaxel showed temporary hematological effects and thymic atrophy that subsided after 14 days. Sirolimus induced a temporary weight reduction of ovaries and uterus. Male rats showed histological changes of testes at 14 days after sirolimus treatment. Notably, sirolimus induced a prolonged body weight reduction compared to paclitaxel and vehicle treatment in male rats.

Both substances showed similar and acceptable tolerability after high single-dose intravenous treatment. The results of this study do not indicate safety concerns that would preclude the use of sirolimus as an active ingredient on balloon catheters as an alternative to paclitaxel.