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<p>This study evaluates the safety, tolerability, pharmacokinetics, and tissue distribution of paclitaxel injection concentrate for nanodispersion (PICN), either as standalone treatment or in comparison with Abraxane® (AbX) and Oncotaxel (OtX, generic formulation of Taxol® from Sun Pharma). <i>In vitro</i> cytotoxicity was assessed in—HT-29, PC-3, SKOV3 and NCI H522 human cancer cell lines. Single- and multiple-dose toxicity studies were conducted in rodents evaluating clinical signs, hematology, histopathology, and organ-specific toxicity. Pharmacokinetic studies were performed in rats analyzing Paclitaxel (PtX) concentrations by LC–MS/MS. PICN demonstrated comparable <i>in vitro</i> cytotoxicity to OtX. Single- and repeat-dose toxicity studies revealed that PICN has similar toxicity profile with AbX, including reversible lymphoid depletion and irreversible testicular toxicity at higher doses. Known PtX class effects, myelosuppression and neuropathy was observed in both PICN and reference groups; with less pronounced effects in females. PICN (at 10 mg/kg) produced a lower reduction in pain threshold (~ 22%) compared to OtX (~ 43%), suggesting a reduced potential for neurotoxicity. PICN showed no local irritation following IV administration and no hemolytic potential in-vitro. It exhibited dose-proportional increases in C<sub>max</sub> and AUC<sub>0–inf</sub> across 5–20 mg/kg, with pharmacokinetic parameters comparable to AbX. Red blood cell (RBC) partitioning studies indicated balanced distribution for PICN compared to OtX, and slightly lower RBC exposure than AbX. PICN also demonstrated moderate PtX distributions with concentrations higher than AbX but substantially lower than OtX in various tissues. Collectively, these results support PICN as a promising alternative, combining favorable safety and comparable pharmacokinetics.</p> Graphical Abstract <p></p>

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Preclinical Toxicity and Pharmacokinetic Evaluation of Paclitaxel Nanodispersion

  • 期刊论文

  • 发表日期：

    2025年12月18日

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  • Ajay J. Khopade,
  • Malay D. Shah,
  • Bhushan S. Borole,
  • Bharat Patel,
  • Bharat Pateliya,
  • Vinod Burade

摘要

This study evaluates the safety, tolerability, pharmacokinetics, and tissue distribution of paclitaxel injection concentrate for nanodispersion (PICN), either as standalone treatment or in comparison with Abraxane® (AbX) and Oncotaxel (OtX, generic formulation of Taxol® from Sun Pharma). In vitro cytotoxicity was assessed in—HT-29, PC-3, SKOV3 and NCI H522 human cancer cell lines. Single- and multiple-dose toxicity studies were conducted in rodents evaluating clinical signs, hematology, histopathology, and organ-specific toxicity. Pharmacokinetic studies were performed in rats analyzing Paclitaxel (PtX) concentrations by LC–MS/MS. PICN demonstrated comparable in vitro cytotoxicity to OtX. Single- and repeat-dose toxicity studies revealed that PICN has similar toxicity profile with AbX, including reversible lymphoid depletion and irreversible testicular toxicity at higher doses. Known PtX class effects, myelosuppression and neuropathy was observed in both PICN and reference groups; with less pronounced effects in females. PICN (at 10 mg/kg) produced a lower reduction in pain threshold (~ 22%) compared to OtX (~ 43%), suggesting a reduced potential for neurotoxicity. PICN showed no local irritation following IV administration and no hemolytic potential in-vitro. It exhibited dose-proportional increases in Cmax and AUC0–inf across 5–20 mg/kg, with pharmacokinetic parameters comparable to AbX. Red blood cell (RBC) partitioning studies indicated balanced distribution for PICN compared to OtX, and slightly lower RBC exposure than AbX. PICN also demonstrated moderate PtX distributions with concentrations higher than AbX but substantially lower than OtX in various tissues. Collectively, these results support PICN as a promising alternative, combining favorable safety and comparable pharmacokinetics.

Graphical Abstract