Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice.

Abstract

PURPOSE:

Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model.

METHODS:

PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling.

RESULTS:

A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg.

CONCLUSIONS:

The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.

• Authors: Feifan Xie, Kaat De Clercq, Chris Vervaet, Jan Van Bocxlaer, Pieter Colin, An Vermeulen
• Journal: Pharmaceutical research (Pharm Res) Vol. 36 Issue 9 Pg. 127 (Jun 24 2019) ISSN: 1573-904X [Electronic] United States
• PMID: 31236836 (Publication Type: Journal Article)

Chemical References

• Albumin-Bound Paclitaxel
• Antineoplastic Agents, Phytogenic
• Cross-Linking Reagents
• Drug Carriers
• Iridoids
• Gelatin
• genipin

Topics

• Albumin-Bound Paclitaxel (chemistry, pharmacokinetics, pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Cross-Linking Reagents (chemistry)
• Drug Carriers
• Gelatin (chemistry)
• Humans
• Iridoids (chemistry)
• Mice, Inbred BALB C
• Mice, Nude
• Microspheres
• Models, Biological
• Peritoneal Neoplasms (drug therapy)
• Xenograft Model Antitumor Assays