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.
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Abbreviations
- AIC:
-
Akaike’s information criterion
- BLI:
-
Bioluminescence imaging
- CRS:
-
Cytoreductive surgery
- DBS:
-
Dried blood spot
- GOF:
-
Goodness of fit
- GP-MS:
-
Genipin-crosslinked gelatin microspheres
- IIV:
-
Inter-individual variability
- IPC:
-
Intraperitoneal chemotherapy
- LLOQ:
-
Lower limit of quantification
- Nab-PTX:
-
Paclitaxel-loaded albumin nanoparticles
- OFV:
-
Objective function value
- pcVPCs:
-
Prediction-corrected visual predictive checks
- PKPD:
-
Pharmacokinetic-pharmacodynamic
- pMRD:
-
Peritoneal minimal residual disease
- PTX:
-
Paclitaxel
- PTX-GP-MS:
-
Paclitaxel-loaded genipin-crosslinked gelatin microspheres
- PTXEtOH-GP-MS:
-
Paclitaxel-ethanolic loaded genipin-crosslinked gelatin microspheres
- PTXnano-GP-MS:
-
Paclitaxel-ethanolic loaded genipin-crosslinked gelatin microspheres
- SIR:
-
Sampling importance resampling
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ACKNOWLEDGMENTS AND DISCLOSURES
This work was supported by a Concerted Research Action (GOA) grant (project number: 01G02916) from Ghent University. Feifan Xie acknowledges the China Scholarship Council (CSC) for his Ph.D. grant. An Vermeulen is an 80% employee of Johnson and Johnson and owns J&J stock/stock options. She is also a visiting Professor at Ghent University. All other authors declare have no conflicts of interest that are directly relevant to the contents of this manuscript. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. (Animal Ethics Committee of the Faculty of Medicine at Ghent University, permit number: ECD 17/83).
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Xie, F., De Clercq, K., Vervaet, C. et al. Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice. Pharm Res 36, 127 (2019). https://doi.org/10.1007/s11095-019-2660-1
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DOI: https://doi.org/10.1007/s11095-019-2660-1