The effect of pH on intratumoural docetaxel release from polymeric nanoparticle CPC634
Pascale C.S. Rietveld (1,2), Stijn L.W. Koolen (1,2), Stefan Zeiser (3), Nelleke Snelder (3), Cristianne J. Rijcken (4), Birgit C.P. Koch (1), Ron H.J. Mathijssen (2), Sebastiaan D.T. Sassen (1)
(1) Department of Clinical Pharmacy, Erasmus MC, Rotterdam, The Netherlands, (2) Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands, (3) LAP&P Consultants, The Netherlands, (4) Cristal Therapeutics, Maastricht, The Netherlands
Objectives:
Docetaxel (DTX), a widely used antimitotic agent for diverse solid cancers, demonstrates great variability in clinical responses. This variability is mainly due to the high inter-patient variability in pharmacokinetics (PK), resulting in inadequate exposure in tumour tissues. Increasing the dose is not feasible due to serious adverse events, underscoring the need for drug delivery strategies that will increase intratumoural concentrations while reducing systemic exposure. The development of nanocarrier systems provides an effective way to address these issues.
CPC634 is a polymeric nanoparticle containing DTX which is covalently bound to core-cross linked polymeric micelles (total DTX) via a hydrolysable ester. A pH-responsive covalent bond (sulfone linker) allows for controlled release of the native DTX over time (released DTX). Additionally, PEG chains in the shell enhance stability and prolonged circulation in vivo by preventing plasma protein binding.
Prior research has evaluated the PK and toxicity profile of CPC634. The NAPOLY Phase I dose escalation study (n = 24) has demonstrated CPC634's dose-proportional PK profile[1]. The CRITAX study (n = 24) further illustrated its enhanced tumour uptake over traditional DTX formulations[2]. Additionally in the PICCOLO study (n = 5), the administration of radiolabelled zirconium-89-desferal CPC634 to patients with advanced solid tumours enabled to non-invasively investigate its biodistribution and tumour accumulation through PET/CT imaging[3].
Through population PK modelling, we aimed to predict the intratumoural PK of CPC634. Using the association between in vivo and in vitro release rates, we focused on how varying pH levels affect the drug release profile from CPC634 in actual patient tumour.
Methods:
The release of CPC634 was examined in vitro across a range of pH values (5, 6, 6.5, 7, 7.4) by measuring the cumulative release of DTX over time. We integrated these data with the PK data of the above described clinical trials, NAPOLY, CRITAX and PICCOLO studies. These data were used to construct pH-specific models using first order (FO) estimation in NONMEM v7.5 to estimate in vitro release rates. A proportional residual error model was used and release rates were estimated in a time dependent manner combined with a first order degradation rate.
Concentration-time data were log transformed and analysed using NONMEM using first-order conditional estimation with interaction (FOCE+I). The population PK model was based on a combined plasma-tumour model for released and unreleased DTX by Zeiser S. et al.[4].
Results:
The in vitro findings indicated that release rates of CPC634 increased with pH, ranging from 0.96*10-3 h-1 at pH 5 to 16.9*10-3 h-1 at pH 7.4, as is expected from an ester linkage. The constructed plasma-tumour popPK model of released and unreleased DTX was updated based on additional data, and accurately described the PK of total, released and unreleased DTX in plasma and tumour tissue. The estimated tumour DTX release rate from CPC634 nanoparticles was 1.29 *10-3 h-1 corresponding with a pH between 5 and 6.
Conclusions:
Our study demonstrates that higher pH levels induce more rapid drug release from CPC634, as evidenced by the increasing in vitro release rates at elevated pH levels. Nonetheless, the estimated release rate within the tumour in vivo was found to be low, which might have hampered DTX release and therefore its biologically relevant exposure in tumour tissue. Incorporating the pH-dependent release kinetics, the model predicted a lower intratumoural pH which is in line with literature. This underscores the importance of pH in the design of nanoparticles with temporarily covalently bound drugs.
References:
[1] Atrafi F, Dumez H, Mathijssen RHJ, et al. A phase I dose-escalation and pharmacokinetic study of a micellar nanoparticle with entrapped docetaxel (CPC634) in patients with advanced solid tumours. J Control Release. 2020;325:191-197. doi:10.1016/j.jconrel.2020.06.020
[2] Atrafi F, van Eerden RAG, van Hylckama Vlieg MAM, et al. Intratumoral Comparison of Nanoparticle Entrapped Docetaxel (CPC634) with Conventional Docetaxel in Patients with Solid Tumors. Clin Cancer Res. 2020;26(14):3537-3545. doi:10.1158/1078-0432.CCR-20-0008
[3] Miedema IHC, Zwezerijnen GJC, Huisman MC, et al. PET-CT Imaging of Polymeric Nanoparticle Tumor Accumulation in Patients. Adv Mater. 2022;34(21):e2201043. doi:10.1002/adma.202201043
[4] Zeiser et al. A Population PK Analysis of Docetaxel after Continuous IV Administration of CPC634 (CriPec® Docetaxel) and Taxotere® in Plasma with an IVIVC Analysis of released Docetaxel in Plasma and Buffer. PAGE 2024 - Rome, Italy
