A population PK analysis of docetaxel after IV administration of CPC634 (CriPec® docetaxel) and generic docetaxel in plasma and tumor
Stefan Zeiser (1), Pascale Rietveld (2), Cristianne Rijcken (3), Nelleke Snelder (1)
(1) LAP&P Consultants BV, Leiden, The Netherlands, (2) Erasmus MC, Rotterdam, The Netherlands, (3) Cristal Therapeutics, Maastricht, The Netherlands
Objectives: CPC634 is a CriPec® nanoparticle entrapping docetaxel (DTX), conjugated via a biodegradable bond, developed to improve the tolerability and tumor accumulation as compared to generic DTX. Over time, DTX bound to the nanoparticle is released from the nanoparticle via linker cleavage. The latter is defined as released DTX, whilst the nanoparticle conjugated is defined as unreleased, and total is the combination of released+unreleased. This pharmacokinetic (PK) investigation aimed to 1) characterize the PK of released and unreleased DTX after IV administration of CPC634 and 2) determine the correlation between the in vivo and in vitro release of DTX from CPC634 in plasma and in pH 7.4 buffer.
Methods: Data from two studies, CriTax [1] and Piccolo [2], were used to develop a population PK model for released and unreleased DTX The CriTax study was a randomized cross-over study including 24 patients with solid tumors who received a 1-hour intravenous (IV) administration of 75 mg/m2 CPC634 in cycle 1 and 75 mg/m2 generic DTX in cycle 2 or vice versa. Total DTX and released DTX were measured in plasma and tumor tissue, and unreleased concentrations were derived. In the Piccolo study, non-invasive PET/CT imaging was performed in five patients with solid tumors by labelling CPC634 with zirconium-89 (89Zr). As a first dose, participants received 0.1 – 2 mg IV of [89Zr]-Df-CPC634 tracer. Two weeks later, patients were administered 60 mg/m2 IV of CPC634 followed by a second 89Zr tracer injection. Total and [89Zr]-Df-CPC634 DTX were determined in plasma and tumor tissue.
A plasma population PK model for unreleased and released DTX was developed in three steps: 1) a population PK model (DTX model) for generic DTX was developed which served as disposition model for released DTX. 2) a population PK model (CPC model) was developed for unreleased DTX based on data from the CriTax and Piccolo studies. It was assumed that the distribution of unreleased DTX is independent of the amount of DTX in the CriPec such that the distribution of [89Zr]-Df-CriPec is similar to the distribution of unreleased DTX. Furthermore, it was assumed that the released DTX follows the same kinetics as generic DTX, and that the depletion of (entrapped) DTX in CPC634 takes place by release of DTX and elimination of intact CPC634 nanoparticles. 3) the two models were combined to a population PK model which simultaneously described released and unreleased DTX, and the estimated in vivo and in vitro release profiles were compared. Finally, the integrated plasma PK model was linked to a tumor PK model for released and unreleased DTX.
Results: The plasma DTX model, a 3-compartment population PK model with linear kinetics, adequately described the disposition of generic DTX with CL = 26.9 L/h, Vc = 7.18 L. The plasma CPC model, a 2-compartment population PK model with linear kinetics, described unreleased DTX adequately after administration of higher dose levels of [89Zr]-Df-CriPec and CPC634 with CL = 0.0229 L/h and Vc = 3.44 L. The two sub-models were combined by assuming that elimination of unreleased DTX in the CPC model takes place by elimination of CPC634 and release of DTX where the latter served as uptake of released DTX in the DTX model. Elimination of CPC634 was described by linear kinetics whereas release of DTX was found to be time dependent (“trial and error interpolation” of rate constants guided by OFV). Under- and over-prediction was observed at time points around 24 and 168 h, respectively, indicating that PK of DTX and CPC634 might exhibit more complex behavior [3].
The in vitro release rate of DTX from CPC634 in a buffer of pH 7.4 was described by first-order release (time-dependent) and degradation processes. Based on this model, around 95% of DTX was released from the nanoparticles after 192 h. Predicted in vivo and in vitro cumulative release profiles were similar.
In tumor, the PK of DTX was adequately described by two effect tumor compartments for unreleased and released DTX, connected by a release rate constant. The IVIVC of the release in tumor was further assessed by Rietveld et al. [4].
Conclusions: Released and unreleased DTX after IV administration of generic DTX CPC634 and [89Zr]-Df-CriPec were adequately described by an integrated plasma-tumor PK model. Predicted in vitro and in vivo cumulative release were similar, indicating that the in vitro release at pH 7.4 buffer is predictive for in vivo release of DTX in plasma.
References:
[1] Atrafi et al. Nanoparticle entrapped docetaxel (CPC634) enhances intratumoral docetaxel exposure compared to conventional docetaxel (Cd) in patients with solid tumors. Journal of Clinical Oncology, Volume 37, Number 15_suppl, 2019.
[2] Miedema et al. First-in-human imaging of nanoparticle entrapped docetaxel (CPC634) in patients with advanced solid tumors using 89Zr-Df-CPC634 PET/CT. Journal of Clinical Oncology, Volume 37, Number 15_suppl,2019.
[3] Hooker et al. Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: Incorporating cytochrome P450 3A activity measurements. Clinical Pharmacology & Therapeutics, 2008; 84: 111-118.
[4] Rietveld et al. The effect of pH on intratumoural docetaxel release from polymeric nanoparticle CPC634. PAGE 2024 - Rome, Italy.