Alessandro De Carlo 1, Simone Zannoni 1, Lars van der Veen 2, Marcel Deken 2, Alessia Tagliavini 1
1 Department of Clinical Development & Translational Medicine, Aptuit an Evotec Company (Verona, Italy), 2 iOnctura BV (Amsterdam, the Netherlands)
Background: Autotaxin (ATX) is an enzyme involved in the synthesis of lysophosphatidic acid (LPA), which regulates cell proliferation, migration and survival [1]. Dysregulation of ATX-LPA pathway is common in many different types of cancer, and it is a key driver of tumor growth and fibrosis which is associated with poor response to immunotherapy [2,3]. Cambritaxestat (IOA-289) is a novel ATX inhibitor developed for the treatment of cancer [4]. It has been evaluated in healthy volunteers (Phase I study, NCT05027568) and in metastatic pancreatic cancer patients treated in combination with chemotherapeutics (Phase Ib study, NCT05586516) [5,6].
Objective: To develop a population PK/PD model describing cambritaxestat-mediated inhibition of LPA levels and to simulate novel dosing regimens in support of the future clinical study designs.
Methods: Plasma concentrations of cambritaxestat and LPA C18:2 from Phase I/Ib studies were gathered to develop the population PK/PD model. Healthy volunteers (n=40) received a single cambritaxestat dose (from 30 to 400 mg). Pancreatic cancer patients (n=16) were daily treated with cambritaxestat bid (from 100 to 800 mg) with 28-day treatment cycles. Chemotherapy (gemcitabine/nab-paclitaxel) was co-administered on Days 1, 8, and 15 of each cycle. A 7-day run-in period (cycle 0) with cambritaxestat bid monotherapy treatment, preceded the first cycle (cycle 1). Demographics characteristics and concomitant medications were considered as potential covariates. A sequential PK/PD modeling approach was adopted in model development.
Prediction corrected VPC, GoF, residual plots, estimation errors (RSE%), AIC and BIC scores were used in the development stage to identify the final model. PK/PD modelling was performed with Monolix Suite while simulations were conducted with Simulx. Results tabulation and output plots generation were done in R.
Results: The final PK model was developed to capture both differences and similarities across the two populations. A two-compartments PK model with linear elimination and zero-order absorption best described cambritaxestat time-profiles in both populations. The elimination rate (k=0.5 h-1) was shared across for the two subpopulations, and it showed a moderate IIV only in cancer patients. Compared to healthy volunteers, cancer patients showed a lower distribution volume (V1: 421.96 L vs 1352.88 L), longer absorption (Tk0: 1.02 h vs 0.52 h) and faster distribution rates (k12: 0.42 h-1 vs 0.32 h-1, k21: 0.16 h-1 vs 0.062 h-1). V1 linearly increased by 44% between cycle 0 and cycle 1 in cancer patients. Additionally, Tk0 and k12 showed significant variability between the two treatment cycles within the same patient, thus IOV term was included.
All parameters were estimated with RSE < 30% except for absorption-related ones (40-50%) likely due to the limited number of samples collected between drug administration and Cmax.
The inhibition mechanism of cambritaxestat on LPA was best described by integrating an effect compartment model with an Imax inhibition model [7]. Pancreatic cancer patients showed higher values for Imax (0.92 vs 0.83) and IC50 (16.76 ng/mL vs 7.4 ng/mL) parameters compared to healthy volunteers. Differently, baseline LPA (LPA0=27.7 ng/mL) and plasma-effect-compartment equilibrium constant (ke0=5.75 h-1) are completely shared across the two populations. Only in pancreatic cancer patients, a linear decrease of 86% in ke0 between treatment cycle 0 and cycle 1 was estimated. All PD model parameters were estimated with RSE ≤ 30%.
The final PK/PD model was used to compare two novel regimens (100 and 200 mg tid) against 200 mg bid in a virtual population of 1000 virtual cancer patients receiving 14 days of treatment (7 for run-in cycle 0 and 7 for cycle 1 with chemotherapy). Simulated LPA time profiles were normalized using individual LPA0 values. All the three dosages guaranteed normalized LPA<0.5 for approximately 100% of both cycles duration (median result). The 200 mg tid regimen achieved LPA<0.4 for 98% and <0.3 for >78% of both cycles durations, outperforming 200 mg bid (LPA<0.4 for >72% and LPA<0.3 for >40%). The 100 mg tid regimen provided no improvement compared to 200 mg bid (LPA<0.4 for >60% and LPA<0.3 for >27%).
Conclusions: A population PK/PD model describing cambritaxestat-mediated inhibition of LPA was successfully developed. Simulation results indicated that switching from bid to tid dosing schedule improved LPA inhibition, with 200 mg tid identified as the optimal regimen. Conversely, 100 mg tid did not achieve better LPA inhibition compared with 200 mg bid.
References:
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Reference: PAGE 34 (2026) Abstr 12042 [www.page-meeting.org/?abstract=12042]
Poster: Drug/Disease Modelling - Oncology