E.M. Tosca (1), E. Borella (2), C. Piana (2), C. Fornari (2), R. Bartolucci (1), P. Mazzei (2), A. Capriati (2), G. Merlino (2), S. Capano (2), D. Laurent (2), A. Pellacani (2), P. Magni (1)
(1) Università degli Studi di Pavia, Dept. Electrical, Computer and Biomedical Engineering, Pavia, Italy, (2) Menarini Ricerche SpA, Italy
Objectives:
A translational pharmacokinetic-pharmacodynamic (PKPD) modelling approach has been applied to determine the minimum target concentration of MEN1611, a novel orally bioavailable PI3K inhibitor in clinical development, when given in combination with trastuzumab (Tzb) in patients with HER2-positive advanced or metastatic breast cancer (BC).
Methods:
(1) A compartmental PK model was developed for both MEN1611 and Tzb from plasma concentration data in tumor-free and in tumor-bearing mice, respectively.
(2) The Simeoni model [1] was used to describe tumor growth data of the single-agent arms from 7 studies in xenograft models with different tumor cell lines representative of the HER2-positive human BC non responsive to Tzb (alterations of the PI3K/AKT/mTOR pathway).
(3) A PKPD model was developed starting from the Simeoni model to describe tumor growth data of the combination arm from the aforementioned 7 xenograft studies (combination model).
(4) A mathematical analysis of the proposed combination model was performed to develop the Tumor Static Concentration Curve (TSCC) tool, that enables to quantify the minimum effective MEN1611 concentration, as a function of Tzb concentration, needed for tumor eradication in xenograft mice.
(5) A range of minimum effective MEN1611 concentrations in BC patients was extrapolated using the TSCC from each xenograft study, considering the typical steady-state Tzb plasma levels in BC patients following 3 alternative regimens (i.v. 4 mg/kg loading dose + 2 mg/kg q1w, i.v. 8 mg/kg loading dose + 6 mg/kg q3w or s.c. 600 mg q3w) [2]. Subsequently, intra- and inter-individual variability at steady state Tzb plasma levels were taken into account.
Results:
A 2-compartment model with linear elimination and absorption was used to describe both MEN1611 and Tzb PK in mice. No PK interaction was expected between these two drugs.
The Simeoni model well described tumor growth inhibition following MEN1611 and Tzb administration as single-agent for all the 7 studies. The developed combination model was successfully applied to describe the synergistic interaction between the two drugs, which was observed in the vast majority of the combination therapy experiments.
The TSCCs derived from each xenograft model were used to identify a range of minimum effective MEN1611 exposures (AUCtau,ss) when administered in combination with Tzb in human. A threshold of 2000 ng*hr/mL for MEN1611 AUCtau,ss was found to be associated with a high likelihood of effective anti-tumor activity. The inter-patient variability on Tzb exposures was found to highly affect the minimum effective MEN1611 exposure. For the 3-weekly Tzb administration regimens, intra-patient fluctuations of Tzb concentration within the 21-days treatment period were more relevant than for the once-weekly regimen, even if the inter-patient variability remained the most impacting factor.
Conclusions:
A range of minimum target exposures to be achieved for MEN1611, when administered in combination with Tzb, in HER2-positive advanced or metastatic breast cancer patients has been identified from a PKPD combination model in xenografts. A threshold for MEN1611 exposure (AUCtau,ss) associated with a high likelihood of effective anti-tumor activity was identified for both the 3-weekly and weekly Tzb i.v. schedule. A slightly lower exposure (i.e. 25% lower) was found for the 3-weekly s.c. schedule. This important information confirmed the adequacy of the therapeutic dose administered in the ongoing Phase 1b B-PRECISE study in HER2-positive advanced or metastatic breast cancer patients [3].
References:
[1] Simeoni M, Magni P, Cammia C, Nicolao G De, Croci V, Pesenti E, et al. Predictive Pharmacokinetic Pharmacodynamic Modeling Tumor Growth Kinetics Xenograft Model After Administration AntiCancer Agents. Cancer Res. 2004;64:1094 101.
[2] European Environment Agency (EEA). https://www.ema.europa.eu/en/documents/productinformation/herceptin-epar-product-information_it.pdf. Vol. 53. 2019. p. 1689 99.
[3] https://clinicaltrials.gov/ct2/show/NCT03767335
Reference: PAGE 29 (2021) Abstr 9657 [www.page-meeting.org/?abstract=9657]
Poster: Drug/Disease Modelling - Oncology