Tumor Static Concentration Curves in Combination Therapy

Self Cite

Radiotherapy is one of the major therapy forms in oncology, and combination therapies involving radiation and chemical compounds can yield highly effective tumor eradication. In this paper, we develop a tumor growth inhibition model for combination therapy with radiation and radiosensitizing agents. Moreover, we extend previous analyses of drug combinations by introducing the tumor static exposure (TSE) curve. The TSE curve for radiation and radiosensitizer visualizes exposure combinations sufficient for tumor regression. The model and TSE analysis are then tested on xenograft data. The calibrated model indicates that the highest dose of combination therapy increases the time until tumor regrowth 10‐fold. The TSE curve shows that with an average radiosensitizer concentration of 1.0 normalμboldg/boldmboldL the radiation dose can be decreased from 2.2 boldGboldy to 0.7 boldGboldy. Finally, we successfully predict the effect of a clinically relevant treatment schedule, which contributes to validating both the model and the TSE concept.

“…Untreated tumor growth is described using a model with one main compartment and three damage compartments, as described in ref. . The main compartment

V_{1}

represents the volume of proliferating cancer cells and follows logistic growth with exponential growth rate

k_{g}

and tumor capacity parameter

K

.…”

Section: Methodsmentioning

confidence: 99%

“…These initial conditions ensure that untreated tumors grow exponentially with rate

k_{g} - k_{k}

, see the derivation in ref. . The total tumor volume

V_{normalt normalo normalt normala normall}

comprises all six compartments:

V_{normalt normalo normalt normala normall} = V_{1} + V_{2} + V_{3} + V_{4} + U_{1} + U_{2}

…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, TSC values and TSC curves were derived based on a condition of input and output balances for each compartment (i.e., constant tumor stasis) . For the model in Eq.…”

Section: Methodsmentioning

confidence: 99%

“…9 cannot be solved directly, because the radiation rate function

R

t = 0

and

t = T .

…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Model‐Based Evaluation of Radiation and Radiosensitizing Agents in Oncology

Cardilin

Almquist

Jirstrand

et al. 2017

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Modeling restoration of gefitinib efficacy by co‐administration of MET inhibitors in an EGFR inhibitor‐resistant NSCLC xenograft model: A tumor‐in‐host DEB‐based approach

Tosca

Gauderat

Fouliard

et al. 2021

MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non‐small cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitors are currently under study in different phases of development. In this work, a novel tumor‐in‐host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly‐targeted combination therapies. The population DEB‐based tumor growth inhibition (TGI) model well‐described the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinib‐resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB‐TGI model allowed to capture gefitinib anticancer activity enhanced by the co‐administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model‐based comparison of the two MET inhibitors highlighted that S49076 exhibited a greater anticancer effect as well as a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib. In summary, the DEB‐based tumor‐in‐host framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumor‐in‐host DEB‐TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies.

Model‐based prediction of effective target exposure for MEN1611 in combination with trastuzumab in HER2‐positive advanced or metastatic breast cancer patients

Tosca

Borella

Piana

et al. 2023

MEN1611 is a novel orally bioavailable PI3K inhibitor currently in clinical development for patients with HER2‐positive (HER2+) PI3KCA mutated advanced/metastatic breast cancer (BC) in combination with trastuzumab (TZB). In this work, a translational model‐based approach to determine the minimum target exposure of MEN1611 in combination with TZB was applied. First, pharmacokinetic (PK) models for MEN1611 and TZB in mice were developed. Then, in vivo tumor growth inhibition (TGI) data from seven combination studies in mice xenograft models representative of the human HER2+ BC non‐responsive to TZB (alterations of the PI3K/AkT/mTOR pathway) were analyzed using a PK‐pharmacodynamic (PD) TGI model for co‐administration of MEN1611 and TZB. The established PK‐PD relationship was used to quantify the minimum effective MEN1611 concentration, as a function of TZB concentration, needed for tumor eradication in xenograft mice. Finally, a range of minimum effective exposures for MEN1611 were extrapolated to patients with BC, considering the typical steady‐state TZB plasma levels in patients with BC following three 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). A threshold of about 2000 ng·h/ml for MEN1611 exposure associated with a high likelihood of effective antitumor activity in a large majority of patients was identified for the 3‐weekly and the weekly i.v. schedule for TZB. A slightly lower exposure (i.e., 25% lower) was found for the 3‐weekly s.c. schedule. This important outcome confirmed the adequacy of the therapeutic dose administered in the ongoing phase 1b B‐PRECISE‐01 study in patients with HER2+ PI3KCA mutated advanced/metastatic BC.