Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

Reig-López, Javier; Maldonado, Maria del Mar; Merino-Sanjuán, Matilde; Cruz-Collazo, Ailed; Ruiz-Calderón, Jean F.; Mangas‐Sanjuán, Víctor; Dharmawardhane, Suranganie; Duconge, Jorge

doi:10.3390/pharmaceutics12100975

Cited by 7 publications

(4 citation statements)

References 35 publications

(44 reference statements)

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“…The TGI model successfully predicts the tumor growth in the control groups where animals were dosed with the vehicle for 28 or 27 days (fold error of 3.6% for GDC‐0927 and 3.8% for GDC‐9545). The model parameters λ0 and λ1, governing the exponential and linear growth rate, and the shape factor (Φ) listed in Table 5 were consistent with parameter values previously reported in Her2+ xenograft experiments (Reig‐López et al., 2020), which is not surprising, since both cell lines are hormone receptor‐dependent cell lines.…”

Section: Discussionsupporting

confidence: 93%

“…xenograft experiments (Reig-López et al, 2020), which is not surprising, since both cell lines are hormone receptor-dependent cell lines.…”

Section: Discussionsupporting

confidence: 88%

“…A rare literature example of such PBPK‐PD analysis was recently performed to characterize the anticancer candidate MBQ‐16 (Reig‐López et al., 2020). The authors developed a mouse PBPK‐PD model of MBQ‐16 that successfully described the observed mouse PK data and tumor growth inhibition (TGI).…”

Section: Introductionmentioning

confidence: 99%

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Physiologically‐based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans

Ganti

Sharpnack

et al. 2023

Biopharm & Drug Disp

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GDC‐9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best‐in‐class drug candidate for early‐stage and advanced drug‐resistant breast cancer. GDC‐9545 was designed to improve the poor absorption and metabolism of its predecessor GDC‐0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically‐based pharmacokinetic/pharmacodynamic (PBPK‐PD) models to characterize the relationships between oral exposure of GDC‐9545 and GDC‐0927 and tumor regression in HCI‐013 tumor‐bearing mice, and to translate these PK‐PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose‐ranging xenograft experiments in mice. The established PK‐PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK‐PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK‐PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC‐9545 than GDC‐0927. Additional sensitivity analysis of key parameters in the PK‐PD model demonstrated that the lower efficacious dose of GDC‐9545 is a result of improvements in clearance and absorption. The presented PBPK‐PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.

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Section: Discussionsupporting

confidence: 93%

“…xenograft experiments (Reig-López et al, 2020), which is not surprising, since both cell lines are hormone receptor-dependent cell lines.…”

Section: Discussionsupporting

confidence: 88%

See 1 more Smart Citation

Physiologically‐based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans

Ganti

Sharpnack

et al. 2023

Biopharm & Drug Disp

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“…Our data show that at these concentrations, a formulation of MBQ-167 in Cremaphor/Ethanol (A) was detected in plasma, tumor tissue, and other organs in sufficient levels to act as an effective inhibitor of Rac and Cdc42, and thus, tumor cell viability and migration/invasion (13). Accordingly, pharmacokinetic/pharmacodynamic modeling of these data predict that the observed inhibition of tumor growth in the MDA-MB-231 mammary fatpad tumors in mice following 1 or 10 mg/kg BW of MBQ-167 3Â a week, result in an IC 50 of 0.1 nmol/L, and demonstrates a higher efficacy for inhibiting TNBC growth compared with HER2 þ breast tumors (36).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Rac and Cdc42 Inhibitor MBQ-167 in Triple-negative Breast Cancer

Cruz-Collazo

Ruiz-Calderón

Picon³

et al. 2021

Molecular Cancer Therapeutics

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Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce cancer metastasis, we developed small molecule inhibitors to target the drivers of metastasis, the Rho GTPases Rac and Cdc42. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively; and consequently, inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, and mammosphere growth; induces cell-cycle arrest and apoptosis; and decreases HER2-type mammary fatpad tumor growth and metastasis (Humphries-Bickley and colleagues, 2017). Herein, we used nuclear magnetic resonance to show that MBQ-167 directly interacts with Rac1 to displace specific amino acids, and consequently inhibits Rac.GTP loading and viability in TNBC cell lines. Phosphokinome arrays in the MDA-MB-231 human TNBC cells show that phosphorylation status of kinases independent of the Rac/Cdc42/PAK pathway are not significantly changed following 200 nmol/L MBQ-167 treatment. Western blotting shows that initial increases in phospho-c-Jun and phospho-CREB in response to MBQ-167 are not sustained with prolonged exposure, as also confirmed by a decrease in their transcriptional targets. MBQ-167 inhibits tumor growth, and spontaneous and experimental metastasis in immunocompromised (human TNBC) and immunocompetent (mouse TNBC) models. Moreover, per oral administration of MBQ-167 at 100 mg/kg body weight is not toxic to immunocompetent BALB/c mice and has a half-life of 4.6 hours in plasma. These results highlight the specificity, potency, and bioavailability of MBQ-167, and support its clinical potential as a TNBC therapeutic.

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Application of Physiologically Based Pharmacokinetic and Pharmacodynamic (Pbpk/Pd) Modeling Comprising Transporters

Harwood¹,

Rostami‐Hodjegan²

2022

Drug Transporters

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Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

Cited by 7 publications

References 35 publications

Physiologically‐based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans

Physiologically‐based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans

Efficacy of Rac and Cdc42 Inhibitor MBQ-167 in Triple-negative Breast Cancer

Application of Physiologically Based Pharmacokinetic and Pharmacodynamic (Pbpk/Pd) Modeling Comprising Transporters

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