Pharmacokinetic and Pharmacodynamic Modeling of Hedgehog Inhibitor TAK-441 for the Inhibition of Gli1 messenger RNA Expression and Antitumor Efficacy in Xenografted Tumor Model Mice

Abstract

6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo [3,2-c]pyridine-2-carboxamide (TAK-441) is a potent, selective hedgehog signaling pathway inhibitor that binds to Smo and is being developed for the treatment of cancer. The objectives of these studies were to explore the possibility of establishing of a link between the pharmacokinetics of TAK-441 and the responses of Gli1 mRNA in tumor-associated stromal or skin cells and the antitumor effect of hedgehog inhibition. To this end, we built pharmacokinetic and pharmacodynamic models that describe the relationship of the concentrations of TAK-441 plasma to the responses of Gli1 mRNA in the tumor (target) and skin (surrogate) and to tumor growth inhibition in mice bearing xenografts of human pancreatic tumors (PAN-04). The responses of Gli1 mRNA and tumor growth were described by an indirect response model and an exponential tumor growth model, respectively. The IC 50 values for Gli1 mRNA inhibition in the tumor and skin by TAK-441 were estimated to be 0.0457 and 0.113 mg/ml, respectively. The IC 90 value for tumor growth inhibition was estimated to be 0.68 mg/ml. These results suggest that a >83% inhibition of Gli1 mRNA expression in the skin or a >94% inhibition of Gli1 mRNA expression in the tumor would be required to sufficiently inhibit (>90%) hedgehog-related tumor growth in the xenografted model mice. We conclude that Gli1 mRNA expression in the tumor and skin could be a useful biomarker for predicting the antitumor effect of hedgehog inhibitors

Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

“…The starting dose was selected on the basis of preclinical findings suggesting that 50 mg daily would be pharmacologically active with an acceptable safety profile. Maximal inhibition of pancreatic xenograft tumors in mice was achieved at a dose of 10 mg/kg (17), which is equivalent to 30 mg/m 2 and corresponds to a human dose of 50 mg/day (based on a human body surface area of 1.7 m 2 ). On day 1 of cycle 1, patients received a single dose of TAK-441, followed by a 1-week washout period to assess the single-dose pharmacokinetic profile; dosing resumed on day 8 and continued daily until day 28.…”

“…TAK-441 is highly specific; assayed against a panel of 126 enzymes and transporters, 10 mmol/L TAK-441 demonstrated >50% inhibition of only the human phosphodiesterase type 4 inhibitor (PDE4) and the human dopamine transporter (Takeda Pharmaceuticals International Co., data on file). Strong antitumor activity was seen in a medulloblastoma murine allograft model harboring a Ptch1 mutation, and in pancreatic, ovarian, pancreas, and colon xenograft models, suggesting activity against both ligand-independent (mutationally driven) and ligand-dependent (via autocrine and paracrine signaling) mechanisms of Hh-driven cancer growth (16,17). Preclinical toxicology evaluation demonstrated reversible bone marrow suppression, weight loss, gastrointestinal disturbances, and blood chemistry imbalances.…”

Developing Exposure/Response Models for Anticancer Drug Treatment: Special Considerations

“…In the absence of effective drug treatment, net tumor growth (the balance of growth and natural cell death) can be described by an exponential function, exponential growth that can be inhibited by tumor volume, or some combination of linear and exponential functions . First order (exponential) net growth is represented in the following equation: where k ng is the first order rate constant (days −1 ).…”

“…For tumor growth data showing a plateau phase, various models have been proposed . Kogame et al . proposed a model including first order growth and inhibition of tumor growth by its tumor volume, which is described as: where TG 50 is the tumor size that inhibits tumor growth by 50% and is based on the underlying physiology where local conditions can limit tumor growth …”

“…The addition of anticancer drug treatment is expected to inhibit tumor growth. In a simple growth model, the model assumes that the exponential growth of the xenograft can be reduced by a drug effect either directly or through inhibition of the target . The cell cycle phase nonspecific model assumes exponential growth, and that drug acts by a first‐order rate constant .…”