Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice
Abstract
Aim: The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor (EGFR-TKI). Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition.
Methods: Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 (50 or 150 mg·kg−1·d−1, ig) or vehicle for 18 d. The pharmacokinetics (PK) and pharmacodynamics (PD) of TM208 were evaluated.
Results: The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC50 (55.9 μg/L), as well as three parameters ('a' of 27.2%, 'b' of 2730%, 'c' of 0.58 h−1) denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/transit compartment model with estimated parameters associated with tumor growth characteristics kng(0.282 day−1), drug potency kTM208 (0.0499 cm3/day) and the kinetics of tumor cell death k1 (0.141 day−1), which provided insight into drug mechanisms and behaviors.
Conclusion: The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance.
Keywords:
TM208; dithiocarbamates; EGFR-TKI; human breast cancer; breast cancer xenograft mice; PK/PD models; drug resistance; model simulation
Methods: Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 (50 or 150 mg·kg−1·d−1, ig) or vehicle for 18 d. The pharmacokinetics (PK) and pharmacodynamics (PD) of TM208 were evaluated.
Results: The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC50 (55.9 μg/L), as well as three parameters ('a' of 27.2%, 'b' of 2730%, 'c' of 0.58 h−1) denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/transit compartment model with estimated parameters associated with tumor growth characteristics kng(0.282 day−1), drug potency kTM208 (0.0499 cm3/day) and the kinetics of tumor cell death k1 (0.141 day−1), which provided insight into drug mechanisms and behaviors.
Conclusion: The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance.