Mechanistically Coupled PK (MCPK) Model to Describe Enzyme Induction and Occupancy Dependent DDI of Dabrafenib Metabolism.

Marco Albrecht,Yuri Kogan,Dagmar Kulms,Thomas Sauter

doi:10.3390/pharmaceutics14020310

Abstract

Dabrafenib inhibits the cell proliferation of metastatic melanoma with the oncogenic BRAF(V600)-mutation. However, dabrafenib monotherapy is associated with pERK reactivation, drug resistance, and consequential relapse. A clinical drug-dose determination study shows increased pERK levels upon daily administration of more than 300 mg dabrafenib. To clarify whether such elevated drug concentrations could be reached by long-term drug accumulation, we mechanistically coupled the pharmacokinetics (MCPK) of dabrafenib and its metabolites. The MCPK model is qualitatively based on in vitro and quantitatively on clinical data to describe occupancy-dependent CYP3A4 enzyme induction, accumulation, and drug–drug interaction mechanisms. The prediction suggests an eight-fold increase in the steady-state concentration of potent desmethyl-dabrafenib and its inactive precursor carboxy-dabrafenib within four weeks upon 150 mg b.d. dabrafenib. While it is generally assumed that a higher dose is not critical, we found experimentally that a high physiological dabrafenib concentration fails to induce cell death in embedded 451LU melanoma spheroids.

Highlights

Melanoma is a cancer type that develops from the pigment-producing melanocytes within the skin
The biochemical reaction network allows the competitive binding of CYP3A4 by dabrafenib and ketoconazole with a DDI effect based on binding capacity
The carbo-dabrafenib concentration increases slightly instead to decline from day 18 to day

Summary

Introduction

Melanoma is a cancer type that develops from the pigment-producing melanocytes within the skin. Metastatic melanoma was considered refractory to treatment with a 3-year survival below 10%. A better understanding of the genetic alterations in metastatic melanoma cells has fundamentally changed systemic therapy and significantly improved the prognosis of patients. The serine-threonine kinase BRAF represents an integral component of the mitogen-activated RAF-MEK-ERK signal transduction pathway [1,2]. Activating mutations of the proto-oncogene BRAF (mutBRAF/wtNRAS, ∼60% of patients) lead to uncontrolled tumor growth [3]. Combinations of mutBRAF inhibitors plus MEK inhibitors are currently accredited in the clinic to treat mutBRAF melanoma, showing a disease control rate of ∼95% and improved median survival [4,5]. The vast majority of patients acquire resistance, resulting in tumor relapse

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