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Background and Objective <p>Encorafenib is a potent and selective adenosine triphosphate-competitive BRAF V600-mutant kinase inhibitor. Encorafenib is approved for multiple indications in combination with binimetinib or cetuximab. This analysis aimed to develop a global population pharmacokinetics (popPK) model characterizing encorafenib disposition across tumor types.</p> Methods <p>The popPK analysis was based on nine phase 1 to 3 studies in participants with melanoma, colorectal cancer (CRC), non-small cell lung cancer, or other solid tumors, and healthy participants. A total of 1310 participants who received encorafenib as monotherapy or in combination were included. Nonlinear mixed effects modeling was performed using NONMEM v7.5.0. A semi-mechanistic enzyme turnover model was assessed to quantify the autoinduction effect. Stepwise covariate modeling using Perl-speaks-NONMEM (version 5.3.0) evaluated a broad range of covariates.</p> Results <p>A two-compartment model with first-order absorption and concentration-dependent autoinduction successfully characterized the concentration-time profile of encorafenib. Encorafenib apparent clearance (CL/<i>F</i>) was estimated to be 12.2 L/h after the first dose in a typical adult and increased by 186% to 35 L/h at steady state. This model indicates that maximum autoinduction is expected within 14 days of daily dosing (autoinduction half-life 64 h). Age and tumor type (melanoma, metastatic CRC, other [healthy, lung tumors, other solid tumors]) on CL/<i>F</i> and body weight on volume of distribution were significant covariates; these effects were not determined to be clinically significant.</p> Conclusions <p>This model successfully described the PK of encorafenib over time and across tumor types. No dose modifications are suggested on the basis of intrinsic or extrinsic factors evaluated.</p>

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Population Pharmacokinetic Modeling of Encorafenib in Healthy Participants and Patients with BRAF V600-Mutant Solid Tumors: A Semi-mechanistic Autoinduction Model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月12日

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  • Derek Z. Yang,
  • Erik M. Hahn,
  • Joseph Piscitelli,
  • Yazdi K. Pithavala,
  • Jennifer E. Hibma

摘要

Background and Objective

Encorafenib is a potent and selective adenosine triphosphate-competitive BRAF V600-mutant kinase inhibitor. Encorafenib is approved for multiple indications in combination with binimetinib or cetuximab. This analysis aimed to develop a global population pharmacokinetics (popPK) model characterizing encorafenib disposition across tumor types.

Methods

The popPK analysis was based on nine phase 1 to 3 studies in participants with melanoma, colorectal cancer (CRC), non-small cell lung cancer, or other solid tumors, and healthy participants. A total of 1310 participants who received encorafenib as monotherapy or in combination were included. Nonlinear mixed effects modeling was performed using NONMEM v7.5.0. A semi-mechanistic enzyme turnover model was assessed to quantify the autoinduction effect. Stepwise covariate modeling using Perl-speaks-NONMEM (version 5.3.0) evaluated a broad range of covariates.

Results

A two-compartment model with first-order absorption and concentration-dependent autoinduction successfully characterized the concentration-time profile of encorafenib. Encorafenib apparent clearance (CL/F) was estimated to be 12.2 L/h after the first dose in a typical adult and increased by 186% to 35 L/h at steady state. This model indicates that maximum autoinduction is expected within 14 days of daily dosing (autoinduction half-life 64 h). Age and tumor type (melanoma, metastatic CRC, other [healthy, lung tumors, other solid tumors]) on CL/F and body weight on volume of distribution were significant covariates; these effects were not determined to be clinically significant.

Conclusions

This model successfully described the PK of encorafenib over time and across tumor types. No dose modifications are suggested on the basis of intrinsic or extrinsic factors evaluated.