Abstract 295P
Background
Tucatinib, an orally administered selective small molecule HER2 inhibitor, was approved by the Food and Drug Administration and Swissmedic for the treatment of patients with HER2-positive metastatic breast cancer, including patients with brain metastasis. To quantitatively understand the CNS penetration, a PBPK model for predicting the CNS PK of tucatinib in patients was developed and verified.
Methods
Tucatinib transcellular permeability and interaction with efflux transporters were determined using MDCKII cell lines. A whole-body PBPK model integrated with a 4-compartment permeability-limited brain model was developed and verified for predicting tucatinib concentration-time profiles in the plasma, cerebrospinal fluid, brain, and brain tumors. Target engagement ratio (TER), defined as the ratio of brain or tumor steady-state average concentration (Css,ave) of unbound drug to the IC50 (3.3 ng/mL) for inhibition of HER2 kinase, was used as a crude predictor of efficacy.
Results
Tucatinib showed high passive permeability (Papp, 12.6×10-6 cm/s). It was a substrate for ABCB1 (net efflux ratio, 13.8) and ABCG2 (7.7). Following 300 mg twice daily dosing for 21 days, the predicted population mean unbound tucatinib Css,ave in the normal brain was 5.37 ng/mL (TER, 1.6), and the mean unbound brain-to-unbound plasma concentration ratio (Kp,uu) was 0.47. Its penetration was increased in brain tumors: unbound tucatinib Css,ave was predicted to be 15.6 ng/mL (TER, 4.7) with Kp,uu of 1.37 in brain tumors with pH 6.8 and reduced ABCB1 and ABCG2 at the disrupted blood-brain barrier (BBB).
Conclusions
The PBPK modeling suggests that tucatinib could achieve sufficient pharmacologically active concentrations for HER2 inhibition not only in brain tumor metastases with a disrupted BBB but also in infiltrating tumor regions behind an intact BBB, key to effective systemic treatment of brain metastases. Physicochemical and PK properties of tucatinib enabled it to penetrate in CNS. This study provides quantitative and mechanistic insights into the outcome of the HER2CLIMB trial demonstrating clinical efficacy of tucatinib in patients with breast cancer brain metastasis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Seattle Genetics Inc.
Funding
Seattle Genetics Inc.
Disclosure
A.J. Lee: Shareholder/Stockholder/Stock options, Full/Part-time employment: Seattle Genetics. V. Kumar: Shareholder/Stockholder/Stock options, Full/Part-time employment: Seattle Genetics. S.C. Alley: Shareholder/Stockholder/Stock options, Full/Part-time employment: Seattle Genetics. S. Peterson: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Seattle Genetics. All other authors have declared no conflicts of interest.