FIGON DMD

Bram Agema

Erasmus MC

Bram Agema’s research enables individualized dosing at the start of treatment

Bram is a pharmacist currently performing his doctoral research at the Erasmus Medical Centre Cancer Institute under supervision of professor Mathijssen, professor Koch and dr. Koolen. Bram utilizes mathematical pharmacometric models to elucidate pharmacokinetic/pharmacodynamic (PK/PD) relationships. His work focuses on predicting drug exposure for individual patient and using this to develop personalized dosing strategies for various cancer treatments. This way, it is ensured that each patient receives the optimal dose and avoids toxicities while maximizing efficacy.

Presentation: Prospective Implementation of Model-Informed Precision Dosing of Tamoxifen

Abstract: After surgical removal of breast cancer, these patients remain at a high risk of breast cancer recurrence. To lower this risk, we treat patients with hormone receptor positive breast cancer with tamoxifen, an estrogen receptor antagonist. Tamoxifen primarily acts through its active metabolite, endoxifen, which is activated mainly through CYP2D6 enzymes. Although patients are typically classified categorically based on the highly polymorphic CYP2D6 genotype, we expressed CYP2D6 activity on a more sensitive continuous scale using a cohort of over 500 patients. This continuous CYP2D6 activity scale and other factors affecting the tamoxifen-to-endoxifen conversion rate were incorporated into a population pharmacokinetic (PK) model.

Using this model, we developed a novel dosing strategy to ensure patients are adequately exposed to endoxifen from the start of treatment. Subsequently, we performed a prospective implementation study involving 106 patients. Our study demonstrated that the model effectively identifies patients adequately treated with the standard dose of 20 mg (7.2% below target vs. 5.2% in the historical cohort). It also identifies patients needing a dose increase to 30 mg (23.5% vs. 44.1%) or 40 mg (0% vs. 87.5%), and those who do not achieving adequate exposure despite being treated with the highest registered dose (53.3% below target). All these patients were identified prior to starting tamoxifen treatment.

To conclude, we successfully performed the first model-informed precision dosing study in the landscape of solid tumours and demonstrated its added value.