1. Erdafitinib’s effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer
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Anne‐Gaëlle Dosne, Elodie Valade, Kim Stuyckens, Peter De Porre, Anjali Avadhani, Anne O’Hagan, Lilian Y. Li, Daniele Ouellet, Ruben Faelens, Quentin Leirens, Italo Poggesi, and Juan Jose Perez Ruixo
- Subjects
Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract A population pharmacokinetic (PK)–pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK‐PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once‐daily oral continuous (0.5–12 mg) and intermittent (10–12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib‐related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23–mediated signaling. PK‐PD model‐based simulations were performed to assess the approved PD‐guided dosing algorithm of erdafitinib (8 mg once‐daily continuous dosing, with up‐titration to 9 mg based on phosphate levels [95% maximal serum phosphate concentration. The peak‐to‐trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68–5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate–parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8‐mg with up‐titration to 9‐mg on Days 14–21 maximized the number of patients within the target serum phosphate concentrations (5.5–7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK‐PD model provided a detailed understanding of the erdafitinib concentration‐related phosphate changes over time, which supports erdafitinib's dosing algorithm.
- Published
- 2022
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