Erdafitinib, a potent oral fibroblast growth factor receptor inhibitor, is a low extraction ratio drug highly bound to alpha-1-acid glycoprotein (AGP) with free fraction (fu ) varying across populations. This analysis aimed to characterize the impact of plasma protein binding on erdafitinib pharmacokinetics (PK). Plasma protein-binding data (fu , AGP, albumin) and PK parameters were pooled from 6 phase 1 studies in healthy participants and 1 first-in-human study in patients with cancer. Binding kinetics were characterized using a nonlinear mixed-effects model. Mean (coefficient of variation, CV%) fu was 0.510% (39.4%) for healthy participants and 0.316% (64.0%) for patients, with a 2.1-fold higher AGP and 10% lower albumin. Linear binding of erdafitinib to AGP and albumin was observed, with >1000-fold higher binding constant for AGP than albumin (17.6 vs 0.017 µM-1 ). The fu decreased with increasing AGP in a nonlinear relationship. Despite its abundance in plasma relative to AGP, albumin contributed to <4% of the overall binding of erdafitinib (1.8% in patients; 4.0% in healthy participants). The AGP-binding constant was 68.0% lower in predose (spiked) versus postdose (ex vivo) samples. Total oral clearance was generally proportional to the fu and higher in healthy participants than in patients, consistent with the differences in AGP. Correcting for fu accounted for the majority of the relationship between oral clearance and fu as expected with a low extraction ratio drug. Characterizing free erdafitinib concentrations is critical to accounting for differences in fu and to further investigating its clinical relevance.
Keywords: alpha-1-acid glycoprotein; erdafitinib; pharmacokinetics; plasma protein binding.
© 2019, The American College of Clinical Pharmacology.