Population Pharmacokinetics of Total and Free Erdafitinib in Adult Healthy Volunteers and Cancer Patients: Analysis of Phase 1 and Phase 2 Studies

Abstract

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single‐ and multiple‐dose administration, to understand clinically relevant covariates, and to quantify the inter‐ and intraindividual variability in erdafitinib PK. An open, linear, 3‐compartment disposition model with first‐order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent. After oral administration, erdafitinib was rapidly absorbed, with a time to maximum concentration between 2 and 4 hours. In patients, erdafitinib total apparent oral clearance was 0.200 L/h (median free fraction = 0.24%), and the effective terminal half‐life of total drug was 76.4 hours. Interindividual variability in PK parameters was moderate for oral clearance and central volume of distribution, and large for absorption rate and peripheral volume of distribution. Sex and renal function were significant covariates on free oral clearance, while weight, sex, and α1‐acid‐glycoprotein were significant on oral central volume of distribution. Age, race, and mild hepatic impairment were not significant covariates of erdafitinib exposure. Given that the magnitude of the covariate effects were within 25% of reference values and that the recommended dosing regimen of erdafitinib comprises individual dose up‐titrations and reductions based on presence or absence of toxicities, the clinical relevance of the investigated covariates is expected to be limited, and no dose adjustments are warranted.

A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib

“…In this case, Fig. 4 A Simulations of erdafitinib unbound concentrations at relevant clinical dosing regimens (6, 8, 9 mg/day or 10 mg 7-dayson/7-days-off) obtained by the pop PK model [25] assuming AGP = 1.24 g/L. The pink and blue bands mark the regions of effica-cious concentrations predicted from the mouse and rat model, respectively.…”

“…Erdafitinib pharmacokinetics in animal models are characterized by high total plasma clearances, which were found to be dose-dependent [23]. The binding to plasma proteins, which ranged from 86.3 to 97.8% across preclinical species and up to 99.62% in human subjects [24], was an important factor for modeling and scaling the PK behaviors of the drug [25]. During preclinical development, multiple studies in immune-deficient rodents bearing tumors derived from diverse human cancer cell lines with FGFR alterations were conducted.…”

Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma

“…Area under the curve of erdafitinib plasma concentration over time (AUC) was also evaluated as a biomarker of efficacy and safety endpoints. Serum PO4 and erdafitinib AUC were derived from previously developed population PK and PK-PD models [ 13 ], which were fitted to the available data to derive individual PK and PD parameters for every patient.…”

“…For efficacy endpoints (OS, PFS and ORR), the exposure metric obtained for each patient was the PK-PD model[ 13 ]-predicted average daily serum PO4 concentration up to the day of first response assessment (i.e., 6 weeks per the study protocol), PO4 ave,6 weeks . In addition, for the OS and PFS analyses, average daily serum PO4 concentration was also computed for each week to investigate whether taking into account PO4 changes over time in a more granular manner better-predicted efficacy.…”

“…Understanding the relationship between serum PO4 concentration and response/safety is important to optimize dosing regimens and assess the benefit-risk profile. The relationships between erdafitinib doses and erdafitinib plasma concentrations [ 13 ], as well as between erdafitinib plasma concentrations and serum PO4 concentrations [ 14 ], have been characterized using a population PK-PD model. In this study, using data from study BLC2001 [ 12 ], we performed exposure–response (ER) analyses that explored the relationships between serum PO4 concentrations and selected clinical endpoints of efficacy and safety in patients with locally advanced or mUC with certain FGFR genetic alterations.…”