Erdafitinib’s effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer

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 [<5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >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 covariateparameter 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 concentrationsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Long-Lasting Proteinaceous Nanoformulation for Tumor Imaging and Therapy

“…Thus, this suggested that the application of the nanodrug effectively reduced the off-target side effects of erdafitinib. Patients may develop hyperphosphatemia after the administration of erdafitinib, which would lead to dose reduction or intermittent or permanent treatment interruption . Therefore, this work developed a new strategy to mitigate the side effects of erdafitinib, which might open up the possibility for its broader clinical application.…”

Reinforcement Learning and PK‐PD Models Integration to Personalize the Adaptive Dosing Protocol of Erdafitinib in Patients with Metastatic Urothelial Carcinoma

“…[28][29][30] Despite the promising results, the number of works applied to real clinical scenario is still limited. 24 In this paper, a new framework combining RL and PK-PD modeling was proposed to improve precision dosing of erdafitinib (Balversa, Janssen Pharmaceutical companies), an anticancer compound approved by the US Food and Drug Administration (FDA) for the treatment of metastatic urothelial carcinoma [31][32][33][34] Erdafitinib is characterized by a narrow therapeutic window and high IIV of the response. 32 The serum phosphate concentration, 35 [PO 4 ] serum , is the most important efficacy and toxicity biomarker.…”

“…24 In this paper, a new framework combining RL and PK-PD modeling was proposed to improve precision dosing of erdafitinib (Balversa, Janssen Pharmaceutical companies), an anticancer compound approved by the US Food and Drug Administration (FDA) for the treatment of metastatic urothelial carcinoma [31][32][33][34] Erdafitinib is characterized by a narrow therapeutic window and high IIV of the response. 32 The serum phosphate concentration, 35 [PO 4 ] serum , is the most important efficacy and toxicity biomarker. 31,32,36 In particular, [PO 4 ] serum ≥ 5.5 mg/dL correlated with a better response to treatment, 31 whereas [PO 4 ] serum < 7 mg/dL represents the safety threshold for hyperphosphatemia, the major cause of drug-related adverse events.…”

“…32 The serum phosphate concentration, 35 [PO 4 ] serum , is the most important efficacy and toxicity biomarker. 31,32,36 In particular, [PO 4 ] serum ≥ 5.5 mg/dL correlated with a better response to treatment, 31 whereas [PO 4 ] serum < 7 mg/dL represents the safety threshold for hyperphosphatemia, the major cause of drug-related adverse events. 31 Consequently, erdafitinib administration requires an adaptive-dosing strategy aiming to maintain the [PO 4 ] serum level within its target range (i.e., 5.5, 7 mg/dL).…”

Quantitative approaches to drug safety: The 2022 PSP special issue

“…When bedaquiline is reintroduced after dose interruption, concerns exist about the risk of QT‐prolongation and potential ventricular arrhythmias, and the results presented by the authors demonstrate a potential strategy for safe reintroduction of the drug. Along similar lines, Marco‐Ariño et al 9 use a PopPD model to address pupillary reflex dilation caused by remifentanil, an opioid used as an analgesic during surgery, and Dosne et al 10 use PK/PD modeling for individualized dosing of erdafitinib, a drug that can treat urothelial carcinoma but can cause acute hyperphosphatemia in some patients. Together, these articles demonstrate the centrality of pharmacometrics approaches in ensuring that highly useful drugs do not cause adverse events due to improper dosing.…”