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17.11.2021 | Original Article

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

verfasst von: E. M. Tosca, N. Terranova, K. Stuyckens, A. G. Dosne, T. Perera, J. Vialard, P. King, T. Verhulst, J. J. Perez-Ruixo, P. Magni, I. Poggesi

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2022

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Abstract

Purpose

Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated.

Methods

A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats. Data from multiple xenograft studies in mice and rats were analyzed using the Simeoni tumor growth inhibition (TGI) model. The model parameters were used to derive a range of erdafitinib exposures that might inform the choice of the doses in oncology phase 1 trials. Conversion of exposures to doses was based on preliminary PK assessments from the first-in human (FIH) study.

Results

A one-compartment PK disposition model, with linear absorption and dose-dependent clearance, adequately described the PK data in both mice and rats via an allometric scaling approach. The TGI model was able to describe tumor growth dynamics, providing quantitative measurements of erdafitinib antitumor potency in mice and rats. Based on these estimates, ranges of efficacious unbound concentration were identified for erdafitinib in mice (0.642–5.364 μg/L) and rats (0.782–2.565 μg/L). Based on the FIH data, it was possible to transpose exposures into doses and doses of above 4 mg/day provided erdafitinib exposures associated with significant TGI in animals. The findings were in agreement with the results of the FIH trial, in which the first hints of clinical activities were observed at 6 mg.

Conclusion

The successful modeling exercise of erdafitinib preclinical data showed how translational PK-PD modeling might be a tool to help to inform the choice of the doses in FIH studies.

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Titel: A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib
verfasst von: E. M. Tosca
N. Terranova
K. Stuyckens
A. G. Dosne
T. Perera
J. Vialard
P. King
T. Verhulst
J. J. Perez-Ruixo
P. Magni
I. Poggesi
Publikationsdatum: 17.11.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2022
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-021-04370-7

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