title: Translational Model-Based Strategy to Guide the Choice of Clinical Doses for Antibody-Drug Conjugates.
abstract: This work proposes a model-based approach to help select the phase 1 dosing regimen for the antibody-drug conjugate (ADC) SAR408701 leveraging the available data for 2 other ADCs of the same construct: SAR3419 and SAR566658. First, monkey and human pharmacokinetic (PK) data of SAR566658 and SAR3419 were used to establish the appropriate allometric approach to be applied to SAR408701 monkey PK data. Second, a population pharmacokinetics-pharmacodynamics (PK-PD) model was developed to describe tumor volume evolution following SAR408701 injection in mice. Third, allometric approaches identified for SAR566658 and SAR3419 were applied to SAR408701 monkey PK data to predict the human PK profile. Both SAR566658 and SAR3419 human and monkey PK were best described by a 2-compartment linear model. The relative difference was less than 10% between predicted and observed clearance using allometric exponents of 0.75 and 1, respectively. Tumor volume evolution following SAR408701 injection was best described by a full Simeoni model with a plasma concentration threshold of 4.6 μg/mL for eradication in mice. Both allometric exponents were used to predict SAR408701 PK in human from PK in monkey and to identify the potential effective dosing regimens. This translational strategy may be a valuable tool to design future clinical studies for ADCs, to support selection of the most appropriate dosing regimen, and to estimate the minimal dose required to assure antitumor activity, according to the schedule used.
authors.affiliation: Translational Medicine and Early Development, Sanofi, Alfortville, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Bouillon-Pichault
authors.affiliation: Translational Medicine and Early Development, Sanofi, Alfortville, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Brillac
authors.affiliation: Drug Metabolism & Pharmacokinetics, Sanofi, Alfortville, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Amara
authors.affiliation: Oncology, Sanofi, Vitry-sur-Seine, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Nicolazzi
authors.affiliation: Translational Medicine and Early Development, Sanofi, Alfortville, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fagniez
authors.affiliation: Translational Medicine and Early Development, Sanofi, Alfortville, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Fau
authors.affiliation: Translational Medicine and Early Development, Sanofi, Alfortville, France.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Koiwai
authors.affiliation: Translational Medicine and Early Development, Sanofi, Alfortville, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Ziti-Ljajic
authors.affiliation: Translational Medicine and Early Development, Sanofi, Bridgewater, NJ, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Veyrat-Follet
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D051379:Mice; D008954:Models, Biological; D057170:Translational Research, Biomedical
chemical_list: D018796:Immunoconjugates
keywords: ADC; PK-PD modeling; allometric scaling; translational; tumor volume