Clemence Pouzin (1)(2), Michel Tod (2), Nathalie Fagniez (1), Laurent Nguyen (1)
(1) Sanofi, Pharmacokinetics Dynamics and Metabolism Department, Chilly-Mazarin, France (2) University of Claude Bernard Lyon 1, Oncology department EMR3738, PKPD modelling unit, Lyon, France
Objectives:
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types. Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC), combining a humanized monoclonal antibody (IgG1) targeting CEACAM5 and DM4, a potent cytotoxic payload. SAR408701 has been administered during a phase I/II clinical trial to patients with advanced solid tumors (https://clinicaltrials.gov/ct2/show/NCT02187848). The administered drug solution is composed of a mixture of conjugated antibodies (species with different payload densities): the drug to antibody ratio (DAR) distribution is heterogeneous and ranges from 0 to 8, with an average DAR in the administered drug of 3.8.
The objectives of the present analysis were to (1) characterize PK of SAR408701 (conjugated antibody), naked antibody (NAB), DM4 and its methylated metabolite (MeDM4, both being active), including DAR measurements, (2) assess the impact of clinically relevant covariates on each entity exposure, (4) compare flat dosing and BSA adjusted dosing regimens and (5) evaluate the impact of various DAR distributions in the administered solution on drug exposure, thanks to a semi-mechanistic population PK model [1; 2].
Methods:
PK data of SAR408701, NAB, DM4 and MeDM4 from 254 patients were included in the analysis (study approved by Medical Ethics Committee). DAR was also characterized in a subset of patients (n=13).
To describe PK of SAR408701 and NAB, species from DAR0 to DAR8 were explicitly represented with two-compartment PK models. Conversion of higher DAR to lower DAR species resulted in a DAR-dependent ADC deconjugation in central compartment and was represented as an irreversible first-order process. Each deconjugation process was assumed to contribute to DM4 formation. DM4 and MeDM4 were modelled successively by one compartment PK models and first order elimination processes.
SAR408701 administered dose was fractioned between each DAR compartments, with administered fractions fixed to values measured in the administered solution. All entities data were fitted simultaneously. The estimation of the nonlinear mixed effect model parameters was performed using SAEM algorithm of MONOLIX software (version 2020R1, Lixoft).
Demographic and pathophysiologic covariates were explored with a sequential approach to avoid interference between covariates effect on SAR408701 and its catabolites. Simulations were performed to evaluate impact of covariates, dosing regimen and DAR distribution on exposure.
Results:
Model parameters were estimated with good precision and model diagnostic plots confirmed good agreement between predicted and observed data for all entities. SAR408701 and NAB distribution volumes were low (as expected for macromolecules) and close to physiological blood volume. Combining central deconjugation and proteolytic clearance, SAR408701 global clearance ranged from 0.587 L/d (for DAR1) to 3.50 L/d (for DAR8), with deconjugation clearance being the major elimination pathway for high DAR species.
Five covariates were included in final PK model: body surface area (BSA), tumor burden, albumin, circulating CEA and gender. Impact was though limited on exposure considering the overall population variability. Simulations supported the current BSA adjusted dosing approach (compared to flat dosing), with less exposure variability in extreme BSA patients.
Simulations of various DAR distributions allowed to support definition of DAR specifications in the administered drug batches to ensure similar drug exposure.
Conclusions:
By integrating mechanistic considerations, this model aimed to improve understanding of SAR408701 complex disposition and deconjugation processes to support drug clinical development.
References:
- Pouzin C, Gibiansky L, Fagniez N, Chadjaa M, Tod M, Nguyen L. Integrated multiple analytes and semi-mechanistic population pharmacokinetic model of tusamitamab ravtansine, a DM4 anti-CEACAM5 antibody-drug conjugate. J Pharmacokinet Pharmacodyn. 2022 Feb 15;
- Pouzin C, Tod M, Chadjaa M, Fagniez N, Nguyen L. Covariate analysis of tusamitamab ravtansine, a DM4 anti-CEACAM5 antibody-drug conjugate, based on first-in-human study. CPT Pharmacomet Syst Pharmacol. 2022 Feb 22;
Reference: PAGE 30 (2022) Abstr 9950 [www.page-meeting.org/?abstract=9950]
Poster: Drug/Disease Modelling - Oncology