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27.04.2021 | Original Article

Time-dependent population PK models of single-agent atezolizumab in patients with cancer

verfasst von: Mathilde Marchand, Rong Zhang, Phyllis Chan, Valerie Quarmby, Marcus Ballinger, Nitzan Sternheim, Benjamin Wu, Jin Y. Jin, René Bruno

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2021

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Abstract

Purpose

The time-varying clearance (CL) of the PD-L1 inhibitor atezolizumab was assessed on a population of 1519 cancer patients (primarily with non-small-cell lung cancer or metastatic urothelial carcinoma) from three clinical studies.

Methods

The first step was to identify the baseline covariates affecting atezolizumab CL without including time-varying components (stationary covariate model). Two time-varying models were then investigated: (1) a model allowing baseline covariates to vary over time (time-varying covariate model), (2) a model with empirical time-varying Emax CL function.

Results

The final stationary covariate model included main effects of body weight, albumin levels, tumor size, anti-drug antibodies (ADA) and gender on atezolizumab CL. Both time-varying models resulted in a clear improvement of the data fit and visual predictive checks over the stationary model. The time-varying covariate model provided the best fit of the data. In this model, the main driver for change in CL over time was variations in albumin level with an increase in serum albumin (improvement in a patient’s status) mirroring a decrease in CL. Time-varying ADAs had a small impact (9% increase in CL). None of the covariates impacted atezolizumab CL by more than ± 30% from median. The estimated maximum decrease in CL with time was 22% with the Emax model.

Conclusion

The overall impact of covariates on atezolizumab CL did not warrant any change in atezolizumab dosing recommendations. The results support the hypothesis that variation in atezolizumab CL over time is associated with patients’ disease status, as shown with other checkpoint inhibitors.

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Titel: Time-dependent population PK models of single-agent atezolizumab in patients with cancer
verfasst von: Mathilde Marchand
Rong Zhang
Phyllis Chan
Valerie Quarmby
Marcus Ballinger
Nitzan Sternheim
Benjamin Wu
Jin Y. Jin
René Bruno
Publikationsdatum: 27.04.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2021
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-021-04276-4

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Time-dependent population PK models of single-agent atezolizumab in patients with cancer