Nonlinear Mixed-effect Models for Prostate-specific Antigen Kinetics and Link with Survival in the Context of Metastatic Prostate Cancer: A Comparison by Simulation of Two-stage and Joint Approaches

The AAPS Journal
Solène DesméeJérémie Guedj

Abstract

In metastatic castration-resistant prostate cancer (mCRPC) clinical trials, the assessment of treatment efficacy essentially relies on the time to death and the kinetics of prostate-specific antigen (PSA). Joint modeling has been increasingly used to characterize the relationship between a time to event and a biomarker kinetics, but numerical difficulties often limit this approach to linear models. Here, we evaluated by simulation the capability of a new feature of the Stochastic Approximation Expectation-Maximization algorithm in Monolix to estimate the parameters of a joint model where PSA kinetics was defined by a mechanistic nonlinear mixed-effect model. The design of the study and the parameter values were inspired from one arm of a clinical trial. Increasingly high levels of association between PSA and survival were considered, and results were compared with those found using two simplified alternatives to joint model, a two-stage and a joint sequential model. We found that joint model allowed for a precise estimation of all longitudinal and survival parameters. In particular, the effect of PSA kinetics on survival could be precisely estimated, regardless of the strength of the association. In contrast, both simplified ap...Continue Reading

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Citations

Jan 26, 2018·Pharmaceutical Research·M CerouE Comets
Mar 22, 2020·CPT: Pharmacometrics & Systems Pharmacology·Vincent MadelainJérémie Guedj
Jun 20, 2020·Clinical Pharmacology and Therapeutics·Sebastien Benzekry
Jun 14, 2019·Clinical Medicine Insights. Oncology·Alexandre Sostelly, François Mercier
Feb 5, 2021·Proceedings of the National Academy of Sciences of the United States of America·Nadège NéantUNKNOWN French COVID Cohort Investigators and French Cohort Study groups
Jun 17, 2020·Journal of Theoretical Biology·Modibo DiabatéAdeline Samson

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