Association of Time‐Varying Clearance of Nivolumab With Disease Dynamics and Its Implications on Exposure Response Analysis

Abstract

Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time-varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post-treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure-response (E-R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E-R analysis. The results showed that E-R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E-R or dose-response relationship than the steady-state PK metrics.

Response to “The Role of FcRn in the Pharmacokinetics of Biologics in Patients with Multiple Myeloma”

“…This idea is consistent with our observations and a report by Liu et al 5. on clearance of nivolumab.…”

An Integrated Population Pharmacokinetic Model Versus Individual Models of Depatuxizumab Mafodotin, an Anti‐EGFR Antibody Drug Conjugate, in Patients With Solid Tumors Likely to Overexpress EGFR

“…This finding from population PK analysis is consistent with noncompartment analysis, where subjects with solid tumors had approximately 2‐fold higher clearance as compared with subjects with GBM. Disease status has been reported to have a significant impact on the clearance of monoclonal antibodies in the literature . Body weight was identified as a significant covariate on depatux‐m clearance.…”

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

“…[30][31][32]44,70 Although these changes in clearance were not considered clinically relevant (as per comments in each package insert), recent PK modeling analyses-in several cases prompted by the regulatory authorities-taking into account the time-varying nature of this parameter have shown that clearance changes appear to be associated with response to treatment. 51,56,74,75 Patients who benefited from treatment with nivolumab, pembrolizumab, or atezolizumab with respect to tumor response and improved OS had lower clearance; tumor shrinkage in patients treated with durvalumab was also associated with decreased clearance. One explanation for this observation is that, as disease state improves, a reduction in cachexia would result in lowered catabolism and thus reduced antibody clearance.…”

“…One explanation for this observation is that, as disease state improves, a reduction in cachexia would result in lowered catabolism and thus reduced antibody clearance. 74,75 The mAbs commonly display modest interpatient variability in PK, and population PK is used to identify intrinsic and extrinsic covariates that can explain part of the observed variability. 60 The covariates chosen for investigation focused primarily on intrinsic factors such as sex and age, as well as those relating to disease state (for example, tumor type, tumor burden, and baseline parameters such as performance status, lactate dehydrogenase [LDH], and albumin), which might rationally be expected to differ between patients and so contribute to interpatient PK variability.…”