Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis.
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.
Food and Drug Administration, Silver Spring, Maryland, USA.
C
C
Liu
Food and Drug Administration, Silver Spring, Maryland, USA.
J
J
Yu
Food and Drug Administration, Silver Spring, Maryland, USA.
H
H
Li
Food and Drug Administration, Silver Spring, Maryland, USA.
J
J
Liu
Food and Drug Administration, Silver Spring, Maryland, USA.
Y
Y
Xu
Food and Drug Administration, Silver Spring, Maryland, USA.
P
P
Song
Food and Drug Administration, Silver Spring, Maryland, USA.
Q
Q
Liu
Food and Drug Administration, Silver Spring, Maryland, USA.
H
H
Zhao
Food and Drug Administration, Silver Spring, Maryland, USA.
J
J
Xu
Food and Drug Administration, Silver Spring, Maryland, USA.
V E
VE
Maher
Food and Drug Administration, Silver Spring, Maryland, USA.
B P
BP
Booth
Food and Drug Administration, Silver Spring, Maryland, USA.
G
G
Kim
Food and Drug Administration, Silver Spring, Maryland, USA.
A
A
Rahman
Food and Drug Administration, Silver Spring, Maryland, USA.
Y
Y
Wang
D000465:Algorithms; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016022:Case-Control Studies; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D000077594:Nivolumab; D011153:Population; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab