Semimechanistically Based Modeling of Pembrolizumab Time-Varying Clearance Using 4 Longitudinal Covariates in Patients With Non–Small Cell Lung Cancer

Abstract

Time-varying clearance (CL) has been recently recognized in U.S. Food and Drug Administration drug labels for oncology monoclonal antibodies. Pembrolizumab population CL at steady state decreased about 20% from the first dose, and individual CL changes varied from 75% decrease to 25% increase, which were correlating with disease conditions. From mechanism of action perspective, this research explored the longitudinal covariate effect on pembrolizumab CL based on data from a phase II/III clinical trial in patients with nonesmall cell lung cancer. Time courses of sum of the longest tumor dimensions, lymphocyte count, albumin, and lactate dehydrogenase were first characterized separately, and the post hoc parameters of each individual patient were fixed in the subsequent semimechanistically based modeling analysis. Pembrolizumab time-varying CL was assumed to be associated with the patient's sum of the longest tumor dimensions, lymphocyte count, albumin, and lactate dehydrogenase, and tumorrelated pembrolizumab CL was assumed to be a fraction of total pembrolizumab CL in the semimechanistically based modeling.

Drug‐Disease Interaction and Time‐Dependent Population Pharmacokinetics of Isatuximab in Relapsed/Refractory Multiple Myeloma Patients

“…For instance, a patient who quickly responds may present a sharp decrease of CL at the early stage of the treatment, thereafter CL decrease may slow down over the treatment course, and ultimately increase in the later treatment stage as the patient relapses. Li et al 24 provided a mechanistic based dynamic model for pembrolizumab CL enabling multidirectional change for a given patient. The change of tumor size, lymphocyte count, albumin, and lactate dehydrogenase were significantly correlated with the change in pembrolizumab CL; the time-course of tumor size showing the highest correlation.…”

“…The change of tumor size, lymphocyte count, albumin, and lactate dehydrogenase were significantly correlated with the change in pembrolizumab CL; the time-course of tumor size showing the highest correlation. 24 For isatuximab, longitudinal variation of M-protein can be used as a surrogate of both tumor burden and disease evolution. Longitudinal changes of serum M-protein were well-predicted by classical PK/pharmacodynamic (PD) modeling and this last model was used to support dose finding rationale before phase III initiation.…”

Nivolumab Clearance Is Stationary in Patients With Resected Melanoma on Adjuvant Therapy: Implications of Disease Status on Time‐Varying Clearance

“…Nivolumab clearance (CL) has been shown to decrease with time, with ~ 25% maximum reduction within 3 months after nivolumab treatment . This change in CL after treatment has also been reported for other checkpoint inhibitors and is believed to be associated with improved disease status . Additionally, baseline nivolumab CL was different among tumor types, with values 20% higher and 25% lower in patients with gastric cancer and classical Hodgkin's lymphoma, respectively, compared with patients with NSCLC or MEL…”

Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia

“…In analyzing parent and metabolite PK data, simultaneous and sequential approaches have both been used as valid methods. [15][16][17][18] PK data included in this analysis were derived only from studies in which quizartinib was orally administered. Therefore, estimation of both F MET (parent-to-metabolite conversion fraction) and metabolite central compartment parameters (CL m and V m ) is not feasible.…”