Higher Doses of Rituximab May Be Required for Patients with CLL as Compared to NHL Based On Population Pharmacokinetic (PK) Modeling.
Authors: Li Jing , Zhi Jianguo , Wenger Michael K. , Valente Nancy , Visich Jennifer 
Published: October 2019

Abstract
Abstract 1742
Poster Board I-768

Introduction
In the randomized Phase III study REACH, the combination of rituximab (R) (375 mg/m2 cycle 1, 500 mg/m2 cycles 2-6) and fludarabine (F) (25mg/m2 X 6 cycles) and cyclophosphamide (C) (250 mg/m2 X6 cycles) was shown to improve clinical response and prolong PFS in patients with relapsed/refractory Chronic Lymphocytic Leukemia (CLL) compared with F and C alone. The use of 500 mg/m2 as the dose of R in R-FC was guided by previous published data in CLL patients treated with R monotherapy demonstrating a probable dose-response relationship of a higher response rate at the higher dose levels (O'Brien JCO 2001, Byrd JCO 2001) and also by the data of high number of circulating malignant cells in CLL population (characteristic of CLL) which indicated that R might exhibit a higher clearance rate in CLL compared to observed clearance rates in NHL. Prior to the REACH study, the pharmacokinetics (PK) of R have not been thoroughly studied in the CLL population. As sub-study in REACH trial, a complete PK analysis of R was performed in CLL patients using a population PK analysis. This approach allowed not only the characterization of R PK in CLL patients, but also allowed for an opportunity to perform comparison of the PK differences between indications (CLL and NHL) and provided data-driven validation for the need of high R in CLL patients.

Patients and Methods
The PK of R were described with plasma concentrations from 21 CLL patients who received R-FC, using nonlinear mixed-effects modeling (NONMEM VI) software. A two-compartment model with time-varying clearance was validated using a bootstrap and visual predictive check method. The concentration vs. time profiles after given different dosages of R in NHL and CLL patients were predicted using the final models based on the observed data.

Results
R concentration data in CLL patients were well described by a two-compartment model with time-varying clearance, which has been used to describe R concentration data in NHL. Total clearance is comprised of two terms, a non-specific clearance pathway (CL1), which remains unchanged throughout treatment, and a specific clearance pathway (CL2) that decreases following a first-order decay rate from its initial value following the first infusion. The term Kdes represents the actual rate of change from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1). The typical population estimates of R nonspecific clearance (CL1), and central compartment volume of distribution (V1) are similar between CLL and NHL (171 vs. 138 mL/day; 2310 vs. 2710 mL, respectively).
However, the specific clearance (CL2) in CLL was much faster than that in NHL (1280 vs. 577 mL/day), and the rate of change (Kdes) from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1) is two times lower for CLL patients compared to NHL patients (0.024 vs. 0.046 /day) and this suggests that it takes longer time for receptor saturation for CLL patients compared to NHL patients. The results of the simulation exercise showed that in the early cycles of the R-FC regimen, trough concentrations (Ctrough) and drug exposure (AUC) in CLL patients given 500 mg/m2 would be lower than those for NHL patients given 375 mg/m2 dose regimen. By the final cycles, the Ctrough and AUC of R are similar in NHL given 375 mg/m2 and CLL given 500 mg/m2.

Conclusions
Retrospective population PK analysis of R in CLL patients using non linear mixed effect modeling confirmed an increased R clearance during the early cycle of treatment as compared to NHL patients. This increased clearance is potentially due to a higher number of malignant cells in circulation for CLL patients, thus a larger dominance of the faster receptor-mediated clearance component in these patients, which overcome the lower CD20 density in CLL. The dose regimen of 500mg/m2 in CLL patients allows for reaching steady state AUC which is similar to the steady state AUC achieved with doses of 375mg/m2 given in NHL patients.

Disclosures
Li: Genentech: Employment. Zhi:Hoffmann-La Roche Inc.: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment. Valente:Genentech: Employment, Equity Ownership. Visich:Genentech: Employment.