Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

Abstract

The anti-CD20 antibody rituximab (RTX; Rituxan®, MabThera®) was the first anti-cancer antibody approved by the US Food and Drug Administration in 1997 and it is now the most-studied unconjugated therapeutic antibody. The knowledge gained over the past 15 y on the pharmacodynamics (PD) of this antibody has led to the development of a new generation of anti-CD20 antibodies with enhanced efficacy in vitro. Studies on the pharmacokinetics (PK) properties and the effect of factors such as tumor load and localization, antibody concentration in the circulation and gender on both PK and clinical response has allowed the design of optimized schedules and novel routes of RTX administration. Although clinical results using newer anti-CD20 antibodies, such as ofatumumab and obinutuzumab, and novel administration schedules for RTX are still being evaluated, the knowledge gained so far on RTX PK and PD should also be relevant for other unconjugated monoclonal antibody therapeutics, and will be critically reviewed here.

Keywords: B-NHL; CLL; FcRn; FcγRs; pharmacodynamics; pharmacokinetics; rituximab.

Figure 1. Possible mechanisms of action of RTX. (A) immune mediated. (B) direct mechanisms. (C) vaccine effect

Figure 2. Major types of binding of RTX that affect PK and PD. (A) Specific binding to CD20 target takes place via Fab, leads to intracellular signaling and mAb metabolism. CD20 binding is saturable. (B) Non-specific binding of RTX includes binding to (1) FcγRs which leads to activation of immune cells (ADCC, phagocytosis) and mAb metabolism, (2) FcRn, which is non saturable and plays a major role antibody PK, and (3) C1q which activates CDC.

Figure 3. Interaction between IgG and FcRn. The mechanism by which IgG is taken up by cells (pinocytosis), binds inside the cell to FcRn in the acidic endosomes and is either recycled to the cell surface, transcytosed across the cell or degraded in lysosomes is shown.

Figure 4. Biphasic PKs of RTX. The model shows high clearance by specific binding /to CD20) which, after saturation, leads to low clearance through non-specific binding via FcγR (RES)

Figure 5. Model of mAb absorption and clearance after i.v. or s.c. administration. Absorption and clearance pathways are shown. Adapted from ref. .

Figure 6. Model of RTX PK after multiple dosing. C_max, C_trough, AUC and steady-state, reached after about 5 cycles, are shown.

Figure 7. Model of RTX PK with 21 d vs. 14 d cycles. The model shows that RTX levels > 25 µg/ml are maintained for a longer period of time when RTX is administered every 21 d (red) rather than every 14 d (blue). Adapted from ref. .