Commonality of rituximab pharmacokinetic disposition in nephrotic syndrome and autoimmune cytopenias in chronic lymphocytic leukemia patients

Excerpt

Recently, Counsilman et al. [1] reported for the first time the pharmacokinetic disposition of rituximab in a patient with nephrotic syndrome accompanied by non-selective proteinuria [1]. The pharmacokinetics of rituximab were characterized by a rapid clearance and low serum levels due to urinary loss and excessive distribution of rituximab into pleural effusion and ascites [1]. The authors postulated the existence of other possible mechanisms that may possibly explain the rapid clearance of rituximab. In this patient, the half-life of rituximab was reported to be less than a day [1]. The use of population pharmacokinetic modeling that factored in elimination and distributive sites enabled delineation of the pharmacokinetic profile of rituximab in the patient with nephrotic syndrome [1]. Interestingly, Mo et al. reported the pharmacokinetics of rituximab in autoimmune cytopenias exhibited by chronic lymphocytic leukemia (CLL) patients; where a rapid clearance of rituximab was observed in all the patients during the first cycle of treatment rendering undetectable trough concentrations of rituximab [2]. However, after each subsequent cycle of rituximab, the clearance appeared to relatively and progressively slow down, such that by the fourth cycle of rituximab dosing the half-life improved by almost eightfold from an average of 27 h (cycle 1) to approximately 199 h (cycle 4) [2]. It was noted that tumor burden and absolute lymphocyte counts were inversely correlated with the clearance of rituximab [2]. Comparing the two studies, it is apparent that there is a commonality in the pharmacokinetic disposition of rituximab—the early treatment phase of autoimmune cytopenias and nephrotic syndrome show a rapid clearance of rituximab. It can be deduced that disease state and modified physiological factors both contributed to the observed rapid clearance of rituximab. Hence, factors such as renal elimination, enhanced distribution into ascites/pleural effusion, increased penetration into tumors, and lymphocyte binding may need to be factored into the dosing decision for optimization of the pharmacokinetics of rituximab. Another area of particular importance may be related to the disposition of rituximab via the biliary excretory process, as clinical improvement has been reported in patients with primary biliary cirrhosis. …