Clinical pharmacokinetics of MabThera

Higher serum concentrations of MabThera have been shown to correlate with response
Serum levels of MabThera have been shown to be dose-dependent over the 10 500 mg/m2 range, given as an intravenous infusion (Maloney et al 1994). The recommended dose was initially established in patients with NHL as 375 mg/m2 administered weekly for four weeks (Maloney et al 1997a; Maloney et al 1997b). Data from 14 patients with NHL receiving this recommended therapeutic regimen show that the peak plasma concentration increases from 206 mg/L after the first infusion to 465 mg/L following the fourth infusion (Berinstein et al 1998), with an associated decrease in clearance from 38.2 mL/h to 9.2 mL/h, resulting in accumulation of MabThera; the area under the concentration versus time curve increases from 16,320 mg/Lh after the first infusion to 86,125 mg/Lh after the fourth. Notably, this accumulation is not associated with increased toxicity and is reflected by an increase in the terminal elimination MabThera half-life from 3.2 days following a single infusion to 8.6 days after the fourth. MabThera was still detectable at a median concentration of 20.3 mg/L (range 0.0 96.8 mg/L) in 63% of 116 evaluable patients 3 months following completion of therapy and remained detectable in 11.2% of evaluable patients after 6 months.

A single infusion of MabThera (250 or 500 mg/m2) administered on day 0 depletes peripheral B-lymphocytes by ~90% within 3 days. Serum concentrations of MabThera have been shown to correlate with clinical response (Berinstein et al 1998; Maloney et al 1997a; Maloney et al 1997b; Tobinai et al 2004), with responders having significantly higher median serum concentrations than non-responders throughout the 4-week treatment period (p<0.01).

Peripheral B-lymphocyte count is reduced by approximately 90% within 3 days of MabThera infusion