Phamacokinetics (PK) Substudy of Rituximab in a Prospective Clinical Trial for Pediatric Chronic Immune Thrombocytopenic Purpura (cITP).

Rationale: Rituximab dosing in pediatric patients is derived from body surface area-based “standard” adult lymphoma regimens. PK data for rituximab in children are lacking.

Methods: We evaluated serum rituximab levels in a subset of 36 children and adolescents with severe cITP treated on a prospective phase I/II study. Patients received four weekly infusions, 375mg/m²/dose. Trough and 30-minute, 24- and 48-hour (hr) post-infusion levels were obtained with doses 1 and 4, and 7 days after dose 1. PK parameters were obtained separately for each patient at the 1-wk and 4-wk infusions by fitting a two-compartment model. Two-factor analysis of variance was employed to compare parameters between younger (2–9 years) and older (10–18 years) subjects and between responders and non-responders at the two infusion times.

Results: Fourteen patients had PK measurements at week 1 and eleven at week 4 (Table). The median initial volume of distribution (V₁), for all patients, calculated by back-extrapolation to t₀, approximated plasma volume, 53 mL/kg. Kinetics fit a two-component model, with relatively rapid initial half-time (exit) reflecting distribution out of plasma space, and equilibration representing slow return into the vascular pool. The drug elimination half-time was too slow to observe in these 7-day periods. Apparent half-time for initial redistribution from the plasma space was significantly longer for younger subjects at week 4 than at week 1 and than for older subjects at week 4 (Table). By comparison, in studies of 14 adults with lymphoma treated with rituximab at the same dosage regimen, the manufacturer reports mean serum half-time of 76 hrs (range, 31–153) at week 1 and 205 hrs (range, 84 – 407) at week 4. In this PK sub-study, we found no significant difference in kinetic parameters between the 5 responders (defined by sustained platelet count >50,000/mm³ at week 12) and 11 non-responders.

Conclusion: In this small number of pediatric patients with cITP treated with 4 weekly infusions of rituximab, the half-time was longer for younger subjects at week 4 than week 1 and than for older subjects at week 4. Trough levels at week 4 do not represent steady state because the elimination half-time is long. The reason for the difference between the two age cohorts is not readily apparent, but we propose that the shorter exit half-time in younger patients at week 1 compared to week 4 corresponds to a higher number of initially accessible CD20 binding sites (B cells) in young children.