The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL

Abstract

Pharmacokinetics of 8 doses of rituximab (375 mg/m 2 ) given in combination with 2-week cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/ prednisolone (CHOP-14) was determined by ELISA in 20 elderly patients with diffuse large B-cell lymphoma (DLBCL) 10 minutes before and after each infusion and 1 week and 1, 2, 3, 6, and 9 months after the last infusion. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Concentration-time data were fitted into an open 2-compartment model and total clearance, central compartment volume, intercompartment clearance, and volume of distribution at steady-state (Vd ss ) were investigated. Total clearance was 9.43 mL/h and Vd ss was 9.61 l. Rituximab clearance was reduced (8.21 mL/h vs 12.68 mL/h; P ‫؍‬ .003) and elimination half-life was prolonged in women compared with men (t 1/2␤ ‫؍‬ 30.7 vs 24.7 days; P ‫؍‬ .003). Body weight also affected Vd ss (0.1 l increase of Vd ss per kilogram above median of 75 kg). A sexdependent effect and the higher weight of males contribute to their faster rituximab clearance, which might explain why elderly males benefit less from the addition of rituximab to CHOP than females. This trial was registered on www.clinicaltrials. gov as numbers NCT00052936, EU-20243

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

“…[54][55][56] The nonlinear PK of these types of antibodies may in part be explained by binding of the antibodies to their respective targets, with a large component of target-mediated elimination after the first dose that is chemotherapy) have an elimination half-life in the magnitude of hours and rapidly achieve steady-state following administration (hours-days), while large molecules (e.g., mAbs) have a very long elimination half-life (in the magnitude of weeks) and may take up to 12 weeks to achieve steady-state. 65,66,69,70 …”

“…30,59 The volume of distribution of RTX at steady-state is approximately 9.6 L. Since the plasma volume is only 3-3.5 L, this suggests that the mAb distributes into the extracellular spaces of tissues, except the CNS. 65,66 Indeed, the blood-brain barrier physically impedes entry of macromolecules into the CNS, severely limiting distribution of RTX after i.v. administration.…”

“…This gender difference correlated with a better PFS observed in the total female population (n = 287) of the RICOVER-60 trial compared with males (n = 325). 66 It was suggested that the higher weight of males contributed to their faster RTX clearance, but sex and weight independently affected RTX clearance and elimination half-life.…”

“…66 In the latter study, RTX concentrations were measured 10 min before each infusion, 1 week and 1, 2, 3, 6 and 9 mo after the last infusion. Females were shown to have a longer elimination half-life than males (30.7 vs. 24.7 d, p = 0.003), which resulted in a higher overall exposure to the drug.…”

Chemotherapeutic intensity and survival differences in young patients with diffuse large B‐cell lymphoma: a Swedish Lymphoma Registry study

“…This finding strengthens an interpretation that R-CHOEP and R-very intensive chemotherapy are preferable to R-CHOP in aaIPI ≥ 2, but it also suggests that some of the Regional survival differences are due to other factors than first-line chemotherapy regimens. previously been more apparent in older patients (Muller et al, 2012;Pfreundschuh et al, 2014). We emphasize that our findings were independent in multivariate analysis adjusted for all prognostic clinical factors (gender, age, aaIPI and bulky disease).…”