Soumya Perinparajah (1), Juliana Silva (2), Austen Worth (1,2), S.Y. Amy Cheung (3), James W.T. Yates (4), Nigel Klein (1), Judith Breuer (1,5), Paul Veys (1,2), Persis J. Amrolia (1,2), Joseph F. Standing (1,6)
(1) UCL Great Ormond Street Institute of Child Health, London, United Kingdom, (2) Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children, London, United Kingdom, (3) Certara, Amsterdam, Netherlands, (4) AstraZeneca, Cambridge, United Kingdom; (5) Infection and Immunity, UCL, London,United Kingdom (6) Department of Pharmacy, Great Ormond Street Hospital for Children, London, United Kingdom
Introduction/Objectives: Rituximab is a chimeric IgG-1 monoclonal antibody that interacts with the CD20 protein on the surface of B cells, targeting them for cell lysis. It is given for a range of conditions including B cell lymphomas and leukaemias but is licensed for adults only, given on an off-label basis to children. Due to its mechanism of action, rituximab is used for Epstein Barr virus (EBV), which is commonly reactivated after haematopoietic stem cell transplantation (HSCT) and is the leading cause of post-transplant lymphoproliferative disease (PTLD). In immunocompetent hosts, EBV is controlled by cytotoxic T cells but reduced immune surveillance in immunocompromised post-HSCT patients leads to an outgrowth of EBV-transformed cells.
The current study aims to identify the pharmacodynamics of rituximab in children with EBV post-HSCT to optimise the dose.
Methods: Retrospective electronic data were collected from children who underwent HSCT at a tertiary paediatric hospital between 2005 and 2017, and were prescribed rituximab for EBV post-HSCT. Intravenous infusions of rituximab were administered at a dose of 375 mg/m2 weekly for either one week on a conservative regimen or four weeks on a pre-emptive regimen. Plasma concentrations of rituximab were not available, but CD19+ B cell counts were available before and after treatment with rituximab.
Time to CD19+ B cell reconstitution was compared between patients given a single dose or four doses of rituximab using the survival and survminer packages in R (version 3.5.1).
A kinetic-pharmacodynamic (K-PD) turnover model, previously constructed and described by Pan et al [1], was applied in NONMEM® (version 7.4.3). Rituximab was assumed to be eliminated by first-order kinetics.
Results: 683 measurements of CD19+ B cell counts were available from 55 children who received rituximab for EBV post-HSCT. Observations (n=317) with a CD19+ B cell count below the lower limit of quantification (LOQ) were assigned a count of 5×106/L (LOQ/2). The median age at HSCT was 2.96 years.
The median time to reconstitution was 267 days in patients administered a single dose of rituximab (n=39) and 370 days in patients administered four doses of rituximab (n=16). There was no significant difference in the fraction of patients achieving age-specific CD19+ B cell reconstitution between the single-dose and four-dose groups (p value = 0.21), although the observed trend was for a slower rate of reconstitution for the four-dose group than for the single-dose group.
The K-PD model described the time course of CD19+ B cells well following treatment with rituximab. The final parameter estimates were as follows; rituximab elimination rate 0.044 day-1; production rate constant was 6.95×106 cells/day; cell death rate 0.037 day-1; Emax was 56.9 (fold increase in cell death rate) and ED50 was 40 mg. These were consistent with values reported in previous literature [1,2], with the exception of ED50 which was higher in the present study.
Conclusions: The model adequately describes CD19+ B cell dynamics in response to rituximab. Refinements to the model are planned to include age [3] and size scaling, and exploration of the M3 method for LOQ handling. EBV viral loads will then be included to better understand the dynamics of viral inhibition in this population, and ultimately inform rituximab dosing.
References:
[1] Pan S, Yu H, Surti A, et al 059 Pharmacodynamics of rituximab on B cells in paediatric patients with immune disorders Archives of Disease in Childhood 2018;103:A24-A25.
[2] Ng, Chee M., et al. “Population pharmacokinetics of rituximab (anti‐CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial.” The Journal of Clinical Pharmacology 45.7 (2005): 792-801
[3] Payne, Helen, et al. “Naive B cell output in HIV-infected and HIV-uninfected children.” AIDS research and human retroviruses 35.1 (2019): 33-39.
Reference: PAGE 28 (2019) Abstr 9092 [www.page-meeting.org/?abstract=9092]
Poster: Drug/Disease Modelling - Paediatrics