Soumya Perinparajah (1), Juliana Silva (2), Austen Worth (1,2), S.Y. Amy Cheung (3), James W.T. Yates (4), Nigel Klein (1), Joanna Lewis (1), Helen Payne (1,5), Judith Breuer (6), Paul Veys (1,2), Persis J. Amrolia (1,2), Joseph F. Standing (1,7)
(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 Ltd, Amsterdam, Netherlands; (4) AstraZeneca Ltd, Cambridge, United Kingdom; (5) Clinical Trials Unit, Medical Research Council, London, United Kingdom; (6) Infection and Immunity, UCL, London; (7) 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 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 extend a previously published B cell model by scaling the model parameters for age, in order to better reflect the underlying biological mechanisms responsible for CD19+ B cell reconstitution in children post-HSCT following administration of rituximab for EBV reactivation.
Methods: Retrospective electronic data were collected from children who underwent HSCT at a tertiary paediatric hospital between 2004 and 2017, and were prescribed rituximab for EBV post-HSCT. Intravenous infusions of rituximab were dosed by body-surface area (375 mg/m2) weekly for either one week (n = 39) or four weeks (n = 16). CD19+ B cell counts were available before and after treatment with rituximab, but plasma concentrations of rituximab were not available.
Biological prior data was sourced to describe two key relationships regarding CD19+ B cell dynamics: the first component was the change in naïve B cell concentration with age and the second component was the change in the fraction of naïve B cells expressing the cell proliferation marker Ki67 with age [2,3]. The data were fitted to three variations of an exponential decay model, and model fit was assessed using the Akaike Information Criterion (AIC). The resulting B cell maturation function was incorporated into a previously constructed kinetic-pharmacodynamic (K-PD) turnover model by Pan et al [1]. Rituximab was assumed to be eliminated by first-order kinetics. Development of the maturation function was conducted using the nls() function in the stats package in R version 3.5.1, and fitting of the K-PD model was done in NONMEM® version 7.4.3 using the first-order and Laplacian conditional estimation with interaction algorithms.
Results: 683 measurements of CD19+ B cell counts were available from 55 children who received rituximab for EBV post-HSCT. The median age at HSCT was 2.96 years. The M5 method was used to handle CD19+ B cell counts below the lower limit of quantification (n = 317).
A mono-exponential decay model with a constant best described each component of the biological prior data (AIC values of 2598 and 1581 respectively) therefore parameters from this model fit were selected to derive a mathematical expression for the B cell maturation function. Incorporation of the resulting B cell maturation function improved the K-PD model fit (decrease in OFV from 6581 to 4233).
The final K-PD model well described the time course of CD19+ B cells following treatment with rituximab, and gave the following parameter estimates; rituximab elimination rate (Ke), 0.046 day-1; CD19+ B cell production rate constant (Kin), 3.82×106 cells/day; CD19+ B cell death rate (Kout), 0.063 day-1; Emax,47.2 (fold increase in cell death rate) and ED50,18.5 mg. These were consistent with values reported in previous literature [1,4], with the exception of ED50 which was higher in the present study. A combined error model was used. Using the estimates obtained for Ke and Kout, the elimination half-lives of rituximab and CD19+ B cells were calculated to be 15 days and 11 days respectively.
Conclusions: A K-PD model quantifying rituximab effect was developed to reflect the age-dependant nature of CD19+ B cell dynamics. The final model well described CD19+ B cell dynamics following rituximab treatment in the post-HSCT study cohort. Future work aims to test the effect of the following covariates on CD19+ B cell reconstitution using the stepwise covariate model approach: receiving alemtuzumab, receiving anti-thymocyte globulin (ATG), a HSCT indication of primary immunodeficiency (PID), HSC source, receiving myeloablative conditioning (MAC) and having a matched donor. In addition, EBV viral loads will be incorporated to better understand dynamics of EBV inhibition to ultimately inform rituximab dosing in this population.
References
[1] Pan S, Yu H, Surti A, Cheng I, Marks SD, Brogan PA, Eleftheriou D, Standing JF. Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases. British journal of clinical pharmacology. 2019 Apr 26
[2] Morbach H, Eichhorn EM, Liese JG, Girschick HJ. Reference values for B cell subpopulations from infancy to adulthood. Clinical & Experimental Immunology. 2010 Nov;162(2):271-9.
[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.
[4] 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.
Reference: PAGE () Abstr 9528 [www.page-meeting.org/?abstract=9528]
Poster: Drug/Disease Modelling - Paediatrics