Oral: Clinical Applications

B-16 Model-based characterization of neutrophil dynamics in children receiving busulfan or treosulfan for hematopoietic stem cell transplant conditioning

Belén P. Solans(1,2), Robert Chiesa(3), Zinnia P. Parra-Guillen(1,2), Paul Veys(3,4), Iñaki F. Trocóniz(1,2), Joseph F Standing(4,5,6)

(1)Pharmacometrics and Systems Pharmacology, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; (2)IdiSNA; Navarra Institute for Health Research, Pamplona, Spain; (3)Bone Marrow Transplantation Department, Great Ormond Street Hospital for Children, London, UK; (4)Infection, Immunity, Inflammation Programme, UCL Great Ormond Street Institute of Child Health, London, UK; (5)Department of Pharmacy, Great Ormond Street Hospital for Children, London, UK; (6)Paediatric Infectious Diseases Group, St George’s, University of London, UK.

Objectives:

Busulfan (Bu) and treosulfan (Treo) are used in the conditioning prior to paediatric haematopoietic stem cell transplantation (HSCT). Myeloid cell suppression leaves patients severely immunocompromised [1,2], increasing mortality.

Bu pharmacokinetics (PK) has been studied [3,4], requiring therapeutic drug monitoring (TDM) and the same therapeutic range in malignant and non-malignant disorders. For Treo less is known about the therapeutic range [5,6].

The objectives of this project were to establish: (i) a PKPD model for the treatment and engraftment effects on neutrophil counts comparing Bu and Treo, (ii) the relationship between neutropenia and overall survival (OS), (iii) optimised dosing schedules with respect to time to HSCT, and (iv) optimised PK sampling for Bu TDM.

Methods:

Electronic records from 72 children receiving Bu (7 m-18 y, 5.1–47.0 Kg) and 54 Treo (4 m–17 y, 3.8–35.8 Kg), were collected. Neutrophil count observations (8,935) were recorded from 1 month prior to 2 months post HSCT. Patients suffered from malignant (48 patients) and non-malignant diseases (78 patients).

Bu concentrations (534) from 72 patients were obtained. Treo samples were obtained in 20 children. Population parameters were used for patients without PK samples. NONMEM 7.3 and the FOCE-I estimation method were used. The Friberg model [7] was extended to account for HSCT effects. EMAX and linear models were tested for drug effect.

Patient, disease and treatment-related covariates were explored with stepwise covariate modelling (SCM) with forward inclusion (p<0.05) and backward deletion (p<0.01).

The model was used to evaluate dosing schedules of both drugs through simulations. In addition, the optimal Bu PK sampling collection times were determined using the R package PopED [8].

A survival analysis performed in R with the package survminer [9] explored the relationship between OS and possible predictors (patient, disease and model-derived metrics).

Results:

A 2-compartment model best described the concentration vs time profiles of Bu and Treo. A maturation function was included affecting clearance (CL) - time to reach half of the adults’ maturation (PM50), and the Hill coefficient, fixed to 45.7 weeks and 2.3 for Bu [10], and 42.2 weeks and 2.3 for Treo.

The final model included separate steady-state neutrophil count (CIRC0) before and after transplant (p<0.01). The HSCT was represented by an amount of cells entering the proliferation compartment. HSCT enhanced cell proliferation and maturation increasing by 2-fold the related parameters (p<0.01), with a latency period of 9 days (99% IIV). Additionally, HSCT elicited a slight but significant (p<0.001) 5% increase in the proliferation constant and the feedback parameter γ.

System parameters (CIRC0, mean transit time (MTT) and γ) were consistent across drugs, estimated as 0.79·10⁹ cells/L (75.9% IIV), 8.02 days (35.4% IIV) and 0.10 (77.1% IIV).

The neutrophil decline was modelled with a linear model for Bu (KKILL=0.7) and an EMAX model for Treo (EMAX=1.2). The SCM showed that the presence of alemtuzumab enhanced the HSCT effect, resulting in a 2.9 fold increase in proliferation, transit and circulating constants.

Results from a multi-variable analysis showed that the area under the neutrophil vs time curve was a predictor of OS independent of Bu or Treo AUC. A univariate analysis shown that patients with malignancies with an area under the neutrophil vs time curve lower than the median values (125·109cells day/L) had significantly increased OS in a 1-year (p=0.045, Hazard ratio (HR)=0.26, 95%CI, 0.06-0.97) and a 3-year follow-up (p=0.013, HR=0.27, 95%CI, 0.09-0.81).

The dosing schedule evaluation showed that a 2-day delay in Treo administration would leave the patient less time immunocompromised without damaging the HSCT.

The optimal design exercise suggested a reduced sampling schedule (4 samples compared to 6), obtaining similar parameter precision (maximum bias <10%).

Conclusions:

The semi-mechanistic PKPD model developed predicts neutrophil reconstitution trajectories from children after HSCT, being a useful tool to improve their clinical management. New dosing (for Treo) and sampling schedules (for Bu) are proposed, and increased neutropenia appears to be beneficial for patients with malignant disease.

References:
[1] Danylesko I, Shimoni A and Nagler A. Treosulfan-based conditioning before hematopoietic DCT: more than a Bu look-alive. Bone Marrow transplant 2012;47(1):5-14.
[2] Krivoy N, Hoffer E, Lurie Y, Bentur Y, and Rowe JM. Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children. Curr Drug Saf 2008;3(1): 60–66.
[3] Bartelink IH, Lalmohamed A, van Reij EML, Dvorak CC, Savic RM, Zwaveling J et al. Association of busulfan exposure with survival and toxicity after hematopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol 2016;3(11):e526-e536.
[4] Philippe M, Goutelle S, Guitton J, Fonrose X, Bergeron C, Girard P et al. Should busulfan therapeutic range be narrowed in paediatrics? Experience from a large cohort of hematopoietic stem cell transplant children. Bone Marrow Transplantation 2016; 51:72-78.
[5] van der Stoep MYEC, Bertaina A, Ten Brink MH, Bredius RG, Smiers FJ, Wanders DCM et al. High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study. Br J of Haematol 2017;179:772-780.
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[8] Nyberg J, Ueckert S, Stroemberg EA, Hennig S, Karlsson MO and Hooker A. PopED: An extended, parallelized, nonlinear mixed effects models optimal design tool. Computer Methods and Programs in Biomedicine. 2012.
[9] Kassambara A and Kosinski M. Survminer: Drawing survival curves using ggplot2. R package version 0.4.3. https://CRAN.R-project.org/package=survminer. 2018.
[10] McCune JS, Bemer MJ, Barret JS, Baker KS, Gamis AL and Holford NHG. Busulfan in infants to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization. Clin Cancer Res 2014; 20(3):754-763.