C.R.S. Uppugunduri (1,2), D.J.A.R. Moes (3), P. Huezo-Diaz Curtis (1,2), T. Nava (1,2), M. Kuntzinger (4), M. Koshbeen-Boudal (1,2), F. Doffey-Lazeyras(4), Y. Daali (4), M. Ansari (1,2)
(1) CANSEARCH Research Laboratory, Department of Pediatrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (2) Onco-Hematology Unit, Department of Pediatrics, Geneva University Hospitals, University of Geneva, Geneva, Switzerland. (3) Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. (4) Clinical Pharmacology and Toxicology Unit, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
Background and Objectives:
Busulfan (Bu) dosing in children has been improved recently with the development of personalized dosing algorithms based on population pharmacokinetic studies (PopPK). However, performance of these models is not optimal but has significantly improved targeted therapy.1, 2 Few PopPK models evaluated the impact of GSTA1 genetic variants on inter-individual variability (IIV) of Bu clearance (CL). Since cumulative AUC of Bu is linked to outcomes,3 inter-occasional variability (IOV) in its CL determines the overall cumulative exposure. It is also well known that Bu conjugation is catalyzed predominantly by GSTA1 enzyme. No model has evaluated the effect of covariates such as hematocrit and genetic variants in GSTA1 on IOV in Bu CL. The objective of this study is to develop a PopPK model for intravenous Bu in children and to evaluate dynamic and static covariates such as anthropometric, clinical (hematocrit) characteristics and genetic variants (GSTA1 functional haplotypes) that might explain IIV and IOV of Bu CL.
Patients and methods:
Retrospective data was derived from 22 pediatric patients (12 males, and 10 females; median age 7.5 years, age range: 0.3 to 13.9 years) who underwent allogeneic hematopoietic stem cell transplantation at the Department of Pediatrics, University Hospitals of Geneva and received intravenous Bu as a component of conditioning. Bu was given in a four times daily dosing schedule and its levels were measured using a validated LC-MS/MS assay.4 Bu first dose was either age or weight-based and dose adjustment based on the first dose PK parameter estimates was performed. GSTA1 promoter region variants were genotyped by PCR amplification followed by Sanger sequencing to derive functional haplotypes.5 327 plasma concentration measurements (173 on the first day, 51 on the second day, 93 on the third day, 8 measurements on the fourth day and 2 measurements on 5th day) were included to be able to explore the IOV and IIV. Age, weight, gender, height, Body surface area (BSA), hematocrit, baseline disease (malignant vs. non-malignant), conditioning regimen (Bu-cyclophosphamide, cyclophosphamide-Bu, Bu-fludarabine) and GSTA1 functional haplotypes (poor metabolizer group, normal metabolizer group, rapid metabolizer group) were evaluated as potential covariates. Bu drug levels and potential covariates influencing drug exposure were analyzed with stepwise covariate modelling on a base model using the nonlinear mixed effects modeling software, NONMEM version 7.3. Plots, visual predictive check (VPC), bootstrap were performed to determine the stability and the reliability of the final model.
Results:
Among the children included, 11 received Bu-cyclophosphamide, 4 received cyclophosphamide-Bu, and 7 received Bu-fludarabine based conditioning. Sixteen of them were diagnosed with malignancies and remaining with non-malignant diseases. Mean hematocrit values were lowered by 15-17% on day 3 from the first day of conditioning with Bu in children receiving cyclophosphamide-Bu and Bu-fludarabine regimen. Bu PopPK was best described by a two compartment model with first order elimination using BSA as covariate on CL. For a typical patient whose BSA is 0.88 m2, the population values of CL and central compartment volume (Vc) were 2.94 L/h and 10.5 L, respectively. Inter-compartmental clearance (Q) was 0.98 L/h and peripheral compartment volume (Vp) was 50.7 L. IIV and IOV (CV %) of the final model was 22% and 21.8%, respectively. BSA showed slightly more significant influence on CL (reduced variability from 48.1 % to 22 %) and Vc compared to bodyweight. Hematocrit and functional haplotype groups of GSTA1 did not have a significant effect on both IIV and IOV (trend seen of 11%) in this data set.
Conclusions:
BSA significantly influenced Bu pharmacokinetics. Hematocrit and GSTA1 functional haplotype groups did not have a clinically relevant effect on Bu IIV and IOV of PK in this dataset. Small number of patients and use of various conditioning regimens may have influenced the model, and this model performance must be evaluated in a larger dataset.
References:
[1] Zao, J.H., Schechter, T., Liu, W.J. et al. Performance of busulfan dosing guidelines for pediatric hematopoietic stem cell transplant conditioning. Biol Blood Marrow Transplant. 2015; 21: 1471–1478.
[2] Nava T, Rezgui MA, Uppugunduri CRS, et al. GSTA1 genetic variants and conditioning regimen: missing key factors in dosing guidelines of Busulfan in pediatric hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2017; 23:1918-1924.
[3] Bartelink IH, Lalmohamed A, van Reij EM, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016; 3(11):e526-e536.
[4] Ansari, M., Uppugunduri, C.R., Déglon, J. et al. A simplified method for busulfan monitoring using dried blood spot in combination with liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2012; 26: 1437–1446.
[5] Ansari M, Curtis PH, Uppugunduri CRS, et al. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget. 2017; 8(53):90852-90867.
Reference: PAGE 27 (2018) Abstr 8473 [www.page-meeting.org/?abstract=8473]
Poster: Drug/Disease Modelling - Paediatrics