Pharmacokinetic Modeling and Simulation with Pharmacogenetic Insights Support the Relevance of Therapeutic Drug Monitoring for Myeloablative Busulfan Dosing in Adult HSCT

Article Article scientifique Article Pharmacokinetic Modeling and Simulation with Pharmacogenetic Insights Support the Relevance of Therapeutic Drug Monitoring for Myeloablative Busulfan Dosing in Adult HSCT eng 2023-12-09 2023-12-09 author Ben Hassine Khalil Department of Pediatrics, Gynecology and Obstetrics, Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 779097 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) author Seydoux Claire Division of Hematology, University Hospital of Basel, Basel, Switzerland. author Khier Sonia Pharmacokinetic and Modeling Department, School of Pharmacy, Montpellier University, Montpellier, France; Probabilities and Statistics Department, Institut Montpelliérain Alexander Grothendieck (IMAG), CNRS, UMR 5149, Inria, Montpellier University, Montpellier, France. 983993 author Daali Youssef Division of Clinical Pharmacology and Toxicology, University Hospital of Geneva, Geneva, Switzerland; Faculty of Medicine & Sciences, University of Geneva, Geneva, Switzerland. 46042 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Medinger Michael Division of Hematology, University Hospital of Basel, Basel, Switzerland and University Basel, Basel, Switzerland. author Halter Joerg Division of Hematology, University Hospital of Basel, Basel, Switzerland and University Basel, Basel, Switzerland. author Heim Dominik Division of Hematology, University Hospital of Basel, Basel, Switzerland and University Basel, Basel, Switzerland. author Chalandon Yves Division of Hematology, Bone Marrow Transplant Unit, University Hospital of Geneva and Faculty of Medicine, University of Geneva, Geneva, Switzerland. 644957 Département de médecine (DEMED) author Schanz Urs Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland. author Nair Gayathri Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland. author Cantoni Nathan Division of Oncology, Hematology and Transfusion Medicine, Kantonsspital Aarau, Aarau, Switzerland. author Passweg Jakob R Division of Hematology, University Hospital of Basel, Basel, Switzerland and University Basel, Basel, Switzerland. author Uppugunduri Satyanarayana Chakradhara Rao 0000-0002-8928-7049 Department of Pediatrics, Gynecology and Obstetrics, Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 740772 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) author Ansari Djaberi Marc Georges Department of Pediatrics, Gynecology and Obstetrics, Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland. Electronic address: Marc.Ansari@hcuge.ch. 61572 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) 332.e1-332.e15 10.1016/j.jtct.2023.12.003 38081414 2666-6367 https://www.sciencedirect.com/science/article/pii/S2666636723017153 Therapeutic drug monitoring (TDM) of busulfan (Bu) is well-established in pediatric hematopoietic stem cell transplantation (HSCT), but its use in adults is limited due to a lack of clear recommendations and scarcity of evidence regarding its utility. GSTA1 promoter variants are reported to affect Bu clearance in both adults and pediatric patients. This study aimed to evaluate the value of preemptive genotyping GSTA1 and body composition (obesity) in individualizing Bu dosing in adults, through pharmacokinetic (PK) modeling and simulations. A population pharmacokinetic (PopPK) model was developed and validated with data from 60 adults who underwent HSCT. Simulations assessed different dosing scenarios based on body size metrics and GSTA1 genotypes. Due to the limited number of obese patients in the cohort, the effect of obesity on Bu pharmacokinetics (PK) was evaluated in silico using a physiologically-based pharmacokinetic (PBPK) model and relevant virtual populations from Simcyp software. Patients with at least 1 GSTA1*B haplotype had 17% lower clearance on average. PopPK simulations indicated that adjusting doses based on genotype increased the probability of achieving the target exposure (3.7 to 5.5 mg.h/L) from 53% to 60 % in GSTA1*A homozygous patients, and from 50% to 61% in *B carriers. Still, Approximately 40% of patients would not achieve this therapeutic window without TDM. A 2-sample optimal design was validated for routine model-based Bu first dose AUC<sub>0-∞</sub>estimation, and the model was implemented in the Tucuxi user-friendly TDM software. PBPK simulations confirmed body surface area-based doses of 29 to 31 mg/m<sup>2</sup>/6h as the most appropriate, regardless of obesity status. This study emphasizes the importance of individualized Bu dosing strategies in adults to achieve therapeutic targets. Preemptive genotyping alone may not have a significant clinical impact, and routine TDM may be necessary for optimal transplantation outcomes. Busulfan Hematopoietic stem cell transplantation Limited sampling strategy Model-informed precision dosing Physiologically-based pharmacokinetics Population pharmacokinetics Therapeutic drug monitoring Dewey 616 Dewey 617 Dewey 618 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 58 Département de pédiatrie, gynécologie et obstétrique 223 56 Département de médecine 221 false 1280 Pharmaco-omiques et médecine de précision 1003 1216 Leucémie et transplantation allogénique de cellules souches hématopoïétiques 982 564 Oncologie et hématologie pédiatriques 907 Transplantation and cellular therapy 30 3 fdc0f7c2-233e-49d6-b4f2-4a1f8db456bb Article (Published version) Public 1-s2.0-S2666636723017153-main.pdf 1438449 application/pdf CC BY-4.0 28cea50d1890867bc8ce883abc07920b476586d1d145a48bf8845b8c00bea466 dc8c5240-81bb-43e5-b1d4-3c1a7a078cb4 Supplemental data Public 1-s2.0-S2666636723017153-mmc1-1.docx 391868 application/vnd.openxmlformats-officedocument.wordprocessingml.document 03063ca032a26b2e2203be033761f5a2ea46cbe7353c88ea5e4034041bbc7888 openAccess Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique Faculté de médecine / Section de médecine clinique / Département de médecine

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Pharmacokinetic Modeling and Simulation with Pharmacogenetic Insights Support the Relevance of Therapeutic Drug Monitoring for Myeloablative Busulfan Dosing in Adult HSCT	Transplantation and cellular therapy			2023	87	107

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