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

Khalil Ben Hassine; Claire Seydoux; Sonia Khier; Youssef Daali; Michael Medinger; Joerg Halter; Dominik Heim; Yves Chalandon; Urs Schanz; Gayathri Nair; Nathan Cantoni; Jakob R Passweg; Chakradhara Rao Satyanarayana Uppugunduri; Marc Ansari

doi:10.1016/j.jtct.2023.12.003

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

Transplant Cell Ther. 2024 Mar;30(3):332.e1-332.e15. doi: 10.1016/j.jtct.2023.12.003. Epub 2023 Dec 9.

Authors

Affiliations

¹ Department of Pediatrics, Gynecology and Obstetrics, Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
² Division of Hematology, University Hospital of Basel, Basel, Switzerland.
³ 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.
⁴ Division of Clinical Pharmacology and Toxicology, University Hospital of Geneva, Geneva, Switzerland; Faculty of Medicine & Sciences, University of Geneva, Geneva, Switzerland.
⁵ Division of Hematology, University Hospital of Basel, Basel, Switzerland and University Basel, Basel, Switzerland.
⁶ Division of Hematology, Bone Marrow Transplant Unit, University Hospital of Geneva and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁷ Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland.
⁸ Division of Oncology, Hematology and Transfusion Medicine, Kantonsspital Aarau, Aarau, Switzerland.
⁹ 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.

PMID: 38081414
DOI: 10.1016/j.jtct.2023.12.003

Abstract

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_0-∞ 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/m²/6h 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.

Keywords: Busulfan; Hematopoietic stem cell transplantation; Limited sampling strategy; Model-informed precision dosing; Physiologically-based pharmacokinetics; Population pharmacokinetics; Therapeutic drug monitoring.

MeSH terms

Adult
Busulfan* / therapeutic use
Child
Drug Monitoring
Hematopoietic Stem Cell Transplantation*
Humans
Obesity
Pharmacogenetics

Substances

Busulfan