In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting.

UGT2B10 is a phase II drug metabolizing enzyme with limited information on its role in the metabolism of drugs, especially in the pediatric hematopoietic stem cell transplantation setting. Previously, we investigated UGT2B10's role through in silico analyses and prioritized acetaminophen (APAP), lorazepam (LOR), mycophenolic acid (MPA), and voriconazole N-oxide (VCZ N-oxide) for in vitro investigations. In this report, we present in vitro screening of these candidates and of voriconazole (VCZ) to assess their potential to be substrates and/or inhibitors of UGT2B10.

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

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.

Effect of pharmacokinetics and pharmacogenomics in adults with allogeneic hematopoietic cell transplantation conditioned with Busulfan.

Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen.

Influence of CYP2C9 Polymorphisms on Plasma Concentration of Warfarin and 7-Hydroxy Warfarin in South Indian Patients.

Background: Warfarin is primarily metabolized by cytochrome P450 2C9 (CYP2C9) enzyme, which is encoded by the CYP2C9 gene. CYP2C9*2 and CYP2C9*3 variants significantly influence warfarin metabolism and subsequently the required dose of warfarin.

Objectives: The current retrospective study was aimed to determine the influence of CYP2C9 variants on warfarin metabolic ratio (MR, warfarin/7-hydroxy warfarin) and warfarin maintenance therapy in 210 patients (mean age 44.

Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study.

Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione-s-transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model-based, first-dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu-based conditioning regimen.

Association of *3 and 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia.

Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3-4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: , , , , , , , , and .

Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation.

Aims: The aim of this study is to develop a population pharmacokinetic (PopPK) model for intravenous busulfan in children that incorporates variants of GSTA1, gene coding for the main enzyme in busulfan metabolism.

Methods: Busulfan concentration-time data was collected from 112 children and adolescents (median 5.4 years old, range: 0.

Therapeutic Drug Monitoring of Busulfan for the Management of Pediatric Patients: Cross-Validation of Methods and Long-Term Performance.

Background: Busulfan (Bu) is an alkylating agent used as part of the conditioning regimen in pediatric patients before hematopoietic stem cell transplantation. Despite intravenous (IV) administration and dosing recommendations based on age and weight, reports have revealed interindividual variability in Bu pharmacokinetics and the outcomes of hematopoietic stem cell transplantation. In this context, adjusting doses to Bu's narrow therapeutic window is advised.

Pharmacogenomics in Pediatric Oncology: Review of Gene-Drug Associations for Clinical Use.

During the 3rd congress of the European Society of Pharmacogenomics and Personalised Therapy (ESPT) in Budapest in 2015, a preliminary meeting was held aimed at establishing a pediatric individualized treatment in oncology and hematology committees. The main purpose was to facilitate the transfer and harmonization of pharmacogenetic testing from research into clinics, to bring together basic and translational research and to educate health professionals throughout Europe. The objective of this review was to provide the attendees of the meeting as well as the larger scientific community an insight into the compiled evidence regarding current pharmacogenomics knowledge in pediatric oncology.

Relative Copy Number Variations of CYP2C19 in South Indian Population.

CYP2C19 is a polymorphic enzyme involved in the metabolism of clinically important drugs. Genotype-phenotype association studies of CYP2C19 have reported wide ranges in the metabolic ratios of its substrates. These discrepancies could be attributed to the variations in the promoter region and this aspect has been reported recently.