The inter-individual variability of CYP450s enzyme activity may be reduced by comparing the effects of bariatric surgery on CYP-mediated drug elimination in comparable patients before and after surgery. The current research will use a low-dose phenotyping cocktail to simultaneously evaluate the activities of six CYP isoforms and P-gp. The results showed that following weight reduction after surgery, the activity of all enzymes increased compared to the obese period, which was statistically significant in the case of CYP3A, CYP2B6, CYP2C9, and CYP1A2. Furthermore, the activity of P-gp after surgery decreased without reaching a statistical significance (p-value > 0.05). Obese individuals had decreased CYP3A and CYP2D6 activity compared with the control group, although only CYP3A was statistically important. In addition, there was a trend toward increased activity for CYP1A2, CYP2B6, CYP2C9, and CYP2C19 in obese patients compared to the control group, without reaching statistical insignificance (p-value ≥ 0.05). After six months (at least), all enzymes and the P-gp pump activity were significantly higher than the control group except for CYP2D6. Ultimately, a greater comprehension of phenoconversion can aid in altering the patient’s treatment. Further studies are required to confirm the changes in the metabolic ratios of probes after bariatric surgery to demonstrate the findings’ clinical application. As a result, the effects of inflammation-induced phenoconversion on medication metabolism may differ greatly across persons and drug CYP pathways. It is essential to apply these results to the clinic to recommend dose adjustments.

Background: Therapeutic drug monitoring (TDM) is crucial in optimizing the outcomes of hematopoietic stem cell transplantation by guiding busulfan (Bu) dosing. Limited sampling strategies show promise for efficiently adjusting drug doses. However, comprehensive assessments and optimization of sampling schedules for Bu TDM in pediatric patients are limited. We aimed to establish optimal sampling designs for model-informed precision dosing (MIPD) of once-daily (q24h) and 4-times-daily (q6h) Bu administration in pediatric patients. Methods: Simulated data sets were used to evaluate the population pharmacokinetic model-based Bayesian estimation of the area under the concentration–time curve (AUC) for different limited sampling strategy designs. The evaluation was based on the mean prediction error for accuracy and root mean square error for precision. These findings were validated using patient-observed data. In addition, the MIPD protocol was implemented in the Tucuxi software, and its performance was assessed. Results: Our Bayesian estimation approach allowed for flexible sampling times while maintaining mean prediction error within ±5% and root mean square error below 10%. Accurate and precise AUC_0–24h and cumulative AUC estimations were obtained using 2-sample and single-sample schedules for q6h and q24h dosing, respectively. TDM on 2 separate days was necessary to accurately estimate cumulative exposure, especially in patients receiving q6h Bu. Validation with observed patient data confirmed the precision of the proposed limited sampling scenarios. Implementing the MIPD protocol in Tucuxi software yielded reliable AUC estimations. Conclusions: Our study successfully established precise limited sampling protocols for MIPD of Bu in pediatric patients. Our findings underscore the importance of TDM on at least 2 occasions to accurately achieve desired Bu exposures. The developed MIPD protocol and its implementation in Tucuxi software provide a valuable tool for routine TDM in pediatric hematopoietic stem cell transplantation.

The optimal busulfan exposure window in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) remains to be defined. We identify this window for patients receiving busulfan within the prospective international, randomized controlled phase 3 ALLSCTped 2012 FORUM trial. We included 145 participants receiving fludarabine-busulfan-thiotepa conditioning, with available busulfan plasma levels. Busulfan exposure was estimated using a validated pediatric population pharmacokinetic model. Primary outcomes were event-free survival (EFS) and graft-versus-host disease-free relapse-free survival (GRFS). Patients were aged between 0.5 and 19.5 years, with a median follow-up of 5.0 years. The optimal busulfan exposure was defined as area under busulfan concentration curve (cAUC) of 73.3 to 98.0 mg.h/L based on EFS and GRFS. Patients with nonoptimal exposure had lower EFS (hazard ratio [HR], 1.93; p = 0.008) and GRFS (HR, 2.01; p = 0.002). Underexposure (cAUC 98.0 mg.h/L) with an increased risk of treatment-related toxicities and graft-versus-host disease. Patients with optimal busulfan exposure showed no differences in EFS, GRFS, overall survival, or relapse with post hoc matched total-body irradiation (TBI) recipients (n = 51 in each group). This study identifies a favorable busulfan exposure window for pediatric patients with ALL undergoing HSCT from an HLA-matched donor. Therapeutic drug monitoring for optimized personalized busulfan dosing improves HSCT outcomes and might be validated for use as an alternative to irradiation. This trial was registered at EudraCT as 2012-003032-22 and on www.ClinicalTrials.gov as NCT01949129.

Background: Childhood and adolescent acute lymphoblastic leukemia (ALL) survival outcomes have improved significantly, but treatment-related toxicities (TRTs) remain a major concern affecting dose intensity and quality of life. Germline pharmacogenetic variations contribute to inter-individual differences in chemotherapy response, yet consistent replication of associations has been limited by differences in treatment protocols, ethnic backgrounds, and toxicity definitions. Methods: This systematic review and meta-analysis (PROSPERO CRD42021229748) included 68 studies in the qualitative synthesis, with 42 high-quality studies undergoing structured synthesis and, where appropriate, quantitative meta-analysis. Studies focused on the toxicities of thiopurines, methotrexate, glucocorticoids, vincristine, and asparaginase. Results: Meta-analyses showed strong evidence linking the NUDT15 rs116855232 variant to thiopurine-induced myelosuppression (OR 19.0, 95% CI 1.6–224; I² = 86.5%) and a significant association between the TYMS enhancer repeat polymorphism and osteonecrosis (OR 6.66, 95% CI 3.67–12.11; I² = 0%). In contrast, MTHFR variants and VDR polymorphisms showed no significant associations with methotrexate-induced myelosuppression or osteonecrosis, respectively. Narrative synthesis highlighted clinically actionable associations: TPMT and NUDT15 with thiopurine toxicity; CEP72 with vincristine neuropathy; and HLA haplotypes with asparaginase hypersensitivity. Population allele frequency comparisons (IndiGenomes, gnomAD, UK Biobank) showed strong concordance (r = 0.919–0.997), supporting the broad generalisability of identified variants, which remains to be evaluated prospectively. The main limitations included heterogeneous toxicity definitions, non-uniform genetic models, evolving treatment protocols, population heterogeneity, and a lack of harmonised reporting. Conclusions: The review supports routine TPMT and NUDT15 genotyping and highlights the need for harmonised definitions, multi-ethnic studies, standardised data representation, and prospective validation. A literature-based candidate gene list for future PGx association studies was generated.

Background: Understanding interindividual variability in treatment response and toxicity is essential for optimizing outcomes in pediatric acute lymphoblastic leukemia (ALL). Molecular and pharmacogenetic markers hold promise in predicting treatment efficacy and adverse effects, particularly in genetically diverse populations. This protocol outlines the methodology for a prospective, nonrandomized observational cohort designed to evaluate molecular and pharmacogenetic factors associated with treatment response and toxicity in Indian children diagnosed with ALL. Objective: The primary objective is to identify genetic markers associated with treatment-related toxicity and therapeutic response. Secondary objectives include evaluating associations between the occurrence of early toxicities and quality of life during active ALL treatment, specific pharmacogenetic variants, and survival outcomes along with generating data to support the future implementation of personalized treatment strategies in Indian children with ALL. Methods: In this prospective, observational cohort, 556 children (≤18 years of age) with newly diagnosed ALL treated under the Indian Childhood Collaborative Leukemia–Acute Lymphoblastic Leukemia 2014 (ICiCLe-ALL-14) protocol at two Indian centers will be enrolled, aiming for a minimum of 500 evaluable children. Eligible participants will be enrolled prior to the initiation of chemotherapy and followed longitudinally throughout treatment. Clinical and laboratory data (demographics, nutritional assessment, quality of life, comorbidities, treatment regimen, toxicity graded by Common Terminology Criteria for Adverse Events v5.0, remission status, and survival) will be collected at predefined intervals up to day 100 of the maintenance phase. Germline and somatic DNA will be sampled at diagnosis and remission. The first phase will use whole-exome sequencing to discover candidate variants by implementing a candidate gene prioritization strategy. The second phase will genotype the top candidates in the full cohort using array technology. Associations with early treatment–related toxicities, steroid response, and survival will be tested by multivariable regression and Cox models. A machine learning approach with pharmacogenetic predictors as classifiers will be implemented further with cross-validation and sensitivity analyses. Results: Ethical committees approved the protocol version 1.0 in 2020: IEC-1167/06.11.2020 (All India Institute of Medical Sciences, New Delhi), JIP/IEC/2020/201 (Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry), and AO_2021-00048 (UNIGE, Geneva). Funding was received from Swiss National Science Foundation, Switzerland; Department of Biotechnology, India; and CANSEARCH Foundation, Switzerland. Recruitment began in December 2022 and is likely to conclude by 2027. A comprehensive analysis of the complete study cohort is anticipated to be completed by 2027. Conclusions: The MPGx-INDALL (Molecular and Pharmacogenetic Marker Evaluation in Relation to the Toxicity and Clinical Response of Acute Lymphoblastic Leukemia Treatment in Indian Children) study will generate actionable insights for individualized ALL therapy in India via systematically evaluating germline and somatic markers in a large ethnically distinct cohort.