Impact of GSTA1 Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation

Background: Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 (GSTA1) gene variants on busulfan oral clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation. Methods: This is a quasi-experimental retrospective study in adult patients (n = 87 included in the final analyses) receiving oral busulfan. Pharmacokinetics data (area under the plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients’ files and GSTA1 *A and *B allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared. Results: Carriers of GSTA1*B exhibited lower busulfan CLo than patients with an *A/*A genotype (p < 0.002): Busulfan CLo was 166 ± 31, 187 ± 37 vs. 207 ± 47 mL/min for GSTA1*B/*B, *A/*B and *A/*A genotypes, respectively. Similar results were obtained with the tested LSMs. Using the standard AUC method, distribution of patients above the therapeutic range after the first dose was 29% for GSTA1*A/*A, 50% for *A/*B, and 65% for *B/*B. The LSMs correctly identified ≥91% of patients with an AUC above the therapeutic range. The misclassified patients had a mean difference less than 5% in their AUCs. Conclusion: Patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan oral dose. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies

Administration support

The ICU is a resource intensive environment where administrative support for resource optimization is crucial for its successful operation. Although various physician staffing models of care exist, the evidence consistently points towards high-intensity physician staffing when aiming for the best possible outcomes for both the patient and the health system. The benefit has been shown in various ICU populations and usually takes the form of a mandatory consult or a closed ICU model. Other components of the model that should be considered include intensivist-to-bed ratio, a unit culture emphasizing patient safety, and consistent quality assurance or performance improvement activities. Increasing compliance with evidence-based interventions through 24-hour intensivist staffing, tele-ICUs, regionalization, protocols and decision-making tools, and advanced practice providers have been tried with varying results. The need to deliver critical care on the move is becoming inevitable for patients but carries high risk. Dedicated transport teams may be one way of decreasing adverse events during transport. The ultimate goal for the ICU would be to function as a high reliability organization and will require everything from a highly dedicated unit culture of excellence to visible support from the leadership