Utilization of a Population Pharmacokinetic Model to Improve a Busulfan Test-Dose Strategy in Allogeneic Hematopoietic Cell Transplant Recipients.

Busulfan is an alkylating agent used as part of conditioning chemotherapy regimens prior to allogeneic hematopoietic cell transplant (allo-HCT). Pharmacokinetic (PK)-guided test-dose strategies have been shown to improve the number of patients achieving busulfan exposure goals and improve clinical outcomes. However, current practices require extensive PK sampling. In this study, PK data were retrospectively collected from busulfan drug monitoring records from adult allo-HCT recipients who received once-daily intravenous busulfan at the University of North Carolina Medical Center (UNCMC). A population pharmacokinetic (popPK) model was developed to identify sources of interindividual variability and evaluate alternative PK sampling strategies. A 2-compartment model, with covariate effects of actual body weight and sex, best described the data. The typical value of clearance for an 83 kg male was estimated to be 11.21 L/h. Fifty-nine percent of allo-HCT recipients were estimated to have met the UNCMC institutional myeloablative conditioning (MAC) exposure goal based on model post hoc estimates of clearance using all PK samples obtained following MAC dosing. Fifty-seven percent of patients were estimated to have met this goal based on post hoc estimates using a single PK sample. Our results indicate once-daily, intravenous busulfan PK in adult allo-HCT recipients receiving MAC dosing can be reasonably described by a popPK model, and the use of a sparse PK sampling strategy may be feasible for determining target exposure attainment following MAC dosing. Use of a popPK model and sparse PK sampling strategy to carry out busulfan test-dose procedures could reduce health care costs and inconvenience to patients.

Change in inappropriate critical care over time.

PURPOSE: Intensive care interventions that prolong life without achieving meaningful benefit are considered clinically "inappropriate". In 2012, the frequency of perceived-inappropriate critical care was 10.8% at one academic health system; and we aimed to re-evaluate this frequency. METHODS: For 4 months in 2017, we surveyed critical care physicians daily and asked whether each patient was receiving appropriate, probably inappropriate, or inappropriate critical care. Patients were categorized into three groups: 1) patients for whom treatment was never inappropriate, 2) patients with at least one assessment that treatment was probably inappropriate, but no inappropriate treatment assessments, and 3) patients who had at least one assessment of inappropriate treatment. RESULTS: Fifty-five physicians made 10,105 assessments on 1424 patients. Of these, 94 (6.6%) patients received at least one assessment of inappropriate critical care, which is lower than 2012 (10.8% (p < 0.01)). Comparing 2017 and 2012, patient age, MS-DRG, length of stay, and hospital mortality were not significantly different (p > 0.05). Inpatient mortality in 2017 was 73% for patients receiving inappropriate critical care. CONCLUSIONS: Over five years the proportion of patients perceived to be receiving inappropriate critical care dropped by 40%. Understanding the reasons for such change might elucidate how to continue to reduce inappropriate critical care.

Synthesis and polymerase activity of a fluorescent cytidine TNA triphosphate analogue.

Threose nucleic acid (TNA) is an artificial genetic polymer capable of undergoing Darwinian evolution to produce aptamers with affinity to specific targets. This property, coupled with a backbone structure that is refractory to nuclease digestion, makes TNA an attractive biopolymer system for diagnostic and therapeutic applications. Expanding the chemical diversity of TNA beyond the natural bases would enable the development of functional TNA molecules with enhanced physiochemical properties. Here, we describe the synthesis and polymerase activity of a fluorescent cytidine TNA triphosphate analogue (1,3-diaza-2-oxo-phenothiazine, tCfTP) that maintains Watson-Crick base pairing with guanine. Polymerase-mediated primer-extension assays reveal that tCfTP is efficiently added to the growing end of a TNA primer. Detailed kinetic assays indicate that tCfTP and tCTP have comparable rates for the first nucleotide incorporation step (kobs1). However, addition of the second nucleotide (kobs2) is 700-fold faster for tCfTP than tCTP due the increased effects of base stacking. Last, we found that TNA replication using tCfTP in place of tCTP exhibits 98.4% overall fidelity for the combined process of TNA transcription and reverse transcription. Together, these results expand the chemical diversity of enzymatically generated TNA molecules to include a hydrophobic base analogue with strong fluorescent properties that is compatible with in vitro selection.