Evaluation of Interprofessional Quality Improvement Interventions Led by an Ambulatory Care Pharmacist on Adherence to a Controlled Substance Agreement Policy.

Background: A controlled substance agreement (CSA) is a risk mitigation strategy for patients managed on controlled substance medications such as opioids and benzodiazepines. Limited literature exists to describe the role of the clinic pharmacy team to promote adherence to CSA monitoring parameters. Objective: The objective of this study is to evaluate the impact of interprofessional educational and clinical interventions led by an ambulatory care pharmacist on adherence to monitoring parameters within a CSA policy. Methods: This retrospective observational study included patients on long-term controlled substances who had a clinic visit every 3 months during the study period. The primary outcomes were the proportion of patients with a signed CSA in the electronic medical record (EMR), urine drug screen (UDS) completion, and documentation of review of the statewide prescription drug monitoring program (PDMP) in the EMR 8 months prior to as compared to 8 months after implementation of pharmacist interventions. Results: Among 79 patients (mean age 55.7 years, 65.8% female, 54.4% African American), 8.9% pre- vs 88.6% post-interventions had a signed CSA (p<0.001), 35.4% pre- vs 65.8% post-interventions had a UDS completed (p<0.001), and 32.9% pre- vs 57% post-interventions had documentation of PDMP review (p=0.002). Conclusion: Adherence to monitoring parameters within a CSA policy significantly improved after educational and clinical interventions led by an ambulatory care pharmacist.

Warfarin Dose Requirements in Adults Hospitalized With COVID-19 Infection: A Retrospective Case Series.

PURPOSE: To describe the impact of hospitalization with COVID-19 infection on warfarin dose requirements in adult inpatients. SUMMARY: A retrospective chart review of 8 adults on warfarin admitted to Michigan Medicine with COVID-19 infection was conducted and reported as a case series. Outcomes of interest were difference in average daily dose of warfarin prior to admission (PTA) and while inpatient (IP), warfarin sensitivity, time in therapeutic range (TTR), confirmed or suspected thromboembolic event, any major or clinically significant bleeding episodes, and in-hospital mortality. IP average daily warfarin doses were lower when compared to PTA average daily doses [1.3 mg (1.3) vs. 6.2 mg (4.1)]. The mean percentage decrease in dose was 68.8% (23) and the mean absolute dose difference was 4.8 mg (4.3). Mean IP percentage tests in range was 30.8% (24.6) and mean IP warfarin sensitivity was 4.2 (3.8), both of which differed from PTA TTR and warfarin sensitivity for those with data available (n = 3, n = 6, respectively). One patient was treated for suspected acute pulmonary embolism while on warfarin and one patient experienced clinically relevant bleeding. In-hospital mortality was zero, mean length of stay (LOS) was 17 days (14.4), and mean intensive care unit (ICU) LOS for the 3 patients requiring ICU level care was 14.3 days (4.5). CONCLUSION: Decreased warfarin dose requirements were evident in this group of adults hospitalized with COVID-19 infection. These findings suggest lower doses of warfarin may be needed to achieve therapeutic anticoagulation while inpatient.

Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer.

Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. CYP2D6 activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether CYP2D6 genotype is associated with tamoxifen efficacy may be due to the imprecision in using CYP2D6 genotype as a surrogate of endoxifen concentration without incorporating the influence of other genetic and clinical variables. This review summarizes the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a novel approach to validate this relationship by generating a precision endoxifen prediction algorithm and comprehensively review the factors that must be incorporated into the algorithm, including genetics of CYP2D6 and other pharmacogenes. A precision endoxifen algorithm could be used to validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations and maximum benefit from tamoxifen treatment.

An Hsp90 co-chaperone protein in yeast is functionally replaced by site-specific posttranslational modification in humans.

Heat shock protein 90 (Hsp90) is an essential eukaryotic molecular chaperone. To properly chaperone its clientele, Hsp90 proceeds through an ATP-dependent conformational cycle influenced by posttranslational modifications (PTMs) and assisted by a number of co-chaperone proteins. Although Hsp90 conformational changes in solution have been well-studied, regulation of these complex dynamics in cells remains unclear. Phosphorylation of human Hsp90α at the highly conserved tyrosine 627 has previously been reported to reduce client interaction and Aha1 binding. Here we report that these effects are due to a long-range conformational impact inhibiting Hsp90α N-domain dimerization and involving a region of the middle domain/carboxy-terminal domain interface previously suggested to be a substrate binding site. Although Y627 is not phosphorylated in yeast, we demonstrate that the non-conserved yeast co-chaperone, Hch1, similarly affects yeast Hsp90 (Hsp82) conformation and function, raising the possibility that appearance of this PTM in higher eukaryotes represents an evolutionary substitution for HCH1.