Pharmacogenomics is a tool for practitioners to provide precision pharmacotherapy using genomics. All providers are likely to encounter genomic data in practice with the expectation that they are able to successfully apply it to patient care. Pharmacogenomics tests for genetic variations in genes that are responsible for drug metabolism, transport, and targets of drug action. Variations can increase the risk for drug toxicity or poor efficacy. Pharmacogenomics can, therefore, be used to help select the best medication or aid in dosing. Nephrologists routinely treat cardiovascular disease and manage patients after kidney transplantation, two situations for which there are several high-evidence clinical recommendations for commonly used anticoagulants, antiplatelets, statins, and transplant medications. Successful use of pharmacogenomics in practice requires that providers are familiar with how to access and use pharmacogenomics resources. Similarly, clinical decision making related to whether to use existing data, whether to order testing, and if data should be used in practice is needed to deliver precision medicine. Pharmacogenomics is applicable to virtually every medical specialty, and nephrologists are well positioned to be implementation leaders.

Background and aims: Treprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing. Methods: Patients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher’s exact test was used for categorical data and Kruskal–Wallis test or Wilcoxon rank sum were used for continuous data. Results: A total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing. Conclusion: Genetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor. The reviews of this paper are available via the supplemental material section.

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The objective of this study was to evaluate patient-specific factors associated with dexmedetomidine dose requirements during continuous infusion. A retrospective cross-sectional analysis of electronic health record-derived data spanning 10 years for patients admitted with a primary respiratory diagnosis at a quaternary children's hospital and who received a dexmedetomidine continuous infusion (n = 346 patients) was conducted. Penalized regression was used to select demographic, clinical, and medication characteristics associated with a median daily dexmedetomidine dose. Identified characteristics were included in multivariable linear regression models and sensitivity analyses. Critically ill children had a median hourly dexmedetomidine dose of 0.5 mcg/kg/h (range: 0.1–1.8), median daily dose of 6.7 mcg/kg/d (range: 0.9–38.4), and median infusion duration of 1.6 days (range: 0.25–5.0). Of 26 variables tested, 15 were selected in the final model with days of dexmedetomidine infusion (β: 1.9; 95% confidence interval [CI]: 1.6, 2.3), median daily morphine milligram equivalents dosing (mg/kg/d) (β: 0.3; 95% CI: 0.1, 0.5), median daily ketamine dosing (mg/kg/d) (β: 0.2; 95% CI: 0.1, 0.3), male sex (β: −1.1; 95% CI: −2.0, −0.2), and non-Black reported race (β: −1.2; 95% CI: −2.3, −0.08) significantly associated with median daily dexmedetomidine dose. Approximately 56% of dose variability was explained by the model. Readily obtainable information such as demographics, concomitant medications, and duration of infusion accounts for over half the variability in dexmedetomidine dosing. Identified factors, as well as additional environmental and genetic factors, warrant investigation in future studies to inform precision dosing strategies.