Pharmacogenetic educational needs and the role of pharmacogenetics in primary care: a focus group study with multiple perspectives.

Background: Pharmacogenomics (PGx) is a well-established concept of how genes impact medication response, with many studies demonstrating reductions in medication side effects, improved efficacy and cost effectiveness. Despite these benefits, implementation of PGx in daily practice remains limited. Studies on the implementation of PGx in clinical practice have previously found that inadequate knowledge is one of the main barriers. Details regarding specifically which educational needs exist among family medicine clinicians requires further study. Objective: The aim of this study was to identify both the perceived role that pharmacogenomics (PGx) could play in primary care practice, the knowledge gaps that family medicine clinicians experience, and the skills they require to use PGx in their daily practice. Methods: To achieve this aim, the attitudes, knowledge, barriers, skills needed, and preferred educational program were explored in a family medicine clinician focus group study via a semi-structured interview and knowledge quiz. Second, multidisciplinary focus groups provided information on the level of knowledge and necessary skills to use PGx in patient care. After gathering key recorded information from both focus groups, the perceived role pharmacogenomics could possibly play in primary care, the predominant knowledge gaps, and the most appropriate educational program was determined by qualitative analysis. Results: Four themes emerged regarding the PGx educational needs and the role of PGx in family medicine: 1) need for PGx competences, 2) insight into the roles and responsibilities of PGx services, 3) optimization of PGx workflow through artificial intelligence integrated in the electronic health record, and 4) the ethical dilemmas and psychological effects related to PGx. These themes reflect a shift in the role of PGx in family medicine with implications for education. Conclusion: The results obtained from this study will help improve the implementation of PGx in daily practice, and consequently, may result in increased utilization of PGx, thereby resulting in improved medication efficacy and reduced side effects.

"CYP3A4 Poor and Intermediate Metabolizers Have a Higher Rate of Steroid-Induced Intraocular Pressure Response".

PURPOSE: Evaluate the relationship between CYP3A4 phenotype, the gene encoding the enzyme that metabolizes exogenous steroid, and the rate of steroid-induced intraocular pressure (IOP) response. MATERIALS AND METHODS: Lymphocyte-derived DNA sequencing of CYP3A4 from 10073 patients was completed using the PGRN-Seq assay. Subjects with CYP3A4 intermediate metabolizer or slower phenotypes were identified and compared with controls matched by age, race and sex. All subjects had at least three eye exams with at least an exam while on topical/systemic/local steroid in any body location except the eye. Patients with pre-existing glaucoma or glaucoma suspect were excluded. RESULTS: Of the 10073 patients, there were 63 patients who had CYP3A4 poor or intermediate metabolizer phenotype. Of the 63 patients, 22 had documented steroid use. Fifty-nine percent (13/22) of patients with CYP3A4 poor/intermediate metabolizer had a steroid-induced IOP response of 3 mmHg or more, significantly higher compared to 23% (5/22) of matched controls (P=0.031). Although more poor /intermediate metabolizers were steroid responders, the average IOP elevation in steroid responders in both groups were similar (5.0 ± 2.5 mmHg in CYP3A4 poor/intermediate metabolizers compared to 4.1 ± 2.1mmHg in controls, P=0.327). Family history of glaucoma was similar in both groups (7/22 vs. 8/22, P=1.0). CONCLUSION: Reduced CYP3A4 phenotypes may help identify patients at a higher risk of steroid-induced IOP elevation. PRCIS: This retrospective study examined patients with sequenced CYP3A4, a gene encoding an enzyme that metabolizes exogenous steroids. When compared to normal metabolizers, CYP3A4 poor or intermediate metabolizers have a higher steroid-induced IOP response rate.

Impact of sex on antidepressant discontinuation in groups of similar cytochrome P450 phenotypes.

Introduction: Although there are studies assessing reasons for antidepressant discontinuation, little is known about the impact of sex differences or cytochrome P450 phenotypes. Our objective is to assess discontinuation rates between males and females and whether CYP450 phenotype influences discontinuation. Methods: This is a retrospective review of patients previously enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment database with major depressive disorder. Patients were evaluated for antidepressants trialed between January 1, 2009, and September 30, 2019. Survival analyses with competing risks were used to analyze discontinuation reasons. A Kaplan-Meier estimation method was used to assess the time to discontinuation and discontinuation rates. Analyses were also completed to assess discontinuation between men and women by phenotypic groups. All tests were two-sided, and p-values ≤ .05 were considered statistically significant. Results: There were 620 antidepressant discontinuation events discovered from 1015 antidepressant trials included. Overall, the median time to discontinuation for males was 2.6 years and 1.9 years for females (hazard ratio [HR] 0.97 [95% confidence interval (CI): 0.80, 1.19], p = .77). The risk of discontinuation was not different between males and females in any of the phenotype groups, which was consistent in the multivariable analyses. Concomitant use of medications that inhibited or induced antidepressant metabolism increased the overall risk of discontinuation (HR 1.45, 95% CI [1.06, 1.99], p = .020) in a time-dependent analysis. Discussion: We did not detect a significant difference in risk of antidepressant discontinuation rates between males and females even when accounting for cytochrome P450 phenotype. Future studies should account for whether medications that inhibit or induce antidepressant metabolism may be a crucial factor in antidepressant discontinuation.

Pharmacogenomics testing in patients with liver transplant and potential impact on prospective management.

Aim: Pharmacogenomics (PGx) tests are performed on whole-blood or saliva specimens. In patients with a transplanted liver, PGx results may be discordant with hepatic drug metabolizing enzyme activity. We evaluate the incidence and impact of PGx testing in liver transplant recipients, detail potential errors and describe clinical decision support (CDS) solution implemented. Materials & methods: A retrospective cohort study of liver transplant recipients at Mayo Clinic who underwent PGx testing between 1 January 1996 and 7 October 2019 were characterized. Impact of a CDS solution was evaluated. Results: There were 129 PGx tests in 117 patients. PGx testing incidence increased before (per year incidence rate ratio = 1.45, 95% CI: 1.20-1.74, p < 0.001) and after transplant (incidence rate ratio = 1.48, 95% CI: 1.27-1.72, p < 0.001). Three erroneous PGx tests were avoided 6 months following CDS implementation. Conclusion: Incidence of PGx testing in liver transplant recipients is increasing, leading to erroneous therapeutic decisions. CDS interventions and education are needed to prevent errors.