Assessment of the current status of real-world pharmacogenomic testing: informed consent, patient education, and related practices.

Introduction: The practice of informed consent (IC) for pharmacogenomic testing in clinical settings varies, and there is currently no consensus on which elements of IC to provide to patients. This study aims to assess current IC practices for pharmacogenomic testing. Methods: An online survey was developed and sent to health providers at institutions that offer clinical germline pharmacogenomic testing to assess current IC practices. Results: Forty-six completed surveys representing 43 clinical institutions offering pharmacogenomic testing were received. Thirty-two (74%) respondents obtain IC from patients with variability in elements incorporated. Results revealed that twenty-nine (67%) institutions discuss the benefits, description, and purpose of pharmacogenomic testing with patients. Less commonly discussed elements included methodology and accuracy of testing, and laboratory storage of samples. Discussion: IC practices varied widely among survey respondents. Most respondents desire the establishment of consensus IC recommendations from a trusted pharmacogenomics organization to help address these disparities.

Estimating the efficacy of pharmacogenomics over a lifetime.

It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given prescriptions over a lifetime that could be contraindicated by their pharmacogenomic profiles. To determine the clinical utility of pharmacogenomics over a lifetime in a general patient population, we sequenced the genomes of 300 deceased Marshfield Clinic patients linked to lifelong medical records. Genetic variants in 33 pharmacogenes were evaluated for their lifetime impact on drug prescribing using extensive electronic health records. Results show that 93% of the 300 deceased patients carried clinically relevant variants. Nearly 80% were prescribed approximately three medications on average that may have been impacted by these variants. Longitudinal data suggested that the optimal age for pharmacogenomic testing was prior to age 50, but the optimal age is greatly influenced by the stability of the population in the healthcare system. This study emphasizes the broad clinical impact of pharmacogenomic testing over a lifetime and demonstrates the potential application of genomic medicine in a general patient population for the advancement of precision medicine.

Preliminary outcomes of preemptive warfarin pharmacogenetic testing at a large rural healthcare center.

PURPOSE: As a preliminary evaluation of the outcomes of implementing pharmacogenetic testing within a large rural healthcare system, patients who received pre-emptive pharmacogenetic testing and warfarin dosing were monitored until June 2017. SUMMARY: Over a 20-month period, 749 patients were genotyped for VKORC1 and CYP2C9 as part of the electronic Medical Records and Genomics Pharmacogenetics (eMERGE PGx) study. Of these, 27 were prescribed warfarin and received an alert for pharmacogenetic testing pertinent to warfarin; 20 patients achieved their target international normalized ratio (INR) of 2.0-3.0, and 65% of these patients achieved target dosing within the recommended pharmacogenetic alert dose (± 0.5 mg/day). Of these, 10 patients had never been on warfarin prior to the alert and were further evaluated with regard to time to first stable target INR, bleeds and thromboembolic events, hospitalizations, and mortality. There was a general trend of faster time to first stable target INR when the patient was initiated at a warfarin dose within the alert recommendation versus a dose outside of the alert recommendation with a mean (± SD) of 34 (± 28) days versus 129 (± 117) days, respectively. No trends regarding bleeds, thromboembolic events, hospitalization, or mortality were identified with respect to the pharmacogenetic alert. The pharmacogenetic alert provided pharmacogenetic dosing information to prescribing clinicians and appeared to deploy appropriately with the correct recommendation based upon patient genotype. CONCLUSION: Implementing pharmacogenetic testing as a standard of care service in anticoagulation monitoring programs may improve dosage regimens for patients on anticoagulation therapy.

Time course of reversal of valproate-mediated inhibition of lamotrigine.

PURPOSE: Conversion to lamotrigine (LTG) monotherapy from sodium valproate (VPA) is complicated by the robust pharmacokinetic interaction between the two AEDs. This study examined changes in LTG serum concentrations immediately following VPA discontinuation. METHODS: Ten healthy female and male adult subjects were initiated on LTG (Lamictal) 10 mg orally every morning for 30 days and VPA (Depakote ER) 500 mg orally every morning for 14 days. Morning trough (pre-dose) venous blood samples were obtained for determination of LTG and VPA concentrations on study days 14, 15, 16, 18, 20, 22, 24, 26, 28, and 30. Following the collection of the blood sample on day 15, VPA was discontinued. RESULTS: Despite stable LTG dosage serum concentrations on study day 20, 22, 24, 26, and 28, all were significantly lower compared to baseline (p < 0.05). CONCLUSIONS: These observations demonstrate that the pharmacokinetic interaction between LTG and VPA is reversible, and that de-inhibition appears to follow a predictable time course. Complete offset, or reversal of this interaction takes place 10-14 days after VPA discontinuation. Our data also confirms the observation that LTG oral clearance may be inhibited by very low concentrations of VPA. These data support the conversion algorithm suggested by the manufacturer, and provide guidance to the clinician. These data provide clinically useful information in developing a dosing algorithm for converting patients to LTG monotherapy.

Genetics of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics.