A Practical First Step Using Needs Assessment and a Survey Approach to Implementing a Clinical Pharmacogenomics Consult Service.

Introduction:Genetic-guided selection of non-oncologic medications is not commonly practiced in general, and at University of California, San Francisco (UCSF) Health, specifically. Understanding the unique position of clinicians with respect to clinical pharmacogenetics (PG) at a specific institution or practice is fundamental for implementing a successful PG consult service. Objectives:To assess clinicians' current practices, needs, and interests with respect to clinical PG at UCSF Health, a large tertiary academic medical center. Methods:A list of 42 target medications with clinical PG recommendations was complied. Clinical specialties that routinely used the target medications were identified. A 12-question survey focused on practice of PG for target medications was developed. Pharmacists and physicians were surveyed anonymously in several clinical specialties. Survey results were analyzed using descriptive statistics. Results:Of the 396 clinicians surveyed, 76 physicians and 59 pharmacists participated, resulting in 27% and 50% average response rates, respectively. The current use of PG in clinical practice for physicians and pharmacists was 29% and 32%, respectively, however this number varied across clinical specialties from 0% to 80%. Of clinicians whom reported they do not currently apply PG, 63% of physicians and 54% of pharmacists expressed interest in integrating PG. However, the level of interest varied from 20% to 100% across specialties. Of the respondents, 64% of physicians and 56% of pharmacists elected to provide contact information to investigators to further discuss their interest related to clinical PG. Conclusions:While PG is not uniformly practiced at UCSF Health, there is considerable interest in utilizing PG by the respondents. Our approach was successful at identifying clinicians and services interested in PG for specific drug-gene pairs. This work has set a foundation for next steps to advance PG integration at UCSF Health. Clinicians can adopt our approach as preliminary work to build a clinical PG program at their institutions

OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis

Objective Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. Methods This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. Results The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P < 0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. Conclusion Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. Design, setting, and participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. Exposures: Prescription of 38 level A medications based on electronic health records. Main outcomes and measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. Conclusions and relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants

The Pharmacogenetics of OATP1B1 Polymorphisms and Drug-Drug Interactions in Cerivastatin Associated Rhabdomyolysis

In this dissertation, the two main mechanisms of adverse event occurrence namely drug-gene and drug-drug interaction were studied to identify the cause of CER induced rhabdomyolysis. Genetic variation in drug metabolizing enzymes and membrane transporters as well as other drugs can modulate the beneficial, as well as the deleterious, effects of drugs. In a study of 126 patients who developed rhabdomyolysis while taking the HMG-CoA reductase inhibitor, cerivastatin, we sought to identify genetic variants and drug-drug interactions that might explain the high incidence of rhabdomyolysis. We re-sequenced three transporter genes, ABCC2 (coding for MRP2), ABCG2 (coding for BCRP) and SLCO1B1 (coding for OATP1B1), three metabolizing enzyme genes CYP2C8, UGT1A1 and UGT1A3 and HMGCR involved in transport, metabolism and target of cerivastatin, respectively. A total of 203 SNPs were identified in these samples and of these 52 were in the coding region. In a previously published case-control analysis of polymorphisms identified in our CYP2C8, SLCO1B1, UGT1A1 and UGT1A3 genes, the V174A SNP was found to be significantly associated with CER induced rhabdomyolysis with an odds ratio of 1.89 (95% CI,1.40-2.56). We were able to only complete in in vitro functional analysis of variants in SLCO1B1 gene on the uptake of cerivastatin in HEK293/frt cells stabely expressing SLCO1B1 reference, polymorphisms and haplotypes. The V174A SNP, along with R57Q, P155T, FS and OATP1B1*15 and N1 haplotypes were shown in in vitro assays to be associated with significant reduction (P>0.001) in CER uptake (32%, 17.9%, 72%, 3.4%, 2.1% and 5.7% of reference, respectively) compared to reference. Furthermore, clopidogrel and rofecoxib, previously identified in our cases to be associated with cerivastatin induced rhabdomyolysis at odds ratio of 29.6 (95% CI, 6.1-143) and 4.9 (95% CI, 1.1-20.8), were shown in vitro to have a significant OATP1B1 mediated interaction, inhibiting cerivastatin uptake with IC50 values of 0.32 µM (95% CI, 0.06-1.71) and 0.73 µM (95% CI, 0.3-1.8), respectively. The calculated R value for clopidogrel and rofecoxib were greater than 2, supporting a further clinical evaluation of this drug interaction

Exploratory cohort study into underlying mechanism of differences in estrogen metabolism between Asian and Caucasian women during assisted reproductive technology treatment

Background: Depression and anxiety are common among people with HIV and are associated with inadequate viral suppression, disease progression, and increased mortality. However, depression and anxiety are underdiagnosed and undertreated in people with HIV owing to inadequate visit time and personnel availability. Conducting population-level depression and anxiety screening via the patient portal is a promising intervention that has not been studied in HIV care settings. Objective: We aimed to explore facilitators of and barriers to implementing population-level portal-based depression and anxiety screening for people with HIV. Methods: We conducted semistructured hour-long qualitative interviews based on the Consolidated Framework for Implementation Research with clinicians at an HIV clinic. Results: A total of 10 clinicians participated in interviews. In total, 10 facilitators and 7 barriers were identified across 5 Consolidated Framework for Implementation Research domains. Facilitators included advantages of systematic screening outside clinic visits; the expectation that assessment frequency could be tailored to patient needs; evidence from the literature and previous experience in other settings; respect for patient privacy; empowering patients and facilitating communication about mental health; compatibility with clinic culture, workflows, and systems; staff beliefs about the importance of mental health screening and benefits for HIV care; engaging all clinic staff and leveraging their strengths; and clear planning and communication with staff. Barriers included difficulty in ensuring prompt response to suicidal ideation; patient access, experience, and comfort using the portal; limited availability of mental health services; variations in how providers use the electronic health record and communicate with patients; limited capacity to address mental health concerns during HIV visits; staff knowledge and self-efficacy regarding the management of mental health conditions; and the impersonal approach to a sensitive topic. Conclusions: We proposed 13 strategies for implementing population-level portal-based screening for people with HIV. Before implementation, clinics can conduct local assessments of clinicians and clinic staff; engage clinicians and clinic staff with various roles and expertise to support the implementation; highlight advantages, relevance, and evidence for population-level portal-based mental health screening; make screening frequency adaptable based on patient history and symptoms; use user-centered design methods to refine results that are displayed and communicated in the electronic health record; make screening tools available for patients to use on demand in the portal; and create protocols for positive depression and anxiety screeners, including those indicating imminent risk. During implementation, clinics should communicate with clinicians and clinic staff and provide training on protocols; provide technical support and demonstrations for patients on how to use the portal; use multiple screening methods for broad reach; use patient-centered communication in portal messages; provide clinical decision support tools, training, and mentorship to help clinicians manage mental health concerns; and implement integrated behavioral health and increase mental health referral partnerships.</p

Ascorbic acid metabolites are involved in intraocular pressure control in the general population.

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Mechanisms involved in its homeostasis are not well understood, but associations between metabolic factors and IOP have been reported. To investigate the relationship between levels of circulating metabolites and IOP, we performed a metabolome-wide association using a machine learning algorithm, and then employing Mendelian Randomization models to further explore the strength and directionality of effect of the metabolites on IOP. We show that O-methylascorbate, a circulating Vitamin C metabolite, has a significant IOP-lowering effect, consistent with previous knowledge of the anti-hypertensive and anti-oxidative role of ascorbate compounds. These results enhance understanding of IOP control and may potentially benefit future IOP treatment and reduce vision loss from glaucoma.Acknowledgements & Author Contributions EPIC-Norfolk infrastructure and core functions are supported by grants from the Medical Research Council (G1000143) and Cancer Research UK (C864/A14136). The clinic for the third health examination was funded by Research into Ageing (262). Genotyping was funded by the Medical Research Council (MC_PC_13048). We thank all staff from the MRC Epidemiology laboratory team for the preparation and quality control of DNA samples. Mr Khawaja is supported by a Moorfields Eye Charity fellowship. Professor Foster has received additional support from the Richard Desmond Charitable Trust (via Fight for Sight) and the Department for Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital and the UCL Institute of Ophthalmology for a specialist Biomedical Research Centre for Ophthalmology. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR) – funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London. CH and PH acknowledge the support from the TFC Frost Charitable Trust

OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis.

ObjectiveGenetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin.MethodsThis study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1.ResultsThe resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P&lt;0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin.ConclusionReduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1

Association of Pharmacogenetic Markers With Atazanavir Exposure in HIV‐Infected Women

SORCS2 rs73208473 was recently associated with decreased atazanavir (ATV) concentration in the hair of women with seropositive HIV. Herein, we report on a pharmacogenetic study of women with seropositive HIV demonstrating a similar association between rs73208473 and dose-adjusted plasma ATV concentration in African Americans