Recommendations for pharmacogenetic testing in clinical practice guidelines in the US.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US. SUMMARY: Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization. CONCLUSION: A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing.

Case Report: Life-Threatening Fluoxetine-Linked Postoperative Bleeding Informed by Pharmacogenetic Evaluation.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRI) are commonly used for the treatment of depression and anxiety. Inhibition of serotonin reuptake in platelets increases bleeding risk in patients taking SSRIs. CASE: Here, we present the case of a 52-year-old patient who developed severe postsurgical bleeding requiring blood transfusion following panniculectomy. CONCLUSION: SSRI-induced bleeding is dose-related and strongly influenced by individual variations in drug metabolizing enzymes and transporters. Supplementary file1 (MP4 8441 KB).

Knowledge, attitudes and practice regarding pharmacovigilance and adverse drug reaction reporting among physicians and pharmacists in Egypt: a step toward personalized medicine implementation.

Aim: To assess the knowledge, attitudes, and practices of the healthcare professionals working at Children's Cancer Hospital Egypt regarding pharmacovigilance (PV) and adverse drug reaction (ADR) reporting, in addition to the ADR reporting barriers. Materials & methods: A cross-sectional study was conducted at Children's Cancer Hospital Egypt from July to September 2021 using a validated questionnaire. Results: About 37 physicians (20.3%) and 145 pharmacists (79.7%) responded to the survey. Overall, the knowledge (median: 40%) and practice (median: 50%) of PV and the reporting of ADRs were low; however, attitudes were mostly positive. The main barrier to reporting ADRs was The difficulty of determining whether or not ADRs occurred (42.3%). Conclusion: Understanding of PV and ADR reporting could improve the huge gap between ADRs experienced and ADRs reported. In order to be able to assess the impact of personalized medicine implementation, adequate ADR reporting should be well established.

Since no medication is completely safe, many of them are associated with multiple adverse reactions that may affect patients' health in terms of morbidity and, even worse, mortality. These concerns greatly increase the importance of reporting adverse drug reactions (ADRs), which highlights the essential role of pharmacovigilance (PV) centers. This study was performed at Children's Cancer Hospital using a validated questionnaire; to collect information on healthcare professionals' demographics and their knowledge of, attitudes toward and practices in PV; analyze reasons for the the under-reporting of ADRs; and recommend possible ways to improve reporting. The majority of the healthcare professionals had poor knowledge and practice of PV and ADR reporting, which clearly explains the huge gap between ADRs experienced and ADRs reported. However, they have a positive attitude toward PV and ADR reporting.

Application of the community dialogues method to identify ethical values and priorities related to pharmacogenomics.

Given the expansion of genetics in medicine, there is a growing need to develop approaches to engage patients in understanding how genetics affects their health. Various qualitative methods have been applied to gain a deeper understanding of patient perspectives in topics related to genetics. Community dialogues (CD) are a bi-directional research method that invites community members to discuss a pertinent, challenging topic over the course of a multi-week period and the community members openly discuss their positions on the topic. Authors discuss the first application of the CD method to the topic of pharmacogenetics testing. Additional CD are needed to engage diverse participant populations on this topic to improve genetics literacy, enhance physician engagement and drive policy change.

Inaugural Pharmacogenomics Access and Reimbursement Symposium.

The Pharmacogenomics Access & Reimbursement Symposium, a landmark event presented by the Golden Helix Foundation and the Pharmacogenomics Access & Reimbursement Coalition, was a 1-day interactive meeting comprised of plenary keynotes from thought leaders across healthcare that focused on value-based strategies to improve patient access to personalized medicine. Stakeholders including patients, healthcare providers, industry, government agencies, payer organizations, health systems and health policy organizations convened to define opportunities to improve patient access to personalized medicine through best practices, successful reimbursement models, high quality economic evaluations and strategic alignment. Session topics included health technology assessment, health economics, health policy and value-based payment models and innovation.

PARC report: a health-systems focus on reimbursement and patient access to pharmacogenomics testing.

Pharmacogenomics test coverage and reimbursement are major obstacles to clinical uptake. Several early adopter programs have been successfully initiated through dedicated investments by federal and institutional research funding. As a result of research endeavors, evidence has grown sufficiently to support development of pharmacogenomics guidelines. However, clinical uptake is still limited. Third-party payer support plays an important role in increasing adoption, which to date has been limited to reactive single-gene testing. Access to and interest in direct-to-consumer genetic testing are driving demand for increasing healthcare providers and third-party awareness of this burgeoning field. Pharmacogenomics implementation models developed by early adopters promise to expand patient access and options, as testing continues to increase due to growing consumer interest and falling test prices.

PARC report: health outcomes and value of personalized medicine interventions: impact on patient care.

The incorporation of personalized medicine interventions into routine healthcare constitutes an opportunity to improve patients' quality of life, as it empowers implementation of innovative, individualized clinical interventions that maximize efficacy and/or minimize the risk of adverse drug reactions. In order to ensure equal access to genomic testing for all patients, the costs associated with these interventions must be reimbursed by payers and insurance bodies. As such, it is of utmost importance to thoroughly evaluate these interventions both in terms of their clinical effectiveness and their economic cost. This article discusses the impact of personalized medicine interventions in terms of both health outcomes and value, which directly impacts on their pricing and reimbursement by the various national healthcare systems.

PARC report: a perspective on the state of clinical pharmacogenomics testing.

In this Perspective, the authors discuss the state of pharmacogenomics testing addressing a number of advances, challenges and barriers, including legal ramifications, changes to the regulatory landscape, coverage of testing and the implications of direct-to-consumer genetic testing on the provision of care to patients. Patient attitudes toward pharmacogenomics testing and associated costs will play an increasingly important role in test acquisition and subsequent utilization in a clinical setting. Additional key steps needed include: further research trials demonstrating clinical utility and cost-effectiveness of pharmacogenetic testing, evidence review to better integrate genomic information into clinical practice guidelines in target therapeutic areas to help providers identify patients that may benefit from pharmacogenetic testing and engagement with payers to create a path to reimbursement for pharmacogenetic tests that currently have sufficient evidence of clinical utility. Increased adoption of testing by payers and improved reimbursement practices will be needed to overcome barriers, especially as the healthcare landscape continues to shift toward a system of value-based care.

A Follow-Up Clinical Trial Evaluating the Consumer-Decides Service Delivery Model.

Objectives There were 2 main objectives. The primary objective was to replicate a prior clinical trial of a consumer-decides (CD) approach to selecting hearing aids in older adults as a potential model for over-the-counter (OTC) intervention using less front-end screening of participants and a wider range of frequency-gain characteristics in the devices. The 2nd objective, only feasible if participant choices allowed, was to evaluate the efficacy of the CD approach relative to a CD-based placebo device. Design The design of this study is a single-site, prospective, double-blind clinical trial. Outcome measures were obtained after a typical 4- to 5-week trial period. An optional follow-up of a 4-week audiology-based (AB) best practices trial was also included for replication and comparison purposes. Setting Older adults from the general community were recruited via newspaper and community flyers to participate at a university research clinic. Participants Participants were adults, aged 54-78 years, with mild-moderate hearing loss. Forty-one participants enrolled as a volunteer sample; 40 completed the intervention. Intervention(s) All participants received the same high-end digital mini-behind-the-ear hearing aids fitted bilaterally. CD participants self-selected their own preprogrammed hearing aids via an OTC-type model. One of the 3 devices from which participants could choose was programmed to be a placebo device with no functional gain. Primary and Secondary Outcome Measures The primary outcome measure is the 66-item self-report Profile of Hearing Aid Benefit ( Cox & Alexander, 1990 ). The secondary outcome measure is the Connected Speech Test ( Cox, Alexander, & Gilmore, 1987 ) benefit. Additional measures of hearing aid benefit and usage were also obtained. Results Per-protocol analyses based on the data from the 40 (of 41) participants who completed the study were performed. Hearing aid outcomes from this follow-up CD (CD2) cohort were positive and generally the same as for the original CD cohort. CD service delivery model was efficacious relative to CD-based placebo control, with medium effect sizes observed. Approximately half of the CD2 group was likely to purchase hearing aids after the trial, similar to findings for the original CD cohort. Outcomes improved significantly for the 32 CD2 participants who elected to complete the optional 4-week AB trial. For this largely unscreened sample, more individuals with healthy hearing sought amplification, and many of these individuals (35%) chose placebo devices for both ears. Conclusions Prior positive outcomes for CD service delivery have been replicated in a less restrictive approach to participant recruitment. The CD approach was again found to be efficacious. Significantly better outcomes were observed after subsequent AB service delivery follow-up, also replicating prior findings. Efficacious OTC models, including those using similar CD approaches to hearing aid self-selection, may increase accessibility and affordability of hearing aids for millions of older adults. Front-end guidance to consumers regarding the best path to intervention, ranging from self-screening of hearing online to a full audiologic assessment, appears to be critical to optimize the success of OTC approaches. Trial Registration Clinicaltrials.gov: NCT01788432; https://clinicaltrials.gov/ct2/show/NCT01788423 Supplemental Material https://doi.org/10.23641/asha.7728479.

Clinical Effectiveness of an At-Home Auditory Training Program: A Randomized Controlled Trial.

OBJECTIVES: To investigate the effectiveness of an at-home frequent-word auditory training procedure for use with older adults with impaired hearing wearing their own hearing aids. DESIGN: Prospective, double-blind placebo-controlled randomized trial with three parallel branches: an intervention group who received the at-home auditory training; an active control group who listened to audiobooks using a similar platform at home (placebo intervention); and a passive control group who wore hearing aids and returned for outcomes, but received no intervention. Outcome measures were obtained after a 5-week period. A mixed research design was used with a between-subjects factor of group and a repeated-measures factor of time (pre- and post-treatment) to evaluate the effects of the at-home auditory training program. The intervention was completed in participants' own homes. Baseline and outcomes measures were assessed at a university research laboratory. The participants were adults, aged 54 to 80 years, with the mild-to-moderate hearing loss. Of the 51 identified eligible participants, 45 enrolled as a volunteer sample and 43 of these completed the study. Frequent-word auditory training regimen completed intervention at home over a period of 5 weeks. The active control group listened to audiobooks (placebo intervention) and the passive control group completed no intervention. The primary outcome measure is a Connected Speech test benefit. The secondary outcome measure is a 66-item self-report profile of hearing aid performance. RESULTS: Participants who received the at-home training intervention demonstrated significant improvements on aided recognition for trained materials, but no generalization of these benefits to nontrained materials was seen. This was despite reasonably good compliance with the at-home training regimen and careful verification of hearing aid function throughout the trial. Based on follow-up post-trial evaluation, the benefits observed for trained materials in the intervention group were sustained for a period of at least 8.5 months. No improvement was seen for supplemental outcome measures of hearing aid satisfaction, hearing handicap, or tolerance of background noise while listening to speech. CONCLUSIONS: The at-home auditory training procedure utilizing frequently occurring words was effective for the trained materials used in the procedure. No generalization was seen to nontrained materials or to perceived benefit from hearing aids.

The Acoustic Environments in Which Older Adults Wear Their Hearing Aids: Insights From Datalogging Sound Environment Classification.

PURPOSE: This report presents data on the acoustic environments in which older adults with age-related hearing loss wear their hearing aids. METHOD: This is an observational study providing descriptive data from 2 primary datasets: (a) 128 older adults wearing hearing aids for an average of 6 weeks and (b) 65 older adults wearing hearing aids for an average of 13 months. Acoustic environments were automatically and continuously classified about every 4 s, using the hearing aids' signal processing, into 1 of 7 acoustic environment categories. RESULTS: For both groups, older adults wore their hearing aids about 60% of the time in quiet or speech-only conditions. The automatic classification of sound environments was shown to be reliable over relatively short (6-week) and long (13-month) durations. Moreover, the results were shown to have some validity in that the obtained acoustic environment profiles matched a self-reported measure of social activity administered prior to hearing aid usage. For a subset of 56 older adults with data from both the 6-week and 13-month wear times, the daily amount of hearing aid usage diminished but the profile of sound environments frequented by the wearers remained stable. CONCLUSIONS: Examination of the results from the automatic classification of sound environments by the hearing aids of older adults provides reliable and valid environment classifications. The present data indicate that most such wearers choose generally favorable acoustic environments for hearing aid use.

The Effects of Service-Delivery Model and Purchase Price on Hearing-Aid Outcomes in Older Adults: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

OBJECTIVES: The objectives of this study were to determine efficacy of hearing aids in older adults using audiology best practices, to evaluate the efficacy of an alternative over-the-counter (OTC) intervention, and to examine the influence of purchase price on outcomes for both service-delivery models. DESIGN: The design of this study was a single-site, prospective, double-blind placebo-controlled randomized trial with three parallel branches: (a) audiology best practices (AB), (b) consumer decides OTC model (CD), and (c) placebo devices (P). Outcome measures were obtained after a typical 6-week trial period with follow-up 4-week AB-based trial for those initially assigned to CD and P groups. SETTING: Older adults from the general community were recruited via newspaper and community flyers to participate at a university research clinic. PARTICIPANTS: Participants were adults, ages 55-79 years, with mild-to-moderate hearing loss. There were 188 eligible participants: 163 enrolled as a volunteer sample, and 154 completed the intervention. INTERVENTION(S): All participants received the same high-end digital mini-behind-the-ear hearing aids fitted bilaterally. AB and P groups received best-practice services from audiologists; differing mainly in use of appropriate (AB) or placebo (P) hearing aid settings. CD participants self-selected their own pre-programmed hearing aids via an OTC model. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measure was a 66-item self-report, Profile of Hearing Aid Benefit (Cox & Gilmore, 1990). Secondary outcome measure was the Connected Speech Test (Cox, Alexander, & Gilmore, 1987) benefit. Additional measures of hearing-aid benefit, satisfaction, and usage were also obtained. RESULTS: Per-protocol analyses were performed. AB service-delivery model was found to be efficacious for most of the outcome measures, with moderate or large effect sizes (Cohen's d). CD service-delivery model was efficacious, with similar effect sizes. However, CD group had a significantly (p < .05) lower satisfaction and percentage (CD: 55%; AB: 81%; P: 36%) likely to purchase hearing aids after the trial. CONCLUSIONS: Hearing aids are efficacious in older adults for both AB and CD service-delivery models. CD model of OTC service delivery yielded only slightly poorer outcomes than the AB model. Efficacious OTC models may increase accessibility and affordability of hearing aids for millions of older adults. Purchase price had no effect on outcomes, but a high percentage of those who rejected hearing aids paid the typical price (85%). TRIAL REGISTRATION: Clinicaltrials.gov: NCT01788432; https://clinicaltrials.gov/ct2/show/NCT01788423.

Lack of interaction between enzalutamide and warfarin in a metastatic castration-resistant prostate cancer patient.

Enzalutamide is an androgen receptor antagonist used for the treatment of metastatic castration-resistant prostate cancer. Enzalutamide is classified as a strong cytochrome P450 3A4 inducer, a moderate 2C9 and 2C19 inducer, and a time-dependent inducer of 1A2. Warfarin's more potent enantiomer is primarily metabolized by cytochrome P450 2C9 and has a narrow therapeutic window. Enzalutamide is thought to decrease therapeutic warfarin concentrations per pharmacokinetic studies performed during drug development. This case report describes a 59-year-old man undergoing treatment with enzalutamide for metastatic castration-resistant prostate cancer with a history of femoral vein thrombosis. The patient was receiving a total weekly warfarin dose of 37.5 mg prior to starting enzalutamide. Enzalutamide was initiated and warfarin continued at a constant dose without decrease in the patient's INR. The patient continued on enzalutamide and warfarin for 1 year without having any documented subtherapeutic INRs. This report illustrates one case in which the interaction between warfarin and enzalutamide was not clinically significant.

Functional modeling identifies paralogous solanesyl-diphosphate synthases that assemble the side chain of plastoquinone-9 in plastids.

It is a little known fact that plastoquinone-9, a vital redox cofactor of photosynthesis, doubles as a precursor for the biosynthesis of a vitamin E analog called plastochromanol-8, the physiological significance of which has remained elusive. Gene network reconstruction, GFP fusion experiments, and targeted metabolite profiling of insertion mutants indicated that Arabidopsis possesses two paralogous solanesyl-diphosphate synthases, AtSPS1 (At1g78510) and AtSPS2 (At1g17050), that assemble the side chain of plastoquinone-9 in plastids. Similar paralogous pairs were detected throughout terrestrial plant lineages but were not distinguished in the literature and genomic databases from mitochondrial homologs involved in the biosynthesis of ubiquinone. The leaves of the atsps2 knock-out were devoid of plastochromanol-8 and displayed severe losses of both non-photoactive and photoactive plastoquinone-9, resulting in near complete photoinhibition at high light intensity. Such a photoinhibition was paralleled by significant damage to photosystem II but not to photosystem I. In contrast, in the atsps1 knock-out, a small loss of plastoquinone-9, restricted to the non-photoactive pool, was sufficient to eliminate half of the plastochromanol-8 content of the leaves. Taken together, these results demonstrate that plastochromanol-8 originates from a subfraction of the non-photoactive pool of plastoquinone-9. In contrast to other plastochromanol-8 biosynthetic mutants, neither the single atsps knock-outs nor the atsps1 atsps2 double knock-out displayed any defects in tocopherols accumulation or germination.

Investigation of the anxiolytic effects of naringenin, a component of Mentha aquatica, in the male Sprague-Dawley rat.

This was a prospective, randomized, between-subjects experimental study to investigate the anxiolytic effects of naringenin, a component of mentha aquatica, and its potential interaction with the benzodiazepine binding site on the γ-aminobutyric acid (GABAA) receptor in the rat. Fifty-five rats were assigned to one of 5 groups with 11 rats per group: control, naringenin, midazolam, midazolam with naringenin, and flumazenil with naringenin. The elevated plus maze measured the behavioral components of anxiety and motor movements. Our data suggest that naringenin does not produce anxiolysis by modulation of the GABAA receptor; however, the findings indicate that naringenin decreases motor movements (P < .05).