Evaluations from pharmacogenetics implementation programs at major US medical centers have reported variability in the clinical adoption of pharmacogenetics across therapeutic areas. A potential ...cause for this variability may involve therapeutic area-specific differences in published pharmacogenetics recommendations to clinicians. To date, however, the potential for differences in clinical pharmacogenetics recommendations by therapeutic areas from prominent US guidance sources has not been assessed. Accordingly, our objective was to comprehensively compare essential elements from clinical pharmacogenetics recommendations contained within Clinical Pharmacogenetics Implementation Consortium guidelines, US Food and Drug Administration drug labels and clinical practice guidelines from US professional medical organizations across therapeutic areas.
We analyzed clinical pharmacogenetics recommendation elements within Clinical Pharmacogenetics Implementation Consortium guidelines, US Food and Drug Administration drug labels and professional clinical practice guidelines through 05/24/19.
We identified 606 unique clinical pharmacogenetics recommendations, with the most recommendations involving oncology (217 recommendations), hematology (79), psychiatry (65), cardiovascular (43) and anesthetic (37) medications. Within our analyses, we observed considerable variability across therapeutic areas within the following essential pharmacogenetics recommendation elements: the recommended clinical management strategy; the relevant genetic biomarkers; the organizations providing pharmacogenetics recommendations; whether routine genetic screening was recommended; and the time since recommendations were published.
On the basis of our results, we infer that observed differences in clinical pharmacogenetics recommendations across therapeutic areas may result from specific factors associated with individual disease states, the associated genetic biomarkers, and the characteristics of the organizations providing recommendations.
Patients carrying DPYD variant alleles have increased risk of severe toxicity from systemic fluoropyrimidine chemotherapy. There is a paucity of data regarding risk of toxicity from topical ...5‐fluorouracil (5‐FU) treatment in these patients, leading to inconsistent guideline recommendations for pretreatment testing and topical 5‐FU dosing. The objective of this retrospective cohort study was to investigate whether DPYD variant allele carriers have increased risk of toxicity from topical 5‐FU. Treatment and toxicity data were retrospectively ed from the electronic medical records. Genotypes for the five DPYD variants that are associated with increased toxicity from systemic fluoropyrimidine chemotherapy (DPYD*2A, DPYD*13, DPYD p.D949V, DPYD HapB3, and DPYD p.Y186C) were collected from a genetic data repository. Incidence of grade 3+ (primary end point) and 1+ (secondary end point) toxicity was compared between DPYD variant carriers vs. wild‐type patients using Fisher's exact tests. The analysis included 201 patients, 7% (14/201) of whom carried a single DPYD variant allele. No patients carried two variant alleles or experienced grade 3+ toxicity. DPYD variant allele carriers did not have a significantly higher risk of grade 1+ toxicity (21.4% vs. 10.2%, odds ratio = 2.40, 95% confidence interval: 0.10–2.53, P = 0.19). Given the low toxicity risk in patients carrying a single DPYD variant allele, there is limited potential clinical benefit of DPYD genetic testing prior to topical 5‐FU. However, the risk of severe toxicity in patients with complete DPD deficiency remains unknown and topical 5‐FU treatment should be avoided in these patients.
Transplant recipients require individualized tacrolimus doses to maximize graft survival. Multiple pediatric tacrolimus population pharmacokinetic (PopPK) models incorporating CYP3A5 genotype and ...other covariates have been developed. Identifying the optimal popPK model is necessary for clinical implementation in pediatric solid organ transplant. The primary objective was to compare the dose prediction capabilities of the developed models in pediatric kidney and heart transplant recipients.
Pediatric kidney or heart transplant recipients treated with tacrolimus and available CYP3A5 genotype data were identified. The initial weight-based tacrolimus dose and first therapeutic tacrolimus dose were collected retrospectively. Three published popPK models were used to predict the tacrolimus dose required to achieve a tacrolimus trough concentration of 10 ng/mL. Model dose predictions were compared with the initial and first therapeutic doses using Friedman test. The first therapeutic dose was plotted against the model-predicted dose.
The median initial dose approximately 2-fold lower than the first therapeutic dose for CYP3A5 expressers. The Chen et al model provided the closest estimates to the first therapeutic dose for kidney transplant recipients; however, all 3 models tended to underpredict the observed therapeutic dose. For heart transplant recipients, Andrews et al model predicted doses that were higher than the initial dose but similar to the actual therapeutic dose.
Weight-based tacrolimus dosing appears to underestimate the tacrolimus dose requirements. The development of a separate popPK model is necessary for heart transplant recipients. A genotype-guided strategy based on the Chen et al model provided the best estimates for doses in kidney transplant recipients and should be prospectively evaluated.
Study Objective
This study investigated the effect of CYP3A5 phenotype on time in therapeutic range (TTR) of tacrolimus post‐transplant in pediatric patients.
Design and Data Source
This ...retrospective study assessed medical records of pediatric kidney and heart recipients with available CYP3A5 genotype for tacrolimus dosing, troughs, and the clinical events (biopsy‐proven acute rejection BPAR and de novo donor‐specific antibodies dnDSA).
Measurements and Main Results
The primary outcome, mean TTR in the first 90 days post‐transplant, was 9.0% (95% CI: −16.1, −1.9) lower in CYP3A5 expressers (p = 0.014) when adjusting for time to therapeutic concentration and organ type. There was no difference between CYP3A5 phenotypes in time to the first clinical event using TTR during the first 90 days. When applying TTR over the first year, there was a significant difference in event‐free survival (EFS) which was 50.0% for CYP3A5 expressers/TTR < 35%, 45.5% for expressers/TTR ≥ 35%, 38.1% for nonexpressers/TTR < 35%, and 72.9% for nonexpressers/TTR ≥ 35% (log‐rank p = 0.03). A post hoc analysis of EFS identified CYP3A5 expressers had lower EFS compared to nonexpressers in patients with TTR ≥ 35% (p = 0.04) but no difference among patients with TTR < 35% (p = 0.6).
Conclusions
The relationship between TTR and CYP3A5 phenotype suggests that achieving a TTR ≥ 35% during the first year may be a modifiable factor to attenuate the risk of BPAR and dnDSA.
ABSTRACT
Introduction
There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the ...extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients.
Methods
An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale.
Results
Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups.
Conclusions
The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi‐center clinical research. Muscle Nerve 55: 869–874, 2017
Using pharmacogenetics (PGx) to inform clinical decision making can benefit patients but clinical use of PGx testing has been limited. Existing genetics data obtained in the course of research could ...be used to identify patients who are suspected, but have not yet been confirmed, to carry clinically actionable genotypes, in whom confirmatory genetic testing could be conducted for highly efficient PGx implementation. Herein, we demonstrate that it is regulatorily and technically feasible to implement PGx by identifying suspected carriers of actionable genotypes within an institutional genetics data repository and conduct confirmatory PGx testing immediately prior to that patient receiving the PGx‐relevant drug, using a case study of DPYD testing prior to fluoropyrimidine chemotherapy. In 2 years since launching this program, ~ 3,000 suspected DPYD carriers have been passively monitored and one confirmed DPYD carrier was prevented from receiving unacceptably toxic fluoropyrimidine treatment, for minimal cost and effort. Now that we have demonstrated the feasibility of this strategy, we plan to transition to PGx panel testing and expand implementation to other genes and drugs for which the evidence of clinical benefit of PGx‐informed treatment is high but PGx testing is not generally conducted. This highly efficient implementation process will maximize the clinical benefits of testing and could be explored at other institutions that have research‐only genetic data repositories to expand the number of patients who benefit from PGx‐informed treatment while we continue to work toward wide‐scale adoption of PGx testing and implementation.
Cytochrome P450 enzyme variant alleles have shown evidence that functional consequences differ between substrates. A systematic effort has not yet been made to confirm substrate-dependent activity. ...This review will discuss the challenges of assessing three examples (CYP2C8*3, CYP2D6*10, and CYP2C9*2) where substrate-dependent activity has been hypothesized with differing levels of evidence and their potential clinical implications. Data supports bidirectional substrate-dependent activity for CYP2C8*3. Although some data suggests CYP2D6*10 causes differences in the magnitude of effect across substrates, confirmatory studies are needed. Convincing evidence for CYP2C9*2 was lacking likely due to compensatory CYP450 metabolism or experimental variability. Confirmed substrate-dependent activity has the potential to impact clinical use of pharmacogenomics, and must be taken into consideration to ensure the goal of improving treatment through personalization is met. It is important for the pharmacogenomics community to begin thinking about this important topic and how it can be best accommodated in clinical practice.
Objective
We assessed changes in quantitative muscle ultrasound data in boys with Duchenne muscular dystrophy (DMD) and healthy controls to determine whether ultrasound can serve as a biomarker of ...disease progression. Two approaches were used: gray scale level (GSL), measured from the ultrasound image, and quantitative backscatter analysis (QBA), measured directly from the received echoes.
Methods
GSL and QBA were obtained from 6 unilateral arm/leg muscles in 36 boys with DMD and 28 healthy boys (age = 2–14 years) for up to 2 years. We used a linear mixed effects model with random intercept and slope terms to compare trajectories of GSL, QBA, and functional assessments. We analyzed separately a subset of boys who initiated corticosteroids.
Results
Compared to healthy boys, increasing GSL in DMD boys >7.0 years old was first identified at 6 months (eg, anterior forearm slope difference of 1.16 arbitrary units/mo, p = 0.004, 95% confidence interval CI = 0.38–1.94); in boys ≤ 7 years old, differences in GSL first appeared at 12 months (0.82 arbitrary units/mo, p = 0.04, 95% CI = 0.075–1.565, in rectus femoris). QBA performed similarly to GSL (eg, DMD boys > 7 years old: 0.41dB/mo, p = 0.01, 95% CI = 0.096–0.72, in anterior forearm at 6 months). Ultrasound identified differences earlier than functional measures including 6‐minute walk and supine‐to‐stand tests. However, neither QBA nor GSL showed an effect of corticosteroid initiation.
Interpretation
QBA performs similarly to GSL, and both appear more sensitive than functional assessments for detecting muscle deterioration in DMD. Additional studies will be required to determine whether quantitative muscle ultrasound can detect therapeutic efficacy. Ann Neurol 2017;81:633–640
Recent advances in technology and expanding therapeutic opportunities in neuromuscular disorders has resulted in greater interest in and development of remote assessments. Over the past year, the ...rapid and abrupt COVID-19 shutdowns and stay-at-home orders imposed challenges to routine clinical management and clinical trials. As in-person services were severely limited, clinicians turned to remote assessments through telehealth to allow for continued care. Typically, disease-specific clinical outcome assessments (COAs) for neuromuscular disorders (NMD) are developed over many years through rigorous and iterative processes to fully understand their psychometric properties. While efforts were underway towards developing remote assessments for NMD before the pandemic, few if any were fully developed or validated. These included assessments of strength, respiratory function and patient-reported outcomes, as well as wearable technology and other devices to quantify physical activity and function. Without many choices, clinicians modified COAs for a virtual environment recognizing it was not yet known how they compared to standard in-person administration. Despite being able to quickly adapt to the demands of the COVID-19 pandemic, these experiences with remote assessments uncovered limitations and opportunities. It became clear that existing COAs required modifications for use in a virtual environment limiting the interpretation of the information gathered. Still, the opportunity for real-world evaluation and reduced patient burden were clear benefits to remote assessment and may provide a more robust understanding and characterization of disease impact in NMD. Hence, we propose a roadmap navigating an informed post-pandemic path toward development and implementation of safe and successful use of remote assessments for patients with NMD.
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