Tabula Rasa HealthCare company profile: involvement in pharmacogenomic and personalized medicine research

Tabula Rasa HealthCare

Tabula Rasa HealthCare (TRHC) improves health by creating patient-specific, data-driven technology and solutions that empower pharmacists, providers and patients to optimize medication regimens. TRHC is trusted to improve medication outcomes, reduce hospitalizations, lower healthcare costs and manage risk.

Medication safety imperatives

Medication overload is a growing problem in the USA. The Lown Institute attributes medication overload to negative prescribing cultures, knowledge gaps and fragmentation of care due to inadequate communication among providers [1]. Nationally, about 40% of older adults take five or more prescription medications, and almost 20% take 10 or more [2]. Thus, medication overload is predicted to account for at least 4.6 million hospitalizations and 150,000 premature deaths between 2020 and 2030 and will cost taxpayers, patients and families an estimated USD $62 billion if current prescribing trends continue [1,3].

The most recognized contributor to this condition of medication overload is excessive prescribing, or overprescribing. Another significant contributor to medication overload is unsafe drug selection. Too often, medication-related problems originate from drug–drug interactions, multidrug interactions, drug–gene interactions (DGIs), phenotype conversions, and other issues for which explanations are rooted in the deep sciences of pharmacokinetics, pharmacodynamics and pharmacogenomics.

TRHC is addressing these medication safety imperatives by developing systems that simplify the medication science to help clinicians reduce inappropriate medication use and to promote and enable safer prescribing.

Expanding the medication safety knowledge base

TRHC’s Research & Development Pillar innovates and redefines the science of medication safety to optimize medication use. The Pillar’s clinical pharmacists, clinical research scientists, pharmaceutical scientists, drug information specialists, data scientists, data analysts and software engineers are committed to the development and validation of the TRHC’s systems which improve patient outcomes and reduce preventable healthcare utilization and costs. In 2020 alone, this team produced 47 articles that were published in peer-reviewed journals [4].

Key research in 2020 illuminated medication safety issues related to treatments explored during the COVID-19 pandemic. Using proprietary advanced modeling systems, TRHC scientists virtually tested COVID-19 repurposed drugs (e.g., azithromycin, hydroxychloroquine, chloroquine, remdesivir and lopinavir/ritonavir). Specifically, they demonstrated the impact of such medications on the MedWise Risk Scores™ (MRS) of various patient populations (Programs of All-Inclusive Care for the Elderly, Medicare, Medicaid and commercially insured), quantified the characteristics of individuals who were at greater risk of adverse drug event (ADEs), and demonstrated the impact of COVID-19 drugs on the risk of drug-induced long QT syndrome [5,6]. TRHC scientists also published one of the first reviews describing the involvement of angiotensin-converting enzyme 2 in SARS coronavirus 2 infection, and reported on the role of telemedicine and drug prescription consummation [7–9].

Opioid safety has also been a TRHC priority. TRHC has repeatedly demonstrated the role of drug interactions in chronic pain management and best practices for avoiding such, including case reports describing interactions in patients with known pharmacogenomics (PGx) results and phenoconversion [10–15]. Other recent research has focused on pharmacokinetic modeling to assess CYP2D6-mediated drug–drug interactions on tramadol exposures via allosteric and competitive inhibition, on costs related to drug interactions involving CYP2D6 individuals who use opioids, and on disease-induced modulation of CYP450 expression and activity [16].

Perhaps most importantly, TRHC scientists have been largely involved, throughout their academic and industry careers, in knowledge development related to PGx. More than 100 publications related to PGx are available in peer-reviewed journals from key TRHC scientists. In recent years, they have contributed to the development of clinical recommendation guidelines, described applied concepts of PGx, and reported on illustrative cases of PGx and the impact of specific polymorphisms on the disposition of drugs [4,17–21].

PGx-informed pharmacy systems: MedWise^®

The ideal model for integration into clinical practice of PGx information requires laboratory-based genetic testing of a DNA sample, results analysis for possible drug–drug and drug–gene risks and interactions, and communication of actionable recommendations through a shared platform. Since 2010, TRHC has embraced this model, providing PGx-informed pharmaceutical care and working to create the systems and technology – now known as MedWise – to meet the above requirements.

Today, TRHC continues to conduct translational and applied research related to current clinical practice, provide PGx services and operate a drug information resource center. PGx testing is a component of comprehensive pharmacy services offered through TRHC. PGx experts, along with pharmacy residents undergoing advanced training in PGx, manage the testing process, create interpretive reports when PGx results are available, perform PGx-informed medication regimen reviews, and consult with healthcare providers and patients.

Since launching their proprietary MedWise technology and systems, TRHC has repeatedly proven the feasibility and value of implementing PGx services into medication risk mitigation strategies [22]. They have demonstrated that PGx-informed interventions with patients taking multiple medications resulted in identification of significant actionable, medication-related problems [23]. Further, they have also shown that, nationwide, individuals enrolled in Programs of All-Inclusive Care for the Elderly frequently use drugs associated with DGI and drug–DGI (DDGI) risks, and the majority of those patients experience more than one interaction [24]. Additionally, TRHC has demonstrated cost avoidance related to pharmacist-led PGx services (i.e., economic consequences that would have occurred without pharmacist intervention) [25]. Overall, the mean cost avoidance per actionable drug–gene pair was USD $1063 [25]. TRHC has demonstrated the value of pharmacist-led interventions – aided by the use of TRHC technologies – for adherence, cost savings and medication safety concerns [26]. Recently, the value of pharmacist-supported transitions-of-care services was demonstrated on 30-day readmission rates [27].

A key component of the PGx-informed TRHC systems is the MRS. The MRS is a numerical indicator of a patient’s risk based on their unique medication list. A patient’s MRS is calculated using active medication ingredients of their entire medication profile. The MRS is used to guide recommendations and to benchmark intervention impact. Scores are categorized into five levels: minimal, low, intermediate, high and severe.

Clinicians use the MRS in tandem with TRHC’s suite of MedWise clinical decision support tools to reduce adverse drug events, improve health and reduce costs. The clinical decision support tools include a risk matrix, which enables clinicians to more easily mitigate the risk of medication-safety related problems by considering pharmacokinetic, pharmacodynamic and PGx risks, including accumulative multidrug interactions, DGI and DDGI.

In MedWise, a proprietary weighted value is assigned to various medication risk factors to provide clinicians with an understanding of total aggregate patient risk and to facilitate actionable insights into the root causes of ADEs. Several unique burden scores are calculated, including: relative odds ratio computed for a drug regimen risk of causing ADEs using the US FDA’s Adverse Event Reporting System, an anticholinergic drug burden, a sedative drug burden, a proprietary drug-induced long QT syndrome burden and a proprietary CYP450–drug interaction burden. Additional consideration is given to PGx variables – when available, providing a PGx phenotype and a final combined phenotype that considers PGx and drug-induced phenoconversion [28]. These calculations rely on evidence-based literature in addition to original research conducted by TRHC in partnership with universities and research organizations.

At the population level, MedWise systems deliver medication risk stratification to identify patients with higher medication risk scores who would benefit the most from medication safety interventions. Population medication risk stratifications help to optimize healthcare services for high-risk subgroups of patients. Prioritizing care for these patients is particularly important, as higher MRSs are associated with increased odds for ADEs, greater Medicare Part A and B healthcare costs, increased emergency department visits, increased hospital admissions and longer hospital stays [29]. A higher MRS has also been associated with an increased likelihood of death [30].

MedWise science in practice

MedWise solutions enable clinicians to assess simultaneous, multidrug interactions in a single view, allowing for quicker identification of the most clinically relevant medication problems and reducing alert fatigue. When a complete medication list is input, comprehensive, personalized safety guidance can be obtained for DGIs, DDGIs, multidrug interactions and phenotype conversions – which may warrant additional monitoring, dose alterations, or therapy changes. When PGx results are also input, MedWise enables clinicians to deliver even more precise, personalized medication safety recommendations [24,31].

In MedWise visualizations, all medications of a drug regimen are displayed simultaneously with their associated CYP450-mediated pathways and relative affinities; the relative affinities distinguish competitive inhibition (i.e., between weak, moderate and strong CYP–enzyme substrates) from noncompetitive interaction (i.e., involving inhibitors or inducers) [22,32]. Mechanisms of CYP450 inhibition were reviewed in detail by Deodhar et al. to describe drug–drug interactions associated with mechanism-based inhibition [33]. This information is crucial for clinicians to consider when developing mitigation strategies between DDIs. For example, in a patient who takes a CYP2D6 weak affinity prodrug (e.g., codeine as a victim drug) at the same time as a CYP2D6 moderate affinity substrate (e.g., duloxetine as a perpetrator), the activation of the weaker affinity prodrug is expected to be reduced as a result of competitive inhibition. Given this scenario, clinicians may opt for one or more mitigation strategies, such as separating the time of administration, dose adjustment, or changing the victim or perpetrator medications. To help support decision making, a MedWise simulation feature allows clinicians to assess the impact of regimen changes to medication safety risk and assess the outcomes of implementing various mitigation strategies [22,32].

When considering the expected response or outcome of CYP-mediated medication therapy, clinicians – and electronic medical record (EMRs) and pharmacy systems – are generally working under the assumption that the patient is a normal metabolizer. However, medication response and outcomes are highly variable between individuals, and science continues to reveal more and more CYP gene variability between and within populations [34]. Thus, TRHC recognizes the importance of including patient-specific gene variant classifications (as per PGx results) in the MedWise medication safety algorithms to support the identification of DGIs, DDGIs and phenotype conversions (phenoconversions).

As mentioned previously, codeine is a prodrug opioid that requires metabolic activation into morphine by the CYP2D6 enzyme. A DGI would occur between codeine and CYP2D6 intermediate metabolizers (IM) because IMs have reduced enzymatic activity and would be expected to activate codeine less extensively than normal metabolizers – increasing the risk for pharmacotherapy failure [31]. Following the same scenario, if a CYP2D6 higher affinity substrate (e.g., duloxetine) was prescribed along with codeine to a CYP2D6 IM, this interaction would result in phenoconversion from a CYP2D6 IM to a poor metabolizer [31]. When MedWise is used to assess interactions and PGx results have been input, phenoconversion is properly calculated in the matrixed medication assessment. Clinicians are presented with clear information that incorporates these patient-specific factors, for quick and easy decision support.

Conclusion

In conclusion, TRHC’s proprietary technology-enabled products and services advance medication safety and improve health outcomes. TRHC is spearheading the evolution of pharmacy clinical practice from preferred drug selection, to personalized, to more precise and predictive outcomes, using advanced medication therapy management strategies and PGx [20].