Pre Emptive Pharmacogenomic Testing: What Is in It for Us?

Did you know—adverse drug reactions (ADRs) cause Singapore patients to spend an extrapolated 48,000 extra days a year in hospitals[1]? According to a study done by a team of researchers at the Agency of Science, Technology and Research (A*STAR) and the Singapore General Hospital (SGH), about 30% of ADRs admitted to SGH were caused by at least one drug with a clinical annotation in the Pharmacogenomics KnowledgeBase (PharmGKB), suggesting that some of these ADRs could have been pre-empted by pharmacogenomic testing.[2]

While opportunities for optimising drug response according to patients’ genetic profiles are significant, the lack of ready clinical pharmacogenomics (PGx) information at the point of medication prescription is currently preventing clinicians from realising these benefits.

Dr Elaine Lo, Principal Clinical Pharmacist, Clinical Support Services, Pharmacy, National University Hospital, said, “In clinical practice, we typically order clinical PGx testing when we are either prescribing a pharmaco-genetically high-risk drug or in response to unexplained adverse events. Even then, PGx is only done on a single-gene for a single-drug basis.”

Professor Goh Boon Cher, Department of Haematology-Oncology, National University Cancer Institute, Singapore, added, “Currently, the whole process is largely reactive, and the panel of PGx information is incomplete—which means to say that a new prescription sometime down the road will require another PGx testing to be conducted. In comparison, if we were to screen a broad panel of about 16 genes for 30 drugs, through pre-emptive PGx testing and store this information in our linked electronic medical records, a clinician would be able to prescribe the required medication promptly and confidently rather than wait several days for PGx results to be returned.”

A Safeguard Against Adverse Drug Events

In August 2013, the Ministry of Health and Health Sciences Authority issued a joint guideline to announce the genotyping of the human leukocyte antigen B gene’s 1502 allele (HLA-B*1502) prior to the initiation of carbamazepine (CBZ) therapy in new patients of Asian ancestry as the standard of care.[3]

Dr Lo elaborated, “A strong association was discovered between the HLA-B*1502 allele and CBZ-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. Hence, before starting new patients on CBZ, doctors need to test for the HLA-B*1502 gene. This means waiting days to weeks for the return of test results before starting therapy. It is not a long wait but it places extra demands on clinics to trace test results, and follow up with patients on whether they can commence their medications.”

“It’s worse if it is a drug-gene pair like tramadol and CYP2D6. The CYP2D6 gene affects the patient’s response to tramadol, a painkiller. But when the patient is in great pain, it is tough to wait hours, let alone days or weeks. With pre-emptive PGx testing, these issues can be addressed in advance and relevant information can be made available at the point when doctors adjust the drug doses. More importantly, we can reduce the incidences of ADRs,” said Dr Lo.

Associate Professor Wee Hwee Lin, Saw Swee Hock School of Public Health, National University of Singapore, said, “What’s more—when we reduce ADRs, we are also reducing the economic burden arising from the associate costs of ADRs. In a 2018 study conducted at the Singapore General Hospital, we found that the total cost of 81 admissions caused by ADRs was S$770,0004. Higher incremental laboratory costs were also incurred due to ADRs causing or being present at admission.”

A Guide for Optimising Prescriptions

Availability of PGx testing results at the point of care can impact prescribing decisions in a practical way. Even when patients are already taking drugs which have Clinical Pharmacogenetics Implementation Consortium (CPIC) Evidence level A or B, a substantial proportion of them would benefit from pre-emptive PGx testing.[5] “That is because all drugs are developed for the average patient. But no two patients are the same—every patient has an optimal dose that is different from the other patient. So if we prescribe a drug according to its recommended dosage to the whole population, we’ll see that only the average patient will benefit from the prescription. Others get excessive toxicity or inefficacy,” Prof Goh said.

Prof Goh continued, “The situation is more acutely felt in drugs with narrow therapeutic windows. One example is the anti-coagulants that are prescribed to prevent stroke. Underdosing the patient may cause another stroke while overdosing may result in increased risk of bleeding. With pre-emptive PGx testing, the goal is to help doctors select the best drug with the most optimal dose so that patients do not lose a chance of response or are subjected to toxicity that could have otherwise been prevented—and yet enjoy the best therapeutic outcomes.”

A Building Block for Population Health

Despite the increasing accessibility of clinical grade PGx testing, the PGx-guided prescribing approach in the current clinical ecosystem is highly dependent on a number of factors. These include the attending clinicians’ knowledge of the required PGx tests, as well as their interpretation and translation into therapeutic decisions for patients. Prof Goh said, “The implementation of pre-emptive PGx testing into clinical practice is part of the journey of this clinical implementation pilot (CIP)—and its fruition hinges on engaging with different stakeholders to educate them on benefits relevant and pertinent to them.”

Dr Lo said, “Yes—for instance, we try and show clinicians how PGx testing can be a useful tool that helps them with their dosing while ensuring that the process is seamless to their clinical practice. Then for patients, we try to cover the grounds—from eliminating the logistics of having to bring PGx results for consults to enjoying more efficacious therapeutics.”

“Cost is also an important consideration for patients. Fortunately, more efficient equipment and workflows have made genotyping much more affordable nowadays. Another advantage pre-emptive PGx testing has over the current reactive single-gene approach is that the likelihood of having to repeat it again in the future is low. With pre-emptive PGx testing, we are looking at a multi-drug or multi-gene panel of about 30 drug-gene pairs. This covers most of the knowledge today and possibly that of new arising drug-gene pairs too,” A/Prof Wee said.

“To realise the full potential of pre-emptive PGx testing, we hope it can involve large proportion of the population. But we recognise that we are only at the beginning of this journey, and the team is assessing proactively where an investment of time and effort will yield the greatest payoffs and makes the most economic sense,” Prof Goh said.

Click here to read more about how Prof Goh, A/Prof Wee and Dr Lo are bringing pre-emptive pharmacogenomic testing into routine clinical practice here.

This project is supported by the National Research Foundation, Singapore, through the Singapore Ministry of Health’s National Medical Research Council and the Precision Health Research, Singapore (PRECISE), under PRECISE’s Clinical Implementation Pilot grant scheme.

[1] On average, patients admitted to SGH with ADRs stayed one day longer than those without, translating to abot 9,400 extra hospital days per year. Extrapolated to all of Singapore, this would be an additional 48,000 hospital days per year caused by ADRs. Read more: https://research.a-star.edu.sg/articles/highlights/avoiding-adverse-reactions-to-medication/

[2] Chan SL, Ang X, Sani LL, Ng HY, Winther MD, Liu JJ, Brunham LR, Chan A. Prevalence and characteristics of adverse drug reactions at admission to hospital: a prospective observational study. Br J Clin Pharmacol. 2016 Dec;82(6):1636-1646. doi: 10.1111/bcp.13081. Epub 2016 Sep 19. PMID: 27640819; PMCID: PMC5099543.

[3] https://www.hsa.gov.sg/announcements/safety-alert/recommendations-for-hla-b-1502-genotype-testing-prior-to-initiation-of-carbamazepine-in-new-patients

[4] Chan SL, Ng HY, Sung C, Chan A, Winther MD, Brunham LR, Wee HL. Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults. Pharmacogenomics J. 2019 Aug;19(4):401-410. doi: 10.1038/s41397-018-0053-1. Epub 2018 Sep 24. PMID: 30250149

[5] Chan SL, Liew HZW, Nguyen F, Thumboo J, Chow WC, Sung C. Prescription patterns of outpatients and the potential of multiplexed pharmacogenomic testing. Br J Clin Pharmacol. 2021;87: 886–894. https://doi.org/10.1111/bcp.14439