Analytics of the clinical implementation of pharmacogenomics testing in 12 758 individuals

Dear Editor, Pharmacogenomics (PGx) testing is still not widely accepted in routinemedical practice, with one of themajor obstacles being the lack of evidence to support its clinical benefit.1,2 In the Chinese population, large-scale comprehensive analytics of clinical PGx testing are still lacking.3,4 Thus, we analysed clinical PGx testing for personalised drug treatment in 12,758 Chinese patients at Xiangya Hospital of Central South University, which is one of the first institutions to conduct clinical PGx testing in China. We aimed to evaluate both its clinical and cost benefits (costeffectiveness). Our clinical PGx testing unit was a multidisciplinary organisation integrating both the Institute of Clinical Pharmacology and a molecular testing laboratory (Figure 1A). After evaluation, 25 drug-gene pairs were selected to be tested (Table 1, Figure S1). A total of 12 758 patients were involved (from 2008 to 2020), and their basic demographic data are summarised in Table S1. They originated from at least 18 provinces, which accounted for most regions of the country (Figure 1B). Figures 1C–E show the composition of all tested genes, drug exposure, and diseases. The top three most commonly tested genes were CYP2C9, VKORC1, and CYP2C19, whichwere genotyped in 7151, 4106 and 3315 subjects, respectively. Warfarin and clopidogrel accounted for more than 10% of all drugs, and they were the most commonly prescribed to patients after PGx testing. Next, we analysed the PGx genotyping results. The details of all the tested variants are summarised in Table S2. The comparison of minor allele frequency between our results and the four other major ethnic populations is shown in Figure 1F. There were significant differences among the various populations in terms of nearly all variants. We further calculated the minor allele frequency correlation coefficients between our data and other populations. The mutations only showed good consistency in the East Asian population (Figure 1G). This result indicated that it should to evaluate clinical PGx testing in different populations because of the remarkable ethnic differences.

To implement PGx testing, all genotyping results were integrated with the patients' clinical parameters to facilitate appropriate clinical decision support. 5 As indicated in Table S1, 55.64% of the patients harboured at least one pharmacogene variant. They received drug dosing adjustment recommendations or risk warnings. We further analysed the data according to drugs and genes, and their percentages were variable. As shown in Figure 2A, the recommendation rate for antihypertensive drugs was much higher than that for all other drugs. In our study, antihypertensive drugs were composed of four types of drugs, including beta blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. They were tested using a panel of four genes, and 76.5% of the patients benefited from PGx testing. This result suggested that simultaneous testing of multiple genes by a panel may improve the clinical benefits. Based on the results sorted by genes, individuals who accepted CYP2D6 genotyping were most likely to benefit from PGx testing. More than 60% of the patients received the PGx recommendation.
In our study, drug-gene pairs assigned the 'A' level of evidence had actionable PGx biomarkers. The patients were most likely to benefit from testing. Thus, further analysis was conducted in detail. As indicated in Table S3, 6626 patients underwent PGx testing, with a proportion of 51.94% in all individuals. Of these, 76.40% were offered recommendations for drug dosing adjustment. More importantly, 250 patients received PGx clinical decision support alerts, which provided reminders of the increased risk of severe or even fatal clinical events. These results showed that most patients benefit from PGx testing, and some may avoid serious drug toxicity. Multiple-gene genotyping using a panel is suggested to further improve the benefit rate.
Next, we conducted a pharmacoeconomics analysis to explore the cost-effectiveness of PGx testing. A decision tree model was used to evaluate the three most tested representative drugs: warfarin, clopidogrel, and irinotecan Thiazolidinedione PPAR-γ C 9 7 0 ( 3 . 3 1 ) *The drug-gene variants pairs were determined based on the following considerations: 1. established evidence from published literature, especially in the Chinese population; 2. annotations from FDA, PharmGKB, CPIC and other clinical guidelines (for example, NCCN and ACCP); 3. the existence of functional or tag SNPs for key pharmacogenes; and 4. specific genes or variants under investigating in our institute. # Level of evidence was important for giving drug dosing adjustment recommendations or risk warnings. They were assigned as three levels: 1. actionable PGx biomarkers: standard therapy should be changed; 2. strong evidence but some discrepancy existed: standard therapy adjustment was recommended; and 3. conflicting evidence: keep standard therapy but pay attention to the drug response or toxicity during treatment.
( Figure 2B). The inputs value and base-case analysis results are summarised in Tables S4, S5, and Table 2.
For warfarin, we evaluated the cost-effectiveness of CYP2C9 and VKORC1 testing during heart valve replacement. 6 Compared with standard dosing, both the cost of the PGx-guided dosing group and quality-adjusted life-years (QALYs) were higher. The incremental costeffectiveness ratio (ICER) was $5264.35 per QALY gained. The willingness to pay (WTP) was notably less, which was $35 661 ( Figure 2C). Clopidogrel is used to prevent thromboembolism after percutaneous coronary intervention therapy. 7 The results showed that the PGx-guided group F I G U R E 1 Pharmacogenomics (PGx) testing unit and characteristics of the participants, tested genes, drugs, diseases, and variants.  increased both the cost ($542.08) and QALYs (0.018). The ICERs were $29 460.83 per QALY gained, which was less than the WTP threshold ( Figure 2C). Irinotecan is the first-line treatment for patients with advanced colorectal cancer, but serious adverse reactions (such as severe neutropenia) may lead to early termination of chemotherapy. 8 The genotype-guided group showed increases in both the cost ($113.44) and QALYs (0.018). The ICERs were $6267.20 per QALY gained, which was also much lower than the WTP threshold ( Figure 2C). In addition, we performed a sensitivity analysis for these three drugs. Figure 2D shows that the benefit of the 'genotyping-guided dosing' versus that of 'standard dosing' medication strategy of warfarin, clopidogrel and irinotecan was mostly affected by the utility of the lack of an event, cost of ticagrelor, and cost of 5-fluorouracil, respectively. The other parameters in the model had less influence on the ICER. Together, these results showed that our established models are robust, and PGx testing for warfarin, clopidogrel, and irinotecan is cost-effective. This study revealed the results of large-scale clinical PGx testing in the Chinese population for the first time. Our results showed that clinical PGx testing analysis may be recommended in the Chinese population. Most patients may benefit from PGx testing, and multiple-gene genotyping by a panel may be suggested. However, the coverage of genotyping needs to be improved in the future to provide more comprehensive results. In conclusion, our results provide a reference for patients, physicians, pharmacists, and policymakers in the future for the clinical implementation of PGx testing in both Chinese and other populations.

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