Insights Into Patient‐Level Exposure to Actionable Pharmacogenomic Medications in Australia Using a New National Pharmacogenomic Guideline

Abstract

This study assessed the use of 35 pharmacogenomic (PGx) medications listed in the Royal College of Pathologists of Australasia (RCPA) guideline, estimated the potential costs of subsidizing PGx testing in Australia, and predicted related prescribing changes. Using administrative claims data from the Pharmaceutical Benefits Scheme, accessed via the Australian Bureau of Statistics DataLab, we identified individuals who received any of the 35 medications between January 2021 and December 2023. Incident prescribing rates were calculated for children (0–17), adults (18–64), and older adults (65+). Adults (14.91%) and older adults (14.44%) had the highest rates of PGx medication use, followed by children (3.53%). Commonly prescribed medications included proton pump inhibitors, with frequent associations to genes such as CYP2C19 across all age groups. Estimated costs of PGx testing, assuming 50% and 75% population uptake, were highest for older adults: AUD$1.95 million and AUD$2.93 million, respectively. Predicted prescribing changes, based on literature‐reported phenotype frequencies by ancestry, suggested that up to 18.58% of individuals using drugs like clopidogrel or voriconazole may need alternative treatments due to poor metabolism. These findings highlight the clinical potential of integrating PGx testing into routine practice, especially for medications included in international pharmacogenomic guidelines. While implementation would entail significant upfront costs, PGx testing could enhance medication safety and effectiveness and health care cost‐efficiency. Future research should focus on scalable strategies for PGx implementation across diverse health care settings to optimize patient care globally.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC?

Prescribing of medicines with known gene‐drug interactions is common; however, the extent of this prescribing within Australia remains unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study assessed the use of 35 medications included in the Royal College of Pathologists of Australasia (RCPA) pharmacogenomic (PGx) testing guideline. It estimated national utilization rates, the potential cost of PGx testing if publicly subsidized, and the number of individuals likely to require prescribing changes based on genetic variation.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Between January 2021 and December 2023, 14.91% of adults, 14.44% of older adults, and 3.53% of children in Australia received an incident prescription for at least one of the 35 RCPA‐listed medications. The highest estimated cost of PGx testing was for older adults: AUD$1.95 million at a 50% uptake rate and AUD$2.93 million at 75%. Proton pump inhibitors and medications metabolized by CYP2C19 were among the most frequently prescribed across all age groups.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides a foundation for prioritizing PGx implementation in Australia, based on real‐world medication use, cost implications, and anticipated prescribing adjustments. These findings support the integration of PGx testing into clinical care for commonly used medications to enhance patient safety, guide treatment decisions, and reduce ADRs and health care costs.

Precision medicine tailors healthcare to individuals by considering their unique characteristics to optimize treatment outcomes. A key component of this approach is pharmacogenomic (PGx) testing, which predicts how an individual will respond to specific medications based on their genetic makeup. PGx testing can help avoid severe adverse drug reactions (ADRs) or therapeutic failure by guiding the choice and/or dose of a medication, especially for patients at higher risk due to specific disease states or medication‐related factors. ¹ Several international studies have reported substantial levels of both incident and prevalent prescribing of medications with known PGx relevance. ² , ³ , ⁴ , ⁵ Further, the PREPARE study, conducted across seven European countries, showed that patients who underwent pre‐emptive PGx testing for 12 genes had a 30% reduction in clinically relevant ADRs compared to those who did not. ⁶ Together, these findings demonstrate the potential for PGx testing to improve patient safety and outcomes and support international interest in broader PGx integration.

The Clinical Pharmacogenetics Implementation Consortium (CPIC, https://cpicpgx.org/) and the Dutch Pharmacogenetics Working Group (DPWG, https://www.pharmgkb.org/page/dpwg) provide internationally recognized guidelines for prescribing medications based on PGx test results. CPIC assigns gene‐drug pairs to evidence levels ranging from A (strongest) to D (weakest), based on the quality of evidence and the strength of recommendations for clinical implementation. However, CPIC does not prioritize which medications should undergo PGx testing to minimize ADRs or therapeutic failure. With 96 CPIC level A gene‐drug pairs involving more than 20 genes and 70 drugs, prioritizing PGx implementation in clinical settings can be challenging. To address this gap in Australia, the Royal College of Pathologists of Australasia (RCPA) recently released a targeted guideline developed by a multidisciplinary team of pharmacogenomics experts, including prescribers, pharmacologists, pharmacists, scientists, and pathologists. ⁷ This guideline provides recommendations for PGx testing for a curated list of 35 medications available in Australia, each of which is associated with a CPIC guideline. Its development was informed by an extensive synthesis of evidence from multiple sources, including CPIC and DPWG guidelines, approved product labels, and recommendations from key professional organizations and international regulatory agencies. ⁸ Of the 35 medications, 32 are classified as CPIC level A, with the remaining three (clomipramine, doxepin and imipramine) classified as level B. These tricyclic antidepressants share metabolic pathways (via CYP2D6 and/or CYP2C19) with other CPIC level A drugs in the same class like amitriptyline and nortriptyline. ⁹ Importantly, the RCPA guideline prioritizes PGx testing for medications with a high risk of severe ADRs or therapeutic failure, aiming to ensure that testing is focused on gene‐drug interactions with the most significant potential for patient harm or clinical benefit. ⁷ While the list may not capture all internationally recognized gene‐drug pairs, it reflects a consensus approach tailored to the Australian health care landscape. Future updates to the guideline could consider broader alignment with international regulatory frameworks, such as those from the US Food and Drug Administration and the European Medicines Agency, to support harmonized implementation of PGx testing globally.

This guideline helps address one barrier to implementing PGx testing in Australia: the lack of clinical prioritization. However, another major barrier is the limited public subsidy for PGx testing. Under the Medicare Benefits Schedule (MBS, https://www.mbsonline.gov.au/)—Australia’s national program for subsidizing medical services—only two gene‐drug pairs are currently covered: HLA‐B*5701/abacavir (since 2007) and TPMT/thiopurines (since 2011). Expanding the MBS subsidy to include additional PGx tests could help reduce ADR‐related hospitalizations, which cost the Australian government an estimated AUD$1.4 billion annually. ¹⁰ This presents a strong economic and clinical case for extending public subsidy for PGx testing to improve patient outcomes and reduce health care costs.

However, the number of Australians who could benefit from PGx testing for the 35 medications listed in the RCPA guideline is unknown. ³ Quantifying the national use of these medications would provide essential evidence to inform public subsidy decisions regarding PGx tests. Additionally, these data could support future research into PGx‐related uncertainties around commonly used medications, supporting consensus‐building in clinical guidelines and recommendations.

This study aimed to determine the incident prescribing rates of the 35 medications listed in the RCPA guideline within the Australian population. In addition, we forecasted the potential costs associated with subsidizing PGx testing for these medications and examined the prescribing changes that may be required based on genotype‐informed recommendations. The findings provide a vital evidence base to support informed decision‐making on expanding PGx testing in Australia and globally, especially for countries seeking to optimize health care costs and patient safety through precision medicine.

MATERIALS AND METHODS

Data source

This population‐level retrospective observational study examined Australians who received an incident prescription for any of the RCPA‐listed medications between 2021 and 2023. Prescription data were drawn from the Pharmaceutical Benefits Scheme (PBS), which provides government‐subsidized prescription medications to eligible individuals under Australia’s universal health insurance scheme, Medicare. ¹¹ , ¹² All Australian residents are eligible for Medicare, and in 2023–2024, 84% of the population attended at least one Medicare‐subsidized primary care physician visit. ¹³ The PBS captures data on all dispensed medications listed on the scheme, including for both concessional and general beneficiaries. Demographic data were obtained from the 2021 Australian Census, conducted every 5 years by the Australian Bureau of Statistics (ABS). ¹⁴ Linked PBS data and Census data were accessed through the Person Level Integrated Data Asset (PLIDA) within the ABS DataLab. ¹⁵ , ¹⁶ PLIDA enables longitudinal linkage of health, social, and demographic datasets for population‐level research. ¹⁷

Study cohort

We analyzed PBS claims data from 1 January 2021 to 31 December 2023 to identify incident users of RCPA‐listed medications. An incident prescription was defined as the first dispensing of a given medication, with no prior dispensing of the same medication in the PBS from 1 January 2013 through to the index prescription date. This 10‐year lookback period was used to minimize misclassification of prevalent users. While this approach enhances the accuracy of incident use estimates, it may not capture lifetime medication exposure. Individuals were categorized into three age groups at the time of prescription: children (0–17 years), adults (18–64 years), and older adults (65+ years). The final cohort (n = 21,805,876) consisted of 4,159,456 children (19.07%), 13,074,127 adults (59.96%), and 4,572,293 (20.97%) older adults. For individuals with missing age data in PBS claims, age was imputed based on information from the 2021 Census data. Age was defined as the age at first PBS‐subsidized prescription during the study period.

Actionable pharmacogenomic medications

The RCPA guideline classifies 35 drugs based on expert consensus regarding their PGx testing evidence. Drugs are categorized as follows: (i) “No consensus” (15 drugs): PGx testing is available but lacks international consensus on the indication for testing, (ii) “Consider” (eight drugs): PGx testing is generally recommended by international agencies due to significant risk of ADRs or therapeutic failure, and (iii) “Recommended” (12 drugs): PGx testing is strongly recommended by international agencies, ideally before initiation of the drug, to prevent severe ADRs or therapeutic failure that could lead to serious patient harm or fatalities. ⁷ For example, abacavir is classified as “Recommended” due to its well‐established interaction with HLA‐B*5701, which can cause severe skin reactions in those who carry the gene. ¹⁸ The relevant Anatomic Therapeutic Chemical (ATC) codes and drug names were mapped to PBS prescription records to identify prescriptions for these 35 drugs, including combination products (e.g., paracetamol/codeine). We excluded formulations with no systemic exposure (e.g., topical fluorouracil).

For comparison, the CPIC categorizes gene‐drug pairs based on the strength of evidence supporting their interaction. Gene‐drug pairs classified as CPIC level A, A/B, or B are considered actionable, meaning there is sufficient evidence to guide prescribing decisions based on PGx test results. ¹⁹

Prescribing rates

We estimated the annual average number of distinct individuals nationwide with an incident prescription of each medication and calculated prescribing rates (per 100,000 people). The denominator for prescribing rates was the average annual number of distinct individuals who received at least one PBS drug from 2021 to 2023 in the respective age group. For doxepin, whose PBS subsidy was discontinued in 2023, the prescribing rate for this drug was based on data from 2021 and 2022. The numerator was the average annual number of unique individuals in each age group who received at least one incident prescription for an RCPA‐listed drug (Tables S1–S9 ). We also estimated the number of individuals—both prevalent and incident users—who were dispensed at least two of the 35 drugs within 30 days. Similarly, we calculated the proportion of individuals dispensed at least two drugs from either the “Recommended” and “Consider” categories combined, or at least two from the “Recommended” category alone, within 30 days. These rates were estimated separately for the three age cohorts (Tables  S4–S6 ).

Testing costs

We also estimated the potential population‐level economic impact if single‐gene PGx tests were subsidized for each of the 35 drugs. Using the average cost of currently MBS‐listed PGx tests (TPMT test: AUD$51.95 per service, HLA‐B*5701 test: AUD$40.95 per service), we assumed a testing cost of AUD$46.45 per service. Based on the average annual number of distinct individuals prescribed each medication, we estimated total PGx testing costs under population uptake rates of 50% and 75%. These uptake rates were chosen to reflect real‐world (50%) and ideal (75%) testing rates. The 50% rate was based on previous research (e.g., Por et al., 2021, ²⁰ which reported a PGx testing rate of up to 51.5% in a US veteran population) and acknowledges that 100% uptake is unlikely. The 75% rate represents a higher uptake assumption for ideal circumstances. For instance, with an annual average of 20,190 adults newly prescribed clopidogrel, the estimated yearly cost of PGx testing would be approximately AUD$469,000 at 50% uptake and AUD$703,000 at 75% uptake across Australia.

Prescribing changes required

We estimated the number of prescribing changes (e.g., alternative drug or dose adjustments) required for patients taking the “Recommended” RCPA drugs across the entire cohort. To account for biogeographical variation in gene phenotype frequencies, we used the 2021 Census data on self‐reported ancestry categories (sourced from https://profile.id.com.au/australia/ancestry). The 130 ancestry categories were consolidated into nine broader groups—aligned with CPIC guidelines—including African American/Afro‐Caribbean, American, Central/South Asian, East Asian, European, Latino, Near Eastern, Oceanian, and Sub‐Saharan African (Table  S7 ). For each gene relevant to at least one “Recommended” drug (n = 9), we applied CPIC‐reported phenotype frequencies (e.g., poor metabolisers) within each ancestry group where available. We then estimated the number of individuals affected by each gene by summing the number of individuals taking the corresponding drugs, stratified by ancestry. For example, based on ancestry distributions, an estimated 8,919 individuals of European ancestry across all three age groups received capecitabine or fluorouracil annually (both associated with the DPYD gene) (Table  S8 ). Applying CPIC phenotype frequencies, we estimated 79 poor metabolisers and 212 intermediate metabolisers in this group (Table  S9 ). Final population‐level estimates were calculated by summing across all ancestry groups for each gene‐drug pair.

Ethics statement

The University of Sydney Human Research Ethics Committee granted an exemption on the basis of negligible risk. This study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement guidelines for reporting observational studies.

RESULTS

Prescribing rates

Tables 1 , 2 , 3 presents the annual average incident prescribing rates for each of the 35 RCPA‐listed drugs by age group. Adults had the highest proportion of incident users (14.91%), followed closely by older adults (14.44%) and then children (3.53%). Adults also had the highest proportion of users prescribed drugs categorized as either “Recommended” or “Consider” for PGx testing (7.92%). However, older adults had the highest rate of prescriptions for “Recommended” drugs specifically (1.88%).

Table 1.

Average annual incident prescribing rates for 35 RCPA‐listed pharmacogenetic drugs in individuals aged 0–17 years (2021–2023), average n = 2,567,955 people per year

RCPA testing guidance	Drug	Biomarker	CPIC level	People (N)	Prescribing rates per 100,000 individuals (%)	Estimated testing costs with assumption of 50% testing rate ($)	Estimated testing costs with assumption of 75% testing rate ($)
Recommended	Abacavir	HLA‐B*5701	A	n/a	n/a	n/a	n/a
Recommended	Allopurinol	HLA‐B*5801	A	245	9.54 (0.01%)	$5,690.13	$8,535.19
Recommended	Azathioprine	TPMT and NUDT15	A	501	19.51 (0.02%)	$11,635.73	$17,453.59
Recommended	Capecitabine	DPYD	A	n/a	n/a	n/a	n/a
Recommended	Carbamazepine	HLA‐B*1502 and HLA‐A*3101 alleles	A	794	30.91 (0.03%)	$18,432.91	$27,649.36
Recommended	Clopidogrel	CYP2C19	A	162	6.30 (0.01%)	$3,754.71	$5,632.06
Recommended	Fluorouracil	DPYD	A	n/a	n/a	n/a	n/a
Recommended	Mercaptopurine	TPMT and NUDT15	A	351	13.66 (0.01%)	$8,144.23	$12,216.35
Recommended	Oxcarbazepine	HLA‐B*1502 and HLA‐A*3101	A, C	366	14.24 (0.01%)	$8,492.61	$12,738.91
Recommended	Phenytoin	HLA‐B*1502 and CYP2C9	A	58	2.27 (0.00%)	$1,354.79	$2,032.19
Recommended	Tioguanine	TPMT and NUDT15	A	131	5.09 (0.01%)	$3,034.73	$4,552.10
Recommended	Voriconazole	CYP2C19	A	67	2.60 (0.00%)	$1,548.33	$2,322.50
Consider	Amitriptyline	CYP2D6 and CYP2C19	A	3,874	150.87 (0.15%)	$89,981.39	$134,972.09
Consider	Atomoxetine	CYP2D6	A	3,287	128.01 (0.13%)	$76,348.32	$114,522.48
Consider	Citalopram	CYP2C19	A	11,529	448.97 (0.45%)	$267,768.77	$401,653.15
Consider	Codeine	CYP2D6	A	17,426	678.61 (0.68%)	$404,726.59	$607,089.89
Consider	Nortriptyline	CYP2D6	A	183	7.11 (0.01%)	$4,242.43	$6,363.65
Consider	Tamoxifen	CYP2D6	A	32	1.25 (0.00%)	$743.20	$1,114.80
Consider	Tramadol	CYP2D6	A	3,687	143.58 (0.14%)	$85,630.58	$128,445.86
Consider	Warfarin	VKORC1, CYP2C9 and CYP4F2	A	117	4.54 (0.00%)	$2,709.58	$4,064.38
No consensus	Atorvastatin	SLCO1B1	A	682	26.56 (0.03%)	$15,839.45	$23,759.18
No consensus	Clomipramine	CYP2C19 and CYP2D6	B	189	7.35 (0.01%)	$4,381.78	$6,572.68
No consensus	Doxepina	CYP2D6	B	75	2.90 (0.00%)	$1,730.26	$2,595.39
No consensus	Escitalopram	CYP2C19	A	10,262	399.63 (0.40%)	$238,342.69	$357,514.04
No consensus	Fluvastatin	SLCO1B1 and CYP2C9	A	n/a	n/a	n/a	n/a
No consensus	Imipramine	CYP2D6 and CYP2C19	B	226	8.80 (0.01%)	$5,248.85	$7,873.28
No consensus	Lansoprazole	CYP2C19	A	2,636	102.65 (0.10%)	$61,221.10	$91,831.65
No consensus	Omeprazole	CYP2C19	A	19,740	768.69 (0.77%)	$458,453.76	$687,680.64
No consensus	Pantoprazole	CYP2C19	A	10,678	415.80 (0.42%)	$247,988.81	$371,983.21
No consensus	Paroxetine	CYP2D6	A	553	21.55 (0.02%)	$12,851.17	$19,276.75
No consensus	Pravastatin	SLCO1B1	A	52	2.01 (0.00%)	$1,199.96	$1,799.94
No consensus	Rosuvastatin	SLCO1B1 and ABCG2	A	932	36.29 (0.04%)	$21,645.70	$32,468.55
No consensus	Sertraline	CYP2C19	A	18,055	703.08 (0.70%)	$419,319.63	$628,979.45
No consensus	Simvastatin	SLCO1B1	A	125	4.88 (0.00%)	$2,910.87	$4,366.30
No consensus	Tacrolimus	CYP3A5	A	183	7.11 (0.01%)	$4,242.43	$6,363.65
People with an incident prescription for one or more of the 35 drugsb				90,593	3527.84 (3.53%)	N/A	N/A
People with an incident prescription for one or more of the recommended/consider drugsb				41,558	1618.32 (1.62%)	N/A	N/A
People with an incident prescription for one or more of the recommended drugsb				2,542	98.99 (0.10%)	N/A	N/A

CPIC, Clinical Pharmacogenetics Implementation Consortium; n/a, counts too low to be cleared by the Australian Bureau of Statistics due to possible risk of re‐identification; N/A, not applicable; RCPA, Royal College of Pathologists of Australasia.

^a PBS subsidy for doxepin discontinued during 2023; hence, average prescribing rates calculated from 2021 and 2022 PBS data only.

^b Total values count unique individuals once even if multiple drugs are prescribed.

Table 2.

Average annual incident prescribing rates for 35 RCPA‐listed pharmacogenetic drugs in individuals aged 18–64 years (2021–2023), average n = 10,304,896 people per year

RCPA testing guidance	Drug	Biomarker	CPIC level	People (N)	Prescribing rates per 100,000 individuals (%)	Estimated testing costs with assumption of 50% testing rate ($)	Estimated testing costs with assumption of 75% testing rate ($)
Recommended	Abacavir	HLA‐B*5701	A	72	0.70 (0.00%)	$1,679.94	$2,519.91
Recommended	Allopurinol	HLA‐B*5801	A	31,352	304.24 (0.30%)	$728,142.46	$1,092,213.69
Recommended	Azathioprine	TPMT and NUDT15	A	4,104	39.83 (0.04%)	$95,323.14	$142,984.71
Recommended	Capecitabine	DPYD	A	3,102	30.10 (0.03%)	$72,036.21	$108,054.31
Recommended	Carbamazepine	HLA‐B*1502 and HLA‐A*3101 alleles	A	6,176	59.94 (0.06%)	$143,445.34	$215,168.01
Recommended	Clopidogrel	CYP2C19	A	20,190	195.93 (0.20%)	$468,920.49	$703,380.74
Recommended	Fluorouracil	DPYD	A	3,926	38.10 (0.04%)	$91,173.61	$136,760.41
Recommended	Mercaptopurine	TPMT and NUDT15	A	1750	16.99 (0.02%)	$40,651.49	$60,977.24
Recommended	Oxcarbazepine	HLA‐B*1502 and HLA‐A*3101	A, C	290	2.81 (0.00%)	$6,735.25	$10,102.88
Recommended	Phenytoin	HLA‐B*1502 and CYP2C9	A	307	2.98 (0.00%)	$7,137.82	$10,706.73
Recommended	Tioguanine	TPMT and NUDT15	A	228	2.21 (0.00%)	$5,287.56	$7,931.34
Recommended	Voriconazole	CYP2C19	A	427	4.15 (0.00%)	$9,924.82	$14,887.23
Consider	Amitriptyline	CYP2D6 and CYP2C19	A	123,654	1199.95 (1.20%)	$2,871,864.15	$4,307,796.23
Consider	Atomoxetine	CYP2D6	A	4,558	44.23 (0.04%)	$105,859.55	$158,789.33
Consider	Citalopram	CYP2C19	A	163,821	1589.74 (1.59%)	$3,804,734.98	$5,707,102.48
Consider	Codeine	CYP2D6	A	347,844	3375.52 (3.38%)	$8,078,684.64	$12,118,026.96
Consider	Nortriptyline	CYP2D6	A	11,623	112.79 (0.11%)	$269,951.92	$404,927.88
Consider	Tamoxifen	CYP2D6	A	4,712	45.73 (0.05%)	$109,436.20	$164,154.30
Consider	Tramadol	CYP2D6	A	117,444	1139.69 (1.14%)	$2,727,636.90	$4,091,455.35
Consider	Warfarin	VKORC1, CYP2C9 and CYP4F2	A	3,811	36.98 (0.04%)	$88,510.48	$132,765.71
No consensus	Atorvastatin	SLCO1B1	A	90,324	876.52 (0.88%)	$2,097,782.64	$3,146,673.96
No consensus	Clomipramine	CYP2C19 and CYP2D6	B	2,203	21.38 (0.02%)	$51,172.42	$76,758.63
No consensus	Doxepina	CYP2D6	B	3,095	30.34 (0.03%)	$71,881.38	$107,822.06
No consensus	Escitalopram	CYP2C19	A	153,187	1486.54 (1.49%)	$3,557,760.33	$5,336,640.50
No consensus	Fluvastatin	SLCO1B1 and CYP2C9	A	156	1.51 (0.00%)	$3,615.36	$5,423.04
No consensus	Imipramine	CYP2D6 and CYP2C19	B	648	6.29 (0.01%)	$15,057.54	$22,586.31
No consensus	Lansoprazole	CYP2C19	A	8,414	81.65 (0.08%)	$195,407.41	$293,111.11
No consensus	Omeprazole	CYP2C19	A	180,653	1753.08 (1.75%)	$4,195,665.93	$6,293,498.89
No consensus	Pantoprazole	CYP2C19	A	269,847	2618.63 (2.62%)	$6,267,196.58	$9,400,794.86
No consensus	Paroxetine	CYP2D6	A	15,821	153.53 (0.15%)	$367,434.98	$551,152.48
No consensus	Pravastatin	SLCO1B1	A	4,417	42.86 (0.04%)	$102,577.08	$153,865.63
No consensus	Rosuvastatin	SLCO1B1 and ABCG2	A	149,748	1453.18 (1.45%)	$3,477,905.04	$5,216,857.56
No consensus	Sertraline	CYP2C19	A	126,876	1231.22 (1.23%)	$2,946,702.84	$4,420,054.26
No consensus	Simvastatin	SLCO1B1	A	7,924	76.90 (0.08%)	$184,034.90	$276,052.35
No consensus	Tacrolimus	CYP3A5	A	1760	17.08 (0.02%)	$40,868.26	$61,302.39
People with an incident prescription for one or more of the 35 drugsb				1,536,025	14905.78 (14.91%)	N/A	N/A
People with an incident prescription for one or more of the recommended/consider drugsb				816,488	7923.30 (7.92%)	N/A	N/A
People with an incident prescription for one or more of the recommended drugsb				70,659	685.68 (0.69%)	N/A	N/A

CPIC, Clinical Pharmacogenetics Implementation Consortium; N/A, not applicable; RCPA, Royal College of Pathologists of Australasia.

^a PBS subsidy for doxepin discontinued during 2023; hence, average prescribing rates are calculated from 2021 and 2022 PBS data only.

^b Total values count unique individuals once even if multiple drugs are prescribed.

Table 3.

Average annual incident prescribing rates for 35 RCPA‐listed pharmacogenetic drugs in individuals aged 65 years and above (2021–2023), average n = 4,401,330 people per year

RCPA testing guidance	Drug	Biomarker	CPIC level	People (N)	Prescribing rates per 100,000 individuals (%)	Estimated testing costs with assumption of 50% testing rate ($)	Estimated testing costs with assumption of 75% testing rate ($)
Recommended	Abacavir	HLA‐B*5701	A	n/a	n/a	n/a	n/a
Recommended	Allopurinol	HLA‐B*5801	A	26,048	591.83 (0.59%)	$604,972.54	$907,458.81
Recommended	Azathioprine	TPMT and NUDT15	A	1,253	28.48 (0.03%)	$29,108.67	$43,663.00
Recommended	Capecitabine	DPYD	A	3,668	83.35 (0.08%)	$85,197.04	$127,795.56
Recommended	Carbamazepine	HLA‐B*1502 and HLA‐A*3101 alleles	A	3,985	90.53 (0.09%)	$92,543.88	$138,815.83
Recommended	Clopidogrel	CYP2C19	A	42,063	955.69 (0.96%)	$976,913.18	$1,465,369.76
Recommended	Fluorouracil	DPYD	A	5,924	134.60 (0.13%)	$137,592.64	$206,388.96
Recommended	Mercaptopurine	TPMT and NUDT15	A	267	6.07 (0.01%)	$6,201.08	$9,301.61
Recommended	Oxcarbazepine	HLA‐B*1502 and HLA‐A*3101	A, C	112	2.54 (0.00%)	$2,601.20	$3,901.80
Recommended	Phenytoin	HLA‐B*1502 and CYP2C9	A	267	6.06 (0.01%)	$6,193.33	$9,290.00
Recommended	Tioguanine	TPMT and NUDT15	A	63	1.43 (0.00%)	$1,463.18	$2,194.76
Recommended	Voriconazole	CYP2C19	A	419	9.53 (0.01%)	$9,739.02	$14,608.53
Consider	Amitriptyline	CYP2D6 and CYP2C19	A	57,236	1300.42 (1.30%)	$1,329,298.36	$1,993,947.54
Consider	Atomoxetine	CYP2D6	A	54	1.23 (0.00%)	$1,261.89	$1,892.84
Consider	Citalopram	CYP2C19	A	38,643	877.98 (0.88%)	$897,483.68	$1,346,225.51
Consider	Codeine	CYP2D6	A	95,270	2164.58 (2.16%)	$2,212,653.49	$3,318,980.24
Consider	Nortriptyline	CYP2D6	A	5,369	121.98 (0.12%)	$124,687.28	$187,030.93
Consider	Tamoxifen	CYP2D6	A	3,030	68.84 (0.07%)	$70,364.01	$105,546.01
Consider	Tramadol	CYP2D6	A	40,517	920.56 (0.92%)	$940,999.58	$1,411,499.38
Consider	Warfarin	VKORC1, CYP2C9 and CYP4F2	A	4,915	111.67 (0.11%)	$114,150.88	$171,226.31
No consensus	Atorvastatin	SLCO1B1	A	65,954	1498.50 (1.50%)	$1,531,781.65	$2,297,672.48
No consensus	Clomipramine	CYP2C19 and CYP2D6	B	218	4.95 (0.00%)	$5,063.05	$7,594.58
No consensus	Doxepina	CYP2D6	B	2,290	52.68 (0.05%)	$53,185.25	$79,777.88
No consensus	Escitalopram	CYP2C19	A	30,207	686.32 (0.69%)	$701,565.32	$1,052,347.98
No consensus	Fluvastatin	SLCO1B1 and CYP2C9	A	223	5.07 (0.01%)	$5,179.18	$7,768.76
No consensus	Imipramine	CYP2D6 and CYP2C19	B	544	12.37 (0.01%)	$12,642.14	$18,963.21
No consensus	Lansoprazole	CYP2C19	A	5,683	129.12 (0.13%)	$131,987.68	$197,981.51
No consensus	Omeprazole	CYP2C19	A	60,449	1373.43 (1.37%)	$1,403,935.77	$2,105,903.65
No consensus	Pantoprazole	CYP2C19	A	133,205	3026.47 (3.03%)	$3,093,686.13	$4,640,529.19
No consensus	Paroxetine	CYP2D6	A	2,556	58.08 (0.06%)	$59,370.84	$89,056.26
No consensus	Pravastatin	SLCO1B1	A	5,284	120.06 (0.12%)	$122,728.64	$184,092.96
No consensus	Rosuvastatin	SLCO1B1 and ABCG2	A	96,073	2182.82 (2.18%)	$2,231,295.43	$3,346,943.14
No consensus	Sertraline	CYP2C19	A	23,319	529.82 (0.53%)	$541,583.78	$812,375.66
No consensus	Simvastatin	SLCO1B1	A	7,293	165.70 (0.17%)	$169,379.93	$254,069.89
No consensus	Tacrolimus	CYP3A5	A	412	9.37 (0.01%)	$9,576.44	$14,364.66
People with an incident prescription for one or more of the 35 drugsb				635,591	14440.88 (14.44%)	N/A	N/A
People with an incident prescription for one or more of the recommended/consider drugsb				312,953	7110.41 (7.11%)	N/A	N/A
People with an incident prescription for one or more of the recommended drugsb				82,856	1882.52 (1.88%)	N/A	N/A

CPIC, Clinical Pharmacogenetics Implementation Consortium; n/a, counts too low to be cleared by the Australian Bureau of Statistics due to possible risk of re‐identification; N/A, not applicable; RCPA, Royal College of Pathologists of Australasia.

^a PBS subsidy for doxepin discontinued during 2023; hence, average prescribing rates calculated from 2021 and 2022 PBS data only.

^b Total values count unique individuals once even if multiple drugs are prescribed.

Prescribing patterns varied by age. Codeine and proton pump inhibitors were common across age groups, while antidepressants were frequently prescribed among children and adults. For children (Table 1 ), the top prescribed drugs were omeprazole (0.77%), sertraline (0.70%), codeine (0.68%), citalopram (0.45%), and pantoprazole (0.42%). Of these, codeine and citalopram fall under the “Consider” category for PGx testing; the rest are in the “No consensus” category. For adults (Table 2 ), the most commonly prescribed drugs were codeine (3.38%), pantoprazole (2.62%), omeprazole (1.75%), citalopram (1.59%), and escitalopram (1.49%). All are classified as “No consensus” drugs, except codeine and citalopram. For older adults (Table 3 ), the top drugs were pantoprazole (3.03%), rosuvastatin (2.18%), codeine (2.16%), atorvastatin (1.50%), and omeprazole (1.37%), with only codeine classified under the “Considered” category.

Of the 35 drugs, PGx tests for four drugs (azathioprine, mercaptopurine, tioguanine and abacavir) are currently subsidized under the MBS (https://www.mbsonline.gov.au/), while PGx tests for three drugs (carbamazepine, fluorouracil and capecitabine) are under review for MBS coverage. ⁷ Despite being “Recommended” and subsidized under the MBS for PGx testing, abacavir and tioguanine show minimal prescribing rates across all age groups. Capecitabine and fluorouracil were rarely prescribed in children, while prescribing was highest for azathioprine (0.04%) and mercaptopurine (0.02%) in adults, and for capecitabine (0.08%), carbamazepine (0.09%), and fluorouracil (0.13%) in older adults.

Biomarkers

A total of 16 biomarkers are associated with the metabolism of the 35 RCPA drugs, with CYP2C19 (in 11 drugs) and CYP2D6 (in 10 drugs) being the most frequently implicated. Three drugs (amitriptyline, clomipramine, and imipramine) are linked to both biomarkers. Despite CYP2C19’s frequent involvement, only two of its associated drugs (voriconazole and clopidogrel) are classified as “Recommended” for PGx testing, together affecting just 0.37% of individuals across all age groups. The remaining CYP2C19 or CYP2D6 related drugs are categorized as either “No consensus” (n = 9) or “Consider” (n = 7). Human leukocyte antigens (HLA) are the most frequent biomarkers for which PGx testing is “Recommended”, covering 0.41% of individuals across all age groups. CYP2C19 and CYP2D6 are shared within the top five most prescribed medications in all age groups.

Overlapping drug use

Table 4 shows the proportion of individuals dispensed two or more medications listed in the RCPA guideline within 30 days, stratified by age group. Overlap in RCPA‐listed drug use was highest among older adults, with 36.43% of individuals receiving two or more RCPA‐listed drugs, followed by adults at 11.01%, and children just 0.32%. When restricted to drugs classified as “Recommended” or “Consider”, the overlap rates dropped significantly: 5.24% for older adults, 2.47% for adults, and 0.07% for children. Overlap involving only “Recommended” drugs was even lower: 0.68% in older adults, 0.09% in adults, and 0.01% in children. These trends remained consistent when analyses were limited to incident users only.

Table 4.

Overlapping dispensing of RCPA‐listed pharmacogenetic drugs within 30 days for each age group

Outcome	Age group
	0–17 (n = 2,567,955)	18–64 (n = 10,304,896)	65 and above (n = 4,401,330)
All users
People with at least two of the RCPA‐list drugs co‐dispensed within 30 days (n, %)	8,320 (0.32%)	1,134,628 (11.01%)	1,603,408 (36.43%)
People with at least two of the RCPA‐recommended/consider drugs co‐dispensed within 30 days (n, %)	1701 (0.07%)	254,019 (2.47%)	230,665 (5.24%)
People with at least two of the RCPA‐recommended drugs co‐dispensed within 30 days (n, %)	197 (0.01%)	9,300 (0.09%)	29,770 (0.68%)
Incident users only
People with at least two of the RCPA‐list drugs co‐dispensed within 30 days (n, %)	6,472 (0.25%)	438,000 (4.25%)	406,191 (9.23%)
People with at least two of the RCPA‐recommended/consider drugs co‐dispensed within 30 days (n, %)	1,366 (0.05%)	114,422 (1.11%)	83,994 (1.91%)
People with at least two of the RCPA‐recommended drugs co‐dispensed within 30 days (n, %)	125 (0.00%)	3,794 (0.04%)	10,415 (0.24%)

RCPA, Royal College of Pathologists of Australasia.

Pharmacogenetic testing cost estimation

Estimated annual costs of PGx testing at 50% and 75% uptake rates for all age groups are shown in Tables 1 , 2 , 3 . For children, testing for all “Recommended” drugs was predicted to cost AUD$62,088 at a 50% uptake and AUD$93,132 at 75%. For adults, the estimated cost was AUD$1,670,458 at a 50% uptake and AUD$2,505,687 at 75% for “Recommended” drugs. Older adults had the highest estimated cost: AUD$1,952,526 at a 50% uptake and AUD$2,928,789 at 75% for “Recommended” drugs. These estimates assume that PGx tests are independent across drugs.

Prescribing changes

The predicted frequencies of phenotypes (e.g., poor metabolisers) associated with genes linked to at least one RCPA “Recommended” drug (n = 9) are presented in Table 5 along with corresponding CPIC guideline recommendations. Medications metabolized by CYP2C19 (clopidogrel and voriconazole) and CYP2C9 (phenytoin) showed the highest predicted prevalence of actionable phenotypes. For example, up to 18.58% of individuals prescribed clopidogrel or voriconazole are predicted to be poor metabolisers and, according to CPIC guidelines, should be considered for an alternative therapy. ²¹ , ²²

Table 5.

Predicted rate of phenotypes with recommended prescribing changes for incident prescriptions of each RCPA “Recommended” drug and their associated gene/s

Gene	Interacting drug/s	Sample size (n)a	Phenotype	Frequency in populationa (n, %)	Recommendation/sb
TPMT	Azathioprine, mercaptopurine, tioguanine	8,601	PM	10 (0.12)	Reduce initial dose or alternative agent
			IM	460 (5.35)	Reduce initial dose or alternative agent
NUDT15	Azathioprine, mercaptopurine, tioguanine	8,601	PM	9 (0.11)	Reduce initial dose or alternative agent
			IM	220 (2.56)	Reduce initial dose or alternative agent
DPYD	Capecitabine, fluorouracil	16,529	PM	86 (0.52)	Reduce initial dose
			IM	242 (1.46)	Alternative agent preferred
HLA‐A*3101	Carbamazepine, oxcarbazepine	11,659	Carrier	266 (2.28)	Alternative agent preferred or increased frequency of clinical monitoring
HLA‐B*1502	Carbamazepine, oxcarbazepine, phenytoin	12,288	Carrier	93 (0.75)	Alternative agent
HLA‐B*5701	Abacavir, carbamazepine, oxcarbazepine, phenytoin	12,359	Carrier	358 (2.90)	Alternative agent
HLA‐B*5801	Allopurinol, carbamazepine, oxcarbazepine, phenytoin	69,618	Carrier	1,154 (1.66)	Alternative agent
CYP2C19	Clopidogrel, voriconazole	62,983	PM	11,700 (18.58)	Clopidogrel: alternative agent preferred Voriconazole: alternative agent
			IM	19,814 (31.46)	Clopidogrel: alternative agent preferred Voriconazole: standard care
			RM	11,032 (17.52)	Clopidogrel: standard care Voriconazole: alternative agent
			UM	1825 (2.90)	Clopidogrel: standard care Voriconazole: alternative agent
CYP2C9	Phenytoin	629	PM	11 (1.75)	Reduced maintenance dose
			IM	161 (25.64)	Standard care or reduced maintenance dose

IM, intermediate metabolizer; PM, poor metabolizer; RCPA, Royal College of Pathologists of Australasia; RM, rapid metabolizer; UM, ultrarapid metabolizer.

^a Sum does not equate to total drug users in the population as some undefined or similar ancestry groups are not included.

^b Estimated rate of each phenotype and recommended prescribing changes derived from Clinical Pharmacogenetics Implementation Consortium guidelines.

DISCUSSION

In this study, we investigated the incident prescribing rates and estimated the potential costs of subsidized PGx testing for the 35 medications listed in the recently released RCPA PGx testing guideline. This guideline is notable for providing a curated list of medications with PGx testing recommendations, filling a critical gap in the Australian clinical landscape. For the first time, we quantified the use of these medications across age cohorts—children, adults, and older adults—and estimated the proportion of individuals prescribed “Recommended” drugs who would likely require prescribing changes (i.e., drug or dose change) based on PGx testing results. Our findings show that adults and older adults had the highest proportion of incident PGx drug use, with older adults exhibiting the greatest potential for concurrent use of PGx drugs. These results suggest a particular need for targeted implementation strategies in these populations. In contrast, children were least likely to be prescribed one or more PGx medications. While prescribing patterns varied by age group, proton pump inhibitors (e.g., pantoprazole) and codeine were consistently among the most commonly prescribed drugs across all age groups. Notably, CYP2C19 and CYP2D6 gene‐drug pairs were among the top 5 drugs prescribed in each age cohort, though PGx testing for these drugs was classified as either “No consensus” or “Consider”. In contrast, HLA‐A/B genes were most frequently implicated in the “Recommended” drugs, underscoring their importance in guiding safer prescribing decisions.

Overall, this study highlights a significant opportunity to implement PGx testing in Australia, where a large proportion of the population is prescribed medications that could benefit from PGx‐guided prescribing. These findings align with studies from the United Kingdom, Europe, and the United States, which also report widespread use of PGx‐recommended medications across populations. ² , ²³ , ²⁴ , ²⁵ Variations in the number of included drugs across studies likely reflect differences in medication availability across health care systems. Importantly, our study focused specifically on the 35 medications listed in the RCPA guideline, rather than the broader scope of medications covered by CPIC (https://cpicpgx.org/) or DPWG (https://www.pharmgkb.org/page/dpwg) guidelines.

The estimated cost of testing from 50% to 75% of older adults using “Recommended” drugs was the highest among the age groups, followed by adults and then children. However, these estimates may be inflated as some drugs share common genetic markers. For instance, HLA‐B is relevant to five RCPA “Recommended” drugs (allopurinol, abacavir, carbamazepine, oxcarbazepine and phenytoin), meaning a single PGx test for HLA‐B could guide prescribing for multiple drugs, reducing the need for separate tests. Similarly, other genes like HLA‐A, TPMT, NUDT15, DPYD, CYP2C19 are associated with multiple “Recommended” RCPA drugs. This overlap highlights the potential value of panel‐based testing, which evaluates multiple variants in one test, offering a more cost‐efficient and clinically comprehensive alternative to single‐gene testing.

Older adults are particularly vulnerable to ADRs due to polypharmacy. ²⁶ Up to 30% of hospitalizations in this group are attributed to ADRs, with as many as 70% considered potentially preventable. ²⁷ , ²⁸ While age‐related physiological changes affect drug metabolism, gene‐drug interactions further compound ADR risk. For example, an estimated 16.6% and 39.6% of the Australian population carry poor‐functioning alleles for CYP2C19 and CYP2D6, respectively. ²⁹ Since CYP enzymes are involved in the metabolism of 70% to 90% of available drugs, these genetic variations can significantly impact drug efficacy and safety—especially in older adults with higher medication burden. ²⁸ Given these factors, older adults are a key target population for PGx testing. However, PGx testing is also valuable across all age groups. Our findings show that 31 of the 35 RCPA‐listed medications are used by individuals in every age cohort, highlighting the lifelong relevance of PGx test results. For example, genes like CYP2C19 influence drug responses across multiple medications and age groups. Early‐life PGx testing, with results stored in health records, could guide prescribing decisions throughout an individual’s lifetime. Additionally, panel‐based PGx testing—assessing multiple gene variants in a single test—offers a cost‐efficient alternative to multiple single‐gene tests. This approach enhances the clinical utility of PGx results, supports personalized prescribing, and has the potential to reduce ADRs, improve treatment outcomes, and lower long‐term health care costs. ³⁰ , ³¹

Recent applications for public subsidy of additional PGx tests for carbamazepine and fluoropyrimidines reflect growing interest in expanding PGx testing in Australia. ⁷ Interestingly, medications with PGx tests currently subsidized or under review by the MBS were prescribed to a relatively small proportion of the population compared to other drugs listed in the RCPA guideline. For example, among older adults, fluorouracil—the most frequently prescribed drug among those with current or pending MBS subsidy—had an incident prescribing rate of just 0.13%, whereas pantoprazole, a proton pump inhibitor with no PGx resting consensus, had a rate of 3.03% in the same population. While the incident use of fluorouracil is comparatively low, its role as a chemotherapy agent means that ADRs or therapeutic failure may incur significantly higher clinical and economic costs than those associated with lower‐risk medications like (an anti‐reflux medication). ⁹ This highlights the need for further research to assess the cost‐effectiveness and clinical impact of PGx testing across diverse drug classes—balancing prescribing frequency, severity of ADRs, and overall healthcare burden.

This study identified substantial incident use of medications eligible for PGx‐guided prescribing in a large, national cohort, highlighting the potential for broader implementation of PGx testing in clinical practice. However, several limitations should be considered. First, many drugs share common gene‐drug interactions, meaning a single PGx test may inform prescribing decisions for multiple drugs. This overlap likely leads to an overestimation of the number of PGx tests needed and associated costs. Second, we did not account for the downstream costs of prescribing changes. These may be higher due to the use of more expensive alternatives or lower due to avoided ADRs. Importantly, some alternative therapies may carry risks of reduced efficacy or new ADRs, which should be explored in future analyses. Third, our estimates were based on self‐reported ancestry data from the Census, which may not accurately reflect genetic ancestry. Additionally, we assumed national ancestry distributions apply uniformly to medication users, which may not hold true across all drugs. Incorporating drug‐specific ancestry data in future analyses would improve the accuracy of prescribing change estimates. Finally, phenotype frequency data for three key genes—DPYD, TPMT, and NUDT15—were unavailable for all ancestry groups, potentially underestimating the number of individuals requiring prescribing changes for affected medications.

While this study supports the broader implementation of PGx testing, it is important to acknowledge that the presence of clinical guidelines alone is insufficient to drive uptake in practice. Successful integration of PGx testing depends on a range of additional factors, including reimbursement policies, clinician awareness and education, availability of clinical decision support tools, and turnaround times for test results. ³² , ³³ , ³⁴ Addressing these practical barriers will be essential to enhance the clinical utility and routine adoption of PGx in clinical settings.

CONCLUSION

This study highlights significant opportunity to implement high‐impact PGx testing within Australian clinical practice. It is the first national study to quantify incident prescribing rates of PGx‐recommended medications by age, estimate the potential cost of subsidizing PGx testing, and forecast the proportion of individuals likely to require prescribing changes based on PGx test results. Adults and older adults had the highest rates of new PGx medication use, often involving drugs associated with severe ADRs or therapeutic failure in individuals with high‐risk genotypes—underscoring the need for targeted interventions in aging populations at risk of polypharmacy and ADRs. However, the consistent use of PGx‐relevant medications across all age groups also supports the value of early‐life testing, with results that can inform treatment throughout life. Future work should now shift toward implementation, including improving prescriber education, integrating clinical decision support, and reducing test turnaround times—especially for medications classified as “Recommended” for PGx testing by the RCPA guideline. Addressing these barriers is essential to ensuring that PGx testing delivers on its promise to improve medication safety, enhance treatment efficacy, and reduce health care costs by minimizing ADRs and therapeutic failures. These findings offer valuable insights for other health care systems globally seeking to integrate precision medicine into routine care.

Funding

No funding was received for this work.

Conflicts of interest

The authors declared no competing interests for this work.

Author contributions

C.Y.L. designed the research. M.A.A. and C.H.Y. performed the research. C.Y.L. and B.D.I. analyzed the data. B.D.I., C.H.Y., and C.Y.L. wrote the manuscript.

Supporting information

Table S1–S9

Data availability statement

Research data are not shared due to restrictions from the Australian Bureau of Statistics (ABS) DataLab.