Is Pharmacogenetic Testing a Vital Tool for Enhancing Therapeutic Management of Patients Worldwide?

Clinical pharmacology is a discipline that includes education, research, and the implementation of knowledge into clinical practice, which ranges from precision dosing to therapeutic drug monitoring, and most recently, to the implementation of pharmacogenetic/pharmacogenomic (PGx) testing services to precisely administer drugs based on an individual's genetic make-up. In fact, PGx has become one of the core scientific pillars of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) and its flagship journal, Clinical Pharmacology & Therapeutics (CPT). PGx implementation services have been rapidly adopted in academic healthcare centers throughout the United States and in Europe. These services are grounded in the availability of new genetic technologies and a wealth of scientific discoveries, generally describing the influence of genetic variants on drug responses in European ancestral populations. With the availability of PGx information, the Clinical Pharmacogenetics Implementation Consortium (CPIC) was established to develop guidelines on drug and dose selection for individuals based on their genetic information.¹ These guidelines, published in CPT,^{2, 3} are increasingly being incorporated into clinical decision support systems, and used to advise providers on how to use PGx information in drug or dose selection.¹ However, despite of their widespread adoption in academic medical centers, there remains a resistance to PGx testing among healthcare providers. This can be attributed to various factors, such as cost of testing, requirements for expensive infrastructure, lack of provider education, and skepticism that there is any major benefit of testing.⁴

With the goal of stimulating discussion among clinical pharmacologists and others, the editors of CPT sponsored a session at the 2024 annual meeting of ASCPT, entitled: “Is pharmacogenetic testing a vital tool for enhancing therapeutic management of patients worldwide?” (Colorado Springs CO, March 28, 2024). The session, which was moderated by CPT Editor-in-Chief, Piet van der Graaf, and Deputy Editor, Kathleen Giacomini, included four clinical pharmacologists or geneticists who brought different types of expertise to the panel discussion: Karen E. Brown, PharmD (University of Montana), David J. Greenblatt, MD (Tufts University School of Medicine), Henk-Jan Guchelaar, PharmD PhD (Leiden University Medical Center), and Neal Hanchard, MD PhD (National Institute of Health). To spark audience engagement, the moderators designed a survey (Supplementary Materials S1 )—distributed to the membership of the ASCPT a month before the annual meeting—with the aim to gain insight into the attitudes of clinical pharmacologists towards PGx testing.

The results of the survey, with 42 respondents, were both interesting and surprising (Supplementary Materials S1 ). Approximately half of the respondents felt that PGx testing was “useful but of little value,” and likewise the majority felt that prospective clinical trials were needed, though not obligate, before a genetic test was implemented in patient care (Figure 1 ). Virtually, all respondents thought that more discovery research in PGx testing was needed, and a majority felt that PGx testing (excluding somatic cell mutations) benefited therapeutic management in oncology more than in other fields such as cardiology and neurology.

The issues of lack of diversity in clinical trials and in PGx testing were discussed by the panelists, who responded to this question. Dr. Hanchard pointed out that many genetic variants that are common in Europeans are extremely rare in other populations. Importantly, he described the tremendous variation in the allele frequencies of various genetic variants within the continent of Africa. Indeed, in their manuscript published in 2023 in CPT,⁶ Dr. Hanchard and colleagues described the enormous variation in glucose-6-phosphate dehydrogenase (G6PD) across Africa. G6PD-deficiency is common in countries including African countries that experience malaria and when certain drugs are administered (for example primaquine), patients with G6PD-deficiency experience acute hemolytic anemia along with other symptoms such as fatigue and jaundice. Though G6PD-deficiency has been thought to be an X-linked recessive condition, occurring primarily in males, it can occur in both males and females: in hemizygous males, in homozygous females and in heterozygous females due to X-linked mosaicism. The G6PD A-haplotype (which includes the rs1050828 T allele, together with the rs1050829 C) is associated with G6PD deficiency in Africa. Interestingly within Africa, the frequency of rs1050828 T in the Tsonga (16%) is significantly higher than that in the Xhosa (0.8%) although both groups are found in South Africa. Dr. Hanchard and his team notes that G6PD testing is critical in Africa before these drugs are administered. CYP2B6 alleles conferring reduced enzymatic function are also common in Africa and show wide variation in continental Africa. He and his group note that CYP2B6 is a critical determinant of the pharmacokinetics of the HIV medication, efavirenz, again highlighting the need for pharmacogenetic testing in Africa.

All panelists agreed that more studies are clearly needed in non-European populations to identify common deleterious or gain-of-function alleles in drug metabolizing enzymes and transporters. A surprising finding of the survey was that the majority of survey responders felt that PGx testing affects global health equity in a positive way. The moderators interpreted this response as global health equity would be affected in a positive way if pharmacogenetic testing would be available in all parts of the world including low- and middle-income countries. Dr Brown highlighted the fact that even in developed countries such as the United States and Canada, there is a need to engage all communities, including indigenous peoples. She and her team have been involved in PGx studies of indigenous communities. She highlighted the importance of long-term partnerships between American Indian and Alaska Native peoples and researchers as being critical for the delivery of healthcare to people who have been historically under-represented in PGx research.⁷

Audience participation was high in the PGx session, with participants reminding panelists of the important need for studies of drug–drug interactions in the context of genetic variants, and the fact that therapeutic and adverse drug reactions are multi-factorial, influenced by a patient's underlying disease, concomitant medications and genetics. Overall, though there were diverse opinions expressed in response to the title and major question raised by the session titled “Is pharmacogenetic testing a vital tool for enhancing therapeutic management of patients worldwide?,” there was clear support for implementation of PGx tests in drug therapy. However, the need to address physician overload is critical, which may occur through other healthcare workers such as pharmacists. Further, the general agreement between the panelists, survey participants and audience members was that research was greatly needed including more discovery research, prospective clinical trials and studies addressing the cost–benefit ratios of PGx testing.

A series of articles in the current issue of CPT (Figure 1 ) builds on the main conclusions and points of discussion from the ASCPT 2024 session described above. As pharmacogenomic testing services are increasingly adopted in healthcare systems, sharing best practices for implementation is critical to reduce disparities in health care. The Tutorial by Shugg and coworkers⁸ from the Indiana University Precision Health Initiative details a multi-faceted PGx implementation program which can provide guidance for other clinical organizations and healthcare providers. Pharmacogenomic implementation services require interpretation of actionable pharmacogenomics variations through guidelines, such as those co-authored by CPIC, or expert consulting services. In this issue, the value and clinical impact of published PGx guidelines are debated by Donnelly et al.¹ and Ingelman-Sundberg⁴ using two new CPIC guidelines^{2, 3} as case studies.

As noted in the survey that preceded the ASCPT session entitled “Is pharmacogenetic testing a vital tool for enhancing therapeutic management of patients worldwide?,” discovery research in pharmacogenomics is needed to expand knowledge of the effects of genetic variation on clinical drug response. Two new “GeneFocus” reviews from the Pharmacogene Variation Consortium (PharmVar) provide comprehensive overviews of genetic variations in two important drug metabolizing enzymes, CYP2A6 ⁹ and CYP4F2,¹⁰ which should facilitate further work into their clinical impact. Pharmacogenomic testing has relied heavily on data generated from clinical studies in populations of European ancestry, often in populations of patients being treated with particular medications, such as patients with dyslipidemias on statins. However, special populations and under-represented groups remain understudied in pharmacogenomics research. In this issue of CPT, several manuscripts describe precision dosing in specific and under-represented patient groups. For example, two studies are focused on pharmacogenomics in African populations.^{11, 12} One of the two studies involves both genetic polymorphisms and pregnant and postpartum patients, showing that both pregnancy status and CYP2B6 polymorphisms affect exposure to efavirenez.¹² Finally two manuscripts describe precision dosing in pediatric populations.^{13, 14} A limitation of genotyping is of course that in isolation it does not take into account the impact of external factors, such as co-medication. Such factors can result in so-called “phenoconversion,” that is, a discrepancy between predicted and observed phenotypes, as demonstrated in the study by Abouir et al.¹⁵ for CYP2C19 subtrates. Therefore, increasingly, physiologically-based pharmacokinetic (PBPK) modeling is being used to quantify the clinical impact of PGx variability between patient groups.¹⁴ In addition, other in silico tools are being developed to predict the consequences of variants in pharmacogenes. For example, AlSaeed et al.¹⁶ present a case study that suggests that molecular dynamic simulations are better than conventional sequence- and structure-based tools for understanding the influences of non-synonymous single nucleotide polymorphisms (nsSNPs) on drug-protein interactions.

New discoveries have continued to expand our knowledge of the effects of genetic variants on drug response, enabling the transition of pharmacogenomics from a discovery-based science to a translational science in clinical pharmacology where genetic testing informs drug and dose selection in individual patients. There is little doubt that PGx will continue to develop as a vital tool for enhancing therapeutic management, however the jury is still out on the critical question of whether all patients worldwide will benefit from the scientific and clinical advancements. A recent analysis showed that only ~ 50% of the PGx studies published in this journal investigated study populations with diverse ethnic backgrounds.¹⁷ We encourage authors to submit research in pharmacogenomics and precision dosing in underrepresented populations to better understand variability in drug response which can be the basis for developing more effective and safer therapies and treatment regimens for all patients.

No funding was received for this work.

The authors declared no competing interests for this work.