Implementation of pharmacogenotyping in pharmaceutical care

“One size fits all” is the common strategy of dose-finding studies and, consequently, in most drug therapies a standard dosage is applied. However, drugs may cause therapy failure (TF), and/or may induce considerable adverse drug reactions (ADRs). Variations in the genes of proteins involved in absorption, distribution, metabolism, and excretion (ADME) can influence their activity and thus lead to phenotypic, i.e. measurable, inter-individual differences in the efficacy and tolerability of a drug. Pharmacogenetics (PGx) is defined as “the study of variations of DNA characteristics as related to drug response”. The influence of patients’ genetic predispositions on drug response has been studied over decades 1 and now, pharmacogenetics is gaining importance in patient-centered research and personalized medicine.
PGx testing (aka pharmacogenotyping) consists of a test where certain genetic variations are associated with drug response to prevent TF or ADRs. In these days, it is uncontested that PGx findings contribute significantly to our current understanding of drug response. Therefore, PGx panel tests comprising several genes involved in the ADME process, have been developed. By covering several genes, PGx panel tests enable to detect reasons for ADRs and TF pre-emptively, i.e. before taking a therapeutic decision.
To date, PGx testing is not standard in primary care in Switzerland. Yet, several attempts of pre-emptive PGx testing have been conducted in other European countries showing the feasibility and a potential real-world impact in primary care 2-5. Furthermore, it has been shown that pharmacists in the primary care setting can contribute to the optimization of pharmacotherapy when considering the patient’s genetic background 6. Besides, pharmacists have expressed their willingness to learn more about PGx already ten years ago 7. As pharmaceutical care 8, 9 designates a field where drug-related problems are identified, resolved, and prevented, it seems to be the right field for the initiation of PGx. Therefore, the Pharmaceutical Care Research Group decided to implement pharmacogenotyping in pharmaceutical care to show the potential of the pharmacist as facilitator of PGx in primary care.
Project A
Project A aimed to identify pharmacogenetic information for clinical practice.
The drug label (DL) is one of the first sources for health care professionals (HCPs) to check for information on a drug. The Pharmacogenomics Knowledge Base (PharmGKB) 10 is an expert curated knowledge base which collects and disseminates information on drug-gene interactions, including information provided in DLs. The Swiss DL is organized in different sections with defined headings; however, no section is dedicated to PGx. At the time, no overview or comparison of PGx information in Swiss DLs existed. Therefore, in this project, we analyzed the Swiss DLs to get an overview of the current state of PGx-relevant information on metabolizing enzymes and transporters as well as HLA risk alleles, to classify the recommendations provided to HCPs by the PGx levels as suggested by PharmGKB 11, and finally, to compare the respective PGx level with those provided in DLs authorized by agencies of other countries. The analysis of PGx information in Swiss DLs revealed a large heterogeneity. PGx information varies not only in wording used to describe the information but also in the section, where the information appears. In addition, the instructions for clinical practice are rather vague. In summary, this makes the identification and the interpretation of PGx information difficult for HCPs.
One of the identified DLs was that for abacavir (commercial name: Ziagen®), where pre-emptive testing for HLA-B*57:01 is required to prevent administration to patients with a higher risk of hypersensitivity reaction 12. This suggested practice is supported by the findings of a randomized controlled trial 13, 14 where carriers of the HLA-B*57:01 allele showed a higher risk to develop the abacavir hypersensitivity syndrome compared to non-carriers. Especially in the case of HLA alleles, it has been suggested that so-called HLA-typing (pre-emptive testing for a specific HLA allele) may prevent the associated ADRs if exposure of carriers of certain HLA alleles is avoided. Besides abacavir, there are other examples of clinically applied drugs where ADRs are assumed to be associated with HLA alleles. Nevertheless, translation into clinical practice is still limited. Presumably, this is due to the opinion of various HCPs saying that there is insufficient evidence for HLA-typing in association with a drug intervention. Therefore, in this project, we summarized studies investigating HLA alleles in relation to ADRs to give an overview of the evidence on the described ADRs and the investigated genetic factors. In conclusion, the literature search identified a considerable number of studies that investigated various substances, HLA alleles, and associated ADRs. It became clear that pre-emptive testing of HLA alleles (HLA-typing) may have a potential; however, it is not possible to derive the actual clinical relevance from these studies. The overview of HLA-associated ADRs ranged from poor to strong available evidence, thereby revealing a prevailing complexity and uncertainty.
Project B
Project B aimed to develop a standard operating procedure for pharmacist-led PGx testing and counseling in primary care.
With the developing knowledge on genetic variants influencing pharmacokinetics and/or pharmacodynamics of frequently applied drugs, multiple providers are now offering PGx testing using DNA isolated from buccal swaps. One of the commercial products offering a PGx test is Stratipharm (humatrix AG, Pfungstadt, Germany, https://www.stratipharm.de). Stratipharm offers genotyping in combination with evidence-based interpretation of the genotype. We established a case series of patients with ADRs or TF where the PGx panel test Stratipharm was applied to determine the hereditable component of the patient’s susceptibility of experiencing the observed ADRs or TF. The aim of the case series was to compile case reports to gather experience and later, develop a standard operating procedure for “PGx testing and counseling” in primary care. In addition to the results of PGx testing, the individual patient cases were always supplemented with information on health-related factors such as medication history, diagnoses, drug-drug interactions, adherence, renal function, etc. This information was collected in two visits of the patient to the study pharmacy and then integrated into a comprehensive medication review led by the pharmacist. In the end, the patient as well as the treating physician received the list of concerned substances and the written recommendation with the individual recommendations. In the following, the patients’ and physicians’ current understanding, appraisal, and implementation of the results from the pharmacist-led service “PGx testing and counseling” were inquired to evaluate the PGx service.
In total, 100 patients were collected for PGx testing and counseling in the community pharmacy. In this thesis, two cases are reported in detail. The case of a patient with tamoxifen suffering from ADRs on the one hand, revealed the added value of a large PGx panel, and on the other hand, showed the complexity of integrating a PGx profile into a recommendation. The case of a patient with methotrexate suffering from ADRs indicated that PGx panel testing is still limited to experts due to the complex pathway and the many genetic variants. A survey of 42 patients indicated that more than two thirds of the patients had changed at least one drug as suggested by the PGx recommendations.
In conclusion, the pharmacist-led service comprising PGx panel testing and counseling in the community pharmacy is appreciated by patients and physicians. The application of a PGx panel test offers the possibility to counsel on several drugs and the results should be integrated into a pharmacist-led medication review. Finally, the PGx service gives opportunity to initiate an interdisciplinary collaboration with physicians and other HCPs.
A detailed overview on the projects is provided in the chapter “Project Overview”.