UGT1A1 genotype-guided dosing of irinotecan: A prospective safety and cost analysis in poor metaboliser patients.

AIM: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1∗28 and UGT1A1∗93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasibility, and costs. RESULTS: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: +32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of €183 per patient. CONCLUSION: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effective systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety.

Budget Impact of Adaptive Abiraterone Therapy for Castration-Resistant Prostate Cancer.

BACKGROUND: The use of a novel strategy known as adaptive abiraterone therapy based on mathematical modeling of evolutionary dynamics of tumor subpopulations was shown in a clinical trial to extend the time to disease progression in patients with metastatic castration-resistant prostate cancer (CRPC) and reduced the use of abiraterone therapy. Although the clinical impact of adaptive abiraterone treatment is clear, the economic impact of this strategy has not been investigated. OBJECTIVE: To compare the cost of care with adaptive abiraterone therapy versus standard continuous abiraterone therapy in patients with metastatic CRPC, using patient billing data. METHODS: We performed a retrospective review of billing data for patients with metastatic CRPC who received abiraterone treatment at a large cancer center between June 1, 2012, and August 31, 2018. Patients were divided into 2 groups based on whether they received adaptive abiraterone therapy (N = 15) or continuous abiraterone therapy (N = 21). All patients with refractory, metastatic prostate cancer after castration that was indicated for abiraterone therapy were eligible for this study. Each patient in the adaptive abiraterone therapy cohort received abiraterone plus prednisone treatment until the patient reached a target threshold of 50% or more reduction in prostate-specific antigen (PSA) level compared with his PSA level before abiraterone therapy; treatment was then suspended until the PSA level rose above the 50% of PSA before abiraterone therapy target threshold. The continuous therapy cohort received abiraterone plus prednisone daily until radiographic progression. The primary outcomes were the mean annual cost of care per patient, including and excluding the cost of abiraterone, and the cost of care, by clinical category. RESULTS: The median time to disease progression was 25.8 months for patients who received adaptive abiraterone therapy compared with 12.1 months for patients who received continuous abiraterone therapy. Overall, the mean total, including the cost of drug, annual cost per patient who received adaptive abiraterone therapy was $79,093 compared with $146,782 for patients who received continuous abiraterone therapy (P <.0001). The annual cost of care per patient, excluding the cost of abiraterone, was $13,883 for those who received adaptive therapy versus $22,322 for those who received continuous abiraterone therapy (P = .2757), which was not statistically significant. CONCLUSION: Practical precision medicine strategies, such as adaptive abiraterone treatment or pharmacogenomics-targeted dosing, can use known biomarkers, such as PSA, to tailor therapy, generate improved outcomes, and reduce costs without the need for novel drug and diagnostic discovery and development. The results of this study suggest that a large clinical study of adaptive abiraterone therapy is warranted to validate the potential of this strategy to extend the time to disease progression and reduce costs of treatment of metastatic CRPC.

Prospective CYP2C19-Guided Voriconazole Prophylaxis in Patients With Neutropenic Acute Myeloid Leukemia Reduces the Incidence of Subtherapeutic Antifungal Plasma Concentrations.

A risk mitigation strategy was implemented to determine if a higher prophylactic voriconazole dosage in patients with CYP2C19 rapid metabolizer neutropenic acute myeloid leukemia (AML) reduces the incidence of subtherapeutic trough concentrations. Patients with AML (n = 263) were preemptively genotyped for CYP2C19*2, *3, and *17 alleles as part of a single-center prospective, interventional, quality improvement study. CYP2C19 rapid metabolizers (CYP2C19*1/*17) were recommended to receive interventional voriconazole 300 mg twice daily, ultrarapid metabolizers (CYP2C19*17/*17) were recommended to avoid voriconazole, and all others received the standard prophylactic dosage of 200 mg twice daily. In this real-world setting, 202 patients (76.8%) were prescribed prophylactic voriconazole, and of these patients 176 (87.1%) received CYP2C19-guided prophylactic dosing. Voriconazole trough concentrations were obtained for 41 of the 58 (70.7%) CYP2C19 rapid metabolizers prescribed prophylactic voriconazole. Interventional voriconazole resulted in higher plasma trough concentrations (median 2.7 µg/mL) compared with the standard prophylactic dosage (median 0.6 µg/mL; P = 0.001). Subtherapeutic concentrations were avoided in 83.8% of CYP2C19 rapid metabolizers receiving interventional dosage compared to 46.2% receiving standard dosage (P = 0.02). CYP2C19 genotyping to preemptively guide prophylactic voriconazole dosing is feasible and may be a potential strategy for reducing the risk of subtherapeutic trough concentrations that potentiate breakthrough fungal infections.

Demographic Composition of Select Oncologic New Molecular Entities Approved by the FDA Between 2008 and 2017.

Race, ethnicity, sex, and age are demographic factors that can influence drug exposure and/or response, and can consequently affect treatment outcome. We evaluated demographic subgroup enrollment patterns in new therapeutic products approved by the US Food and Drug Administration (FDA) for the treatment of select cancers-breast, colorectal, lung, and prostate-that have comparative differences in morbidity and/or mortality among some demographic subgroups. In submissions of products approved between 2008 and 2013, participants (n = 22,481) were white (80%), from outside the United States (74%), between 17 and 64 years old (59%), and men (56% and 53%, including and excluding sex-specific indications, respectively). In pivotal trials of products approved between2014 and 2017, participants (n = 3,612) were white (71%), between 17 and 64 years old (61%), and men (48% and 63%, including and excluding sex-specific indications, respectively). The US-relevant minority populations were under-represented. A broader representation of patient subgroups in clinical trials may contribute to better understanding of exposure and/or response variability, and consequently help personalize drug therapy.

Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment.

OBJECTIVES: Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations. PATIENTS AND METHODS: Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Predicted activity phenotype for 19 enzymes and transporters were analyzed for univariate association with endoxifen concentration, and then adjusted for CYP2D6 and clinical covariates. RESULTS: In univariate analysis, higher activity of CYP2C8 (regression ß=0.22, P=0.020) and CYP2C9 (ß=0.20, P=0.04), lower body weight (ß=-0.014, P<0.0001), and endoxifen measurement during winter (each ß<-0.39, P=0.002) were associated with higher endoxifen concentrations. After adjustment for the CYP2D6 diplotype, weight, and season, CYP2C9 remained significantly associated with higher concentrations (P=0.02), but only increased the overall model R by 1.3%. CONCLUSION: Our results further support a minor contribution of CYP2C9 genetic variability toward steady-state endoxifen concentrations. Integration of clinician and genetic variables into individualized tamoxifen dosing algorithms would marginally improve their accuracy and potentially enhance tamoxifen treatment outcomes.

Metabolic Correction in Patients Sample with Diabetes: Clinical Outcomes and Costs Reductions.

Diabetes is a leading cause of mortality and morbidity worldwide. Diabetes complications produce profound impact on patient's quality of life and represent very significant economic cost to patients, their family, the government and society as a whole. Metabolic correction has been proposed as an efficient method to improve clinical outcomes and reduce costs in diabetes. Metabolic correction is a concept that supports health maintenance and promotes the healing processes by improving the body's biochemical-physiological mechanisms. This is done by helping activate the metabolic enzymes necessary to facilitate key physiological pathways. A group of 50 patients followed a simple metabolic correction strategy based on hydration, diet, and magnesium supplementation during a 6 months period. Outcomes measures included laboratory testing, anthropometric measures and medication use including its related costs. Patients had an average weight loss of 9.4 lbs (↓5.0%) from baseline at month 3 and 12 lbs (↓6.4%) at month 6. Waist circumference decreased on average 3.7 inches (↓9.0%) from baseline at month 3 and had further decrease to 5.5 inches (↓13.4%) from baseline at month 6. Laboratory testing of average triglycerides decreased from a baseline of 156.9 to 116.7 (↓25.6%) at month 3 and maintained a reduction of ↓24.2% by month 6. Total cholesterol concentration decreased from a baseline of 181.1 mg/dL to 173.9 (↓4.0%) in month 3 and to 171.1 (↓5.5%) at month 6. Average HgA1c decreased from baseline of 7.17 to 6.52 (↓9.1%) at month 3 and maintained 6.52 at months 6. The atherogenic index decreased from 4.18 at baseline to 3.85 at month 3 (↓7.9%) and then 3.47 (17.0%) at month 6. Medication use and cost was quantified in various ways. The average baseline monthly diabetes medication cost per patient of $124.10 was reduced to $ 78.23 (↓36.7% reduction) at month 3 and to $62.80 (↓49.4% reduction) at month 6. A simple and well structured metabolic correction program that includes a significant educational component, dietary modifications and dietary supplement intake was able to maintain or improve vital signs, anthopometric and laboratory measurements that correlate with improved clinical diabetes and cardiovascular health. This outcome was achieved while decreasing the use medications at month 3 and 6 at significant cost savings.

Budget impact analysis of CYP2C19-guided voriconazole prophylaxis in AML.

OBJECTIVES: The objective of this study was to determine the economic impact of proactive, CYP2C19 genotype-guided voriconazole prophylaxis in AML. METHODS: An Excel-based model was created to project the cost of treating a simulated cohort of severely neutropenic AML patients undergoing antifungal prophylaxis. The model compares (i) standard prophylactic dosing with voriconazole and (ii) CYP2C19 genotyping of all AML patients to guide voriconazole dosing and prescribing. RESULTS: Based on the model, genotype-guided dosing of voriconazole conservatively spares 2.3 patients per year from invasive fungal infections. Implementing proactive genotyping of all AML patients in a simulated 100 patient cohort is expected to save a total of $41467 or $415 per patient. CONCLUSIONS: The model, based on the robust literature of clinical and economic data, predicts that proactive genotype-guided voriconazole prophylaxis is likely to yield modest cost savings while improving patient outcomes. The primary driver of savings is the avoidance of expensive antifungal treatment and extended hospital stays, costing $30 952 per patient, in patients succumbing to fungal infection.

Pharmacogenomic assessment of Mexican and Peruvian populations.

BACKGROUND: Clinically relevant polymorphisms often demonstrate population-specific allele frequencies. Central and South America remain largely uncategorized in the context of pharmacogenomics. MATERIALS & METHODS: We assessed 15 polymorphisms from 12 genes (ABCB1 3435C>T, ABCG2 Q141K, CYP1B1*3, CYP2C19*2, CYP3A4*1B, CYP3A5*3C, ERCC1 N118N, ERCC2 K751Q, GSTP1 I105V, TPMT 238G>C, TPMT 460G>A, TPMT 719A>G, TYMS TSER, UGT1A1*28 and UGT1A1 -3156G>A) in 81 Peruvian and 95 Mexican individuals. RESULTS: Six polymorphism frequencies differed significantly between the two populations: ABCB1 3435C>T, CYP1B1*3, GSTP1 I105V, TPMT 460G>A, UGT1A1*28 and UGT1A1 -3156G>A. The pattern of observed allele frequencies for all polymorphisms could not be accurately estimated from any single previously studied population. CONCLUSION: This highlights the need to expand the scope of geographic data for use in pharmacogenomics studies.

In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles.

AIMS: A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles. METHODS: Three hundred and fifty-five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen : N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively. RESULTS: Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014). CONCLUSION: The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.

Implementation of a pharmacogenomics service in a community pharmacy.

OBJECTIVE To determine the feasibility of implementing a pharmacogenomics service in a community pharmacy. SETTING A single community pharmacy that is part of a regional chain known for offering innovative pharmacy services. PRACTICE DESCRIPTION Community pharmacists at the project site routinely provide clinical pharmacy services, including medication therapy management, immunizations, point-of-care testing, blood pressure monitoring, and diabetes education. PRACTICE INNOVATION The implementation of a pharmacogenomic testing and interpretation service for the liver isoenzyme cytochrome P450 2C19. PARTICIPANTS 18 patients taking clopidogrel, a drug metabolized by CYP2C19. MAIN OUTCOME MEASURES Rate of patient participation, rate of prescriber acceptance of pharmacist recommendation, time to perform genetic testing service, and number of claims submitted to and paid by insurance. RESULTS Of 41 patients taking clopidogrel and meeting project criteria, 18 (43.9%) enrolled and completed testing and interpretation of pharmacogenomic results. The mean time pharmacists spent completing all stages of the project with each participant was 76.6 minutes. The mean time to complete participation in the project (time between person's first and second visit) was 30.1 days. Nine patients had wild-type alleles, and pharmacists recommended continuation of therapy as ordered. Genetic variants were found in the other nine patients, and all pharmacist recommendations for modifications in therapy were ultimately accepted by prescribers. Overall, 17 patients consented to filing of reimbursement claims with their insurers. Five were not able to be billed due to submission difficulties. Of the remaining 12, none was paid. CONCLUSION A pharmacogenomics service can be an extension of medication therapy management services in a community pharmacy. Prescribers are receptive to having community pharmacists conduct pharmacogenomics testing, but reimbursement is a challenge.

Making pharmacogenetic testing a reality in a community pharmacy.

OBJECTIVE: To provide information for community pharmacies considering implementation of a pharmacogenetic testing service. SETTING: A single community pharmacy from a regional chain. PRACTICE DESCRIPTION: Community pharmacists at the study site routinely provide pharmacy services including medication therapy management, immunizations, point-of-care testing, blood pressure monitoring, and diabetes education. The pharmacy is a training site for post-graduate year 1 and 2 community-pharmacy residents and for introductory and advanced pharmacy practice experience students. PRACTICE INNOVATION: Implementation of a pharmacogenetics testing service in a community pharmacy. MAIN OUTCOME MEASURES: Feasibility of offering a pharmacogenetics testing service in a community pharmacy. RESULTS: Study investigators identified several internal and external barriers to the community pharmacy when initiating a pharmacogenetics service. This article shares experiences of the study team and solutions to the identified barriers. CONCLUSION: Community pharmacies interested in providing pharmacogenetic testing can overcome barriers by identifying practice partners and planning appropriately.

Pharmacogenetics and rational drug use around the world.

The WHO embraces evidence-based medicine to formulate an essential medicines list (EML) considering disease prevalence, drug efficacy, drug safety and cost-effectiveness. The EML is used by developing countries to build a national formulary. As pharmacogenetics in developed countries evolves, the Pharmacogenetics for Every Nation Initiative (PGENI) convened with representatives from China, Mexico, Ghana and South Africa in August 2009 to evaluate the use of human pharmacogenetics to enhance global drug use policy. The diseases causing mortality, the lack of integration of pharmacovigilance at the national formulary level, the pharmacogenetics research agenda and pharmacogenetics clinician education did not differ greatly among the countries. While there are many unanswered questions, systematically incorporating pharmacogenetics at the national formulary level promises to improve global drug use.

Systems pharmacology assessment of the 5-fluorouracil pathway.

AIM: To assess the impact of the 5-fluorouracil (5-FU) drug-pathway genes on cytotoxicity, and determine whether loss-of-function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes. MATERIALS & METHODS: Dose-response experiments were used to quantify the phenotype of sensitivity to 5-FU following the specific knockdown of genes selected from the 5-FU PharmGKB drug pathway in three human colorectal cell lines. Changes in sensitivity were considered significant if the IC(50) for shRNA-exposed cells were three standard deviations outside the mean IC(50) for control-treated cells. RESULTS: Of the 24 genes analyzed, 13 produced significant changes on the phenotype of sensitivity to 5-FU (DHFR, DPYS, DTYMK, DUT, FPGS, GGH, NME1, NT5C, RRM1, TYMS, UCK2, UNG and UMPS). CONCLUSION: The RNAi screening strategy enabled prioritization of the genes from the 5-FU drug pathway. Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples.

Enabling pharmacogenomic clinical trials through sampling.

Discussion and output from the US FDA and the pharmaceutical industry from the Drug Information Association/FDA 5th Workshop in a series on pharmacogenomics entitled: 'Generating and Weighing Evidence in Drug Development and Regulatory Decision Making'. A major topic area at the 5th FDA/Industry Workshop on Pharmacogenomics, February 2-4, 2010 in Bethesda (MD, USA), was enabling pharmacogenomic clinical trials through collection of future use samples. The importance of the collection of samples with permission for future analyses was affirmed by both industry and the FDA. In addition, current barriers for the collection of such samples were detailed and possible solutions for overcoming barriers at sites, as well as globally within countries, were discussed. The importance of international concordance on collection of these samples was emphasized, and potential areas for industry to harmonize sample collection practices. A standalone workshop on issues related to sampling was determined to be a key step for solving issues related to future use sample collection during drug development.

Applying the genome to national drug formulary policy in the developing world.

With pharmacogenetics comes the promise of individualized therapy selection for many common diseases where multiple treatment options are available. Recent advances including the Human Genome Project, the International HapMap project, advances in throughput technology and reduction in cost of genetic testing, and the inclusion of genotype-related dosing recommendations into package inserts all point to the integration of pharmacogenetics into clinical practice. However, many countries will not have access to pharmacogenetics resources to individualize patient therapy for decades to come. The PharmacoGenetics for Every Nation Initiative (PGENI) is a first step to making pharmacogenetics applicable on a global level. Generation of genotype profiles for 'common' population groups within a country will provide a useful, but not perfect resource for incorporating pharmacogenetics into national drug formularies in the form of prioritization or tailored surveillance recommendations for a country's population. Targeted educational efforts will also prepare the Ministry of Health staff from participating countries to better integrate genetic information into many areas of healthcare, including disease management and therapeutic development. The goal should always be optimizing therapy for each individual patient, but pharmacogenetics can be useful now and essential in the future for the developing world.

Economic opportunities and challenges for pharmacogenomics.

Economic evaluation provides health care decision makers with a powerful tool for resource allocation decisions because it offers a framework for comparing the costs and benefits of competing interventions or options. This paper reviews how economic analyses have been applied to the field of pharmacogenomics, both by the pharmaceutical industry to inform investment decisions and by payers to make coverage decisions. There is much anticipation that pharmacogenomic testing is likely to be cost-effective because it uses genomic information to improve drug effectiveness and reduce toxicity both in the drug development process and at the bedside. However, the demonstration of economic benefits first requires that pharmacogenomic testing show evidence of clinical effectiveness. This will only be achieved by greater participation of pharmacogenomics experts in comparative effectiveness research and additional emphasis on including costs in the determination of the relative value of pharmacogenomic testing to the health care system.

A health services research agenda for cellular, molecular and genomic technologies in cancer care.

BACKGROUND: In recent decades, extensive resources have been invested to develop cellular, molecular and genomic technologies with clinical applications that span the continuum of cancer care. METHODS: In December 2006, the National Cancer Institute sponsored the first workshop to uniquely examine the state of health services research on cancer-related cellular, molecular and genomic technologies and identify challenges and priorities for expanding the evidence base on their effectiveness in routine care. RESULTS: This article summarizes the workshop outcomes, which included development of a comprehensive research agenda that incorporates health and safety endpoints, utilization patterns, patient and provider preferences, quality of care and access, disparities, economics and decision modeling, trends in cancer outcomes, and health-related quality of life among target populations. CONCLUSIONS: Ultimately, the successful adoption of useful technologies will depend on understanding and influencing the patient, provider, health care system and societal factors that contribute to their uptake and effectiveness in 'real-world' settings.

Validation of clinical testing for warfarin sensitivity: comparison of CYP2C9-VKORC1 genotyping assays and warfarin-dosing algorithms.

Responses to warfarin (Coumadin) anticoagulation therapy are affected by genetic variability in both the CYP2C9 and VKORC1 genes. Validation of pharmacogenetic testing for warfarin responses includes demonstration of analytical validity of testing platforms and of the clinical validity of testing. We compared four platforms for determining the relevant single nucleotide polymorphisms (SNPs) in both CYP2C9 and VKORC1 that are associated with warfarin sensitivity (Third Wave Invader Plus, ParagonDx/Cepheid Smart Cycler, Idaho Technology LightCycler, and AutoGenomics Infiniti). Each method was examined for accuracy, cost, and turnaround time. All genotyping methods demonstrated greater than 95% accuracy for identifying the relevant SNPs (CYP2C9 *2 and *3; VKORC1 -1639 or 1173). The ParagonDx and Idaho Technology assays had the shortest turnaround and hands-on times. The Third Wave assay was readily scalable to higher test volumes but had the longest hands-on time. The AutoGenomics assay interrogated the largest number of SNPs but had the longest turnaround time. Four published warfarin-dosing algorithms (Washington University, UCSF, Louisville, and Newcastle) were compared for accuracy for predicting warfarin dose in a retrospective analysis of a local patient population on long-term, stable warfarin therapy. The predicted doses from both the Washington University and UCSF algorithms demonstrated the best correlation with actual warfarin doses.