Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data.

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.

Pharmacogenetic testing among patients with depression in a US managed care population.

Actionable drug-gene pairs relevant to depression treatment include CYP2D6 and CYP2C19 with specific antidepressants. While clinical use of pharmacogenetic testing is growing, little is known about pharmacogenetic testing for depression treatment in managed care. We determined the incidence of single-gene CYP2D6 and CYP2C19 testing following a new depression episode among US managed care patients, and described characteristics and antidepressant use of patients receiving tests. We used paid medical and pharmacy claims for patients from commercial health plans in the US. For adult patients with a new depression episode from January 1, 2013 to June 30, 2018, we identified covered claims for single-gene CYP2D6 and CYP2C19 pharmacogenetic tests and antidepressant fills. Fewer than 1% (n = 1795) of the depressed cohort (n = 438,534) received a single-gene CYP2D6 or CYP2C19 test through their insurance within 365 days of their earliest depression episode. The percentage of patients who received a test nearly tripled from 0.2% in 2013 to 0.5% in 2014 before plateauing at 0.4% from 2014 to 2017. Among the patients who received a single-gene CYP2D6 or CYP2C19 test and filled an antidepressant within 365 days of their depression diagnosis, up to 30% may have had their initial antidepressant informed by the test result. Our findings describe the use of antidepressants before and after pharmacogenetic testing, which is clinically relevant as pharmacogenomic testing becomes more common in clinical practice. Our study also emphasizes the need for procedure and billing codes that capture multiple-gene panel tests to be more widely implemented in administrative databases.

Providers' perspectives on the clinical utility of pharmacogenomic testing in pediatric patients.

Aim: To assess providers' knowledge, attitudes, perceptions, and experiences related to pharmacogenomic (PGx) testing in pediatric patients. Materials & methods: An electronic survey was sent to multidisciplinary healthcare providers at a pediatric hospital. Results: Of 261 respondents, 71.3% were slightly or not at all familiar with PGx, despite 50.2% reporting prior PGx education or training. Most providers, apart from psychiatry, perceived PGx to be at least moderately useful to inform clinical decisions. However, only 26.4% of providers had recent PGx testing experience. Unfamiliarity with PGx and uncertainty about the clinical value of testing were common perceived challenges. Conclusion: Low PGx familiarity among pediatric providers suggests additional education and electronic resources are needed for PGx examples in which data support testing in children.

Patients' Perspectives on Psychiatric Pharmacogenetic Testing.

INTRODUCTION: There is growing interest to adopt pharmacogenetic (PGx) testing in psychiatric medicine, despite mixed views regarding its clinical utility. Nevertheless, providers are utilizing PGx testing among patients with mental health disorders. This study sought to assess genotyped patients' perspectives and experiences with psychiatric PGx testing. METHODS: Individual semi-structured interviews were conducted among patients with depression who had undergone psychiatric PGx testing. The audio-recorded interviews were transcribed and analyzed inductively and deductively for salient themes. RESULTS: Twenty patients (100% Caucasian, 60% female, mean age 39±18 years) were interviewed. The majority of the PGx tests were provider-initiated for patients who failed multiple pharmacotherapies (50%) and/or had medication intolerances (45%). Patients' pre-testing expectations ranged from hopefulness to indifference to skepticism. Their post-testing experiences varied from optimism to disappointment, with the perceived value of the test influenced by the results and cost of the test. DISCUSSION: Genotyped patients had mixed perspectives, expectations, and experiences with psychiatric PGx testing. Their perceived value of the test was influenced by the test outcomes and its cost.

Assessment of healthcare professionals' knowledge, attitudes, and perceived challenges of clinical pharmacogenetic testing in Egypt.

Aim: We evaluated healthcare practitioners' perspectives regarding clinical pharmacogenetics in Cairo, Egypt. Materials & methods: We administered a paper-based survey to pharmacists and physicians practicing at Children's Cancer Hospital Egypt. The survey assessed practitioners' knowledge, attitudes, and perspectives about pharmacogenetic testing. Results: The study included 184 respondents (67.9% pharmacists; 32.1% physicians. Overall, the pharmacogenetic knowledge was low (mean = 41.7%) but attitudes toward pharmacogenetic testing and its potential clinical application were generally positive. Pharmacists responded more favorably than physicians to statements attributing the responsibility of applying pharmacogenetics in the clinical setting to their profession. However, several challenges were identified; the most common being: lack of pharmacogenetic knowledge and skill, lack of pharmacogenetic testing devices, and limited funding. Conclusion: Future efforts to promote pharmacogenetic implementation should focus on foundational education, practical training, and exploration of potential funding sources.

The landscape of pharmacogenetic testing in a US managed care population.

PURPOSE: Little is known about how many insured patients receive pharmacogenetic testing. We describe trends of single-gene pharmacogenetic testing in a US managed care population, and demographic and clinical characteristics of patients who received a test. METHODS: We leveraged a random sample of nearly 11 million patients from a data set of paid medical and pharmacy claims to identify patients with at least one claim indicating receipt of at least one of these single-gene pharmacogenetic tests: CYP2C19, CYP2D6, CYP2C9, VKORC1, UGT1A1, and HLA class 1 typing. RESULTS: From 1 January 2013 to 30 September 2017, 5712 patients received at least one pharmacogenetic test (55% female; mean age = 43 years). The median number of tests per patient was 3 (mean = 2.7, max = 12); 54% were processed through Managed Medicare/Medicaid, while 45% were processed through commercial insurance. The total number of pharmacogenetic tests received more than doubled from 2013 (n = 1955) to 2015 (n = 4192), then decreased slightly in 2016 (n = 3946). The most common test was CYP2C19 (n = 4719), and "long-term (current) use of other medications" was the most common diagnosis. CONCLUSION: Pharmacogenetic testing through patients' insurance was low, but more than doubled from 2013 to 2016. This study highlights the need to better understand utilization patterns and insurance coverage for pharmacogenetic tests.

The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety.

BACKGROUND: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). METHODS: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset. RESULTS: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75-1.10) in Medicaid and 0.88 (0.61-1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54-0.93] and 1.16 [0.89-1.52] in men and women respectively, interaction term p-value = 0.01). CONCLUSIONS: Rosiglitazone and pioglitazone appear to be associated with similar risks of SCA/VA.

Stakeholder perspectives of the clinical utility of pharmacogenomic testing in solid organ transplantation.

Aims: To assess stakeholder perspectives regarding the clinical utility of pharmacogenomic (PGx) testing following kidney, liver, and heart transplantation. Methods: We conducted individual semi-structured interviews and focus groups with kidney, liver, and heart transplantation patients and providers. We analyzed the qualitative data to identify salient themes. Results: The study enrolled 36 patients and 24 providers. Patients lacked an understanding about PGx, but expressed interest in PGx testing. Providers expressed willingness to use PGx testing, but reported barriers to implementation, such as lack of knowledge, lack of evidence demonstrating clinical utility, and patient healthcare burden. Conclusion: Patient and provider educational efforts, including foundational knowledge, clinical evidence, and applications to patient care beyond just immunosuppression, may be useful to facilitate the use of PGx testing in transplant medicine.

A population pharmacokinetic-pharmacogenetic analysis of atazanavir.

Atazanavir is a first-line HIV protease inhibitor commonly co-dosed with ritonavir. Ritonavir inhibits atazanavir metabolism, decreasing variability and increasing plasma concentrations. However, ritonavir use results in higher costs and increased drug-related adverse events. Elucidating atazanavir pharmacokinetics might allow for individualized ritonavir boosting. We previously demonstrated that genetically determined CYP3A5 nonexpression was associated with slower atazanavir clearance CL/F and higher trough concentrations. This effect was prominent in non-African-American men but absent in African-Americans. The present study considers additional genetic predictors of atazanavir CL/F with a focus on race differences. Nine polymorphisms in CYP3A4, ABCG2, NR1I2 (PXR), and SLCO1B1 were evaluated; 330 plasma samples from 30 HIV-negative volunteers, balanced by sex, race, and CYP3A5 expressor status, were available. Analyses were performed using nonlinear mixed-effects modeling (NONMEM). The following factors were univariately associated with atazanavir CL/F (% effect) : African-American race (decreased 35%), female sex (decreased 25%), older age (decreased 1.7%/year), CYP3A5 nonexpressors (decreased 26%), ABCB1 CGC haplotype carriers (1236C/2677G/3435C) (decreased 33%), and CYP3A4*1B carriers (decreased 31%). However, an independent genetic explanation for the differential race effect could not be identified. An interaction was observed with PXR 63396 C>T and CYP3A5 expressor status (p=0.0002). CYP3A5 nonexpressors with a PXR 63396 CC genotype had 37% slower CL/F versus those with CT or TT genotypes. For CYP3A5 expressors, those with a PXR 63396 CC genotype had 63% faster CL/F versus those with CT or TT genotypes. Although this study has as its main limitation a small overall sample size, these results nonetheless provide new leads and impetus to evaluate ways to individualize the need for ritonavir boosting using demographic and genetic predictors of atazanavir pharmacokinetics.

Race, ethnicity, and use of thiazolidinediones among US adults with diabetes.

OBJECTIVE: Significant race and ethnic disparities exist in diabetes-related health care. Using a nationally representative database, we sought to determine if use of thiazolidinediones (TZDs) differs by race and ethnicity. As a secondary objective, we sought to determine if race and ethnicity is associated with use of older oral antidiabetic agents, such as sulfonylureas and metformin. RESEARCH DESIGN AND METHODS: Adult respondents to the 2003 Medical Expenditure Panel Survey with diabetes, identified by diagnosis code or self-report, were included. Race/ethnic groups were defined as: White/not-Hispanic; Black/not-Hispanic; Hispanic; or Other/not-Hispanic. Associations between use of oral antidiabetic agents (defined as > or = 1 prescription for a TZD, sulfonylurea, or metformin) and race/ethnicity, sex, age, insurance status, poverty status, and having a usual source of care were evaluated in univariate analyses with chi(2) tests and in adjusted analyses using logistic regression methods for survey data. RESULTS: A total of 1873 US adults with diabetes were identified, with use of oral antidiabetic agents varying by drug class: 23.1% received TZDs, 45.3% received metformin, and 43.8% received sulfonylureas. Use of oral antidiabetic agents, by drug class, did not differ significantly by race/ethnicity (p = 0.33 for TZDs, p = 0.43 for metformin, p = 0.38 for sulfonylureas). In univariate analyses, only insurance status was significantly associated with use of TZDs (p = 0.03), and no variables were associated with use of sulfonylureas or metformin. In adjusted logistic regression analyses, there were no significant predictors of the use of TZDs or metformin, and only age was significantly associated with the use of sulfonylureas. CONCLUSIONS: In a nationally representative database, fewer US adults with diabetes received TZDs compared with sulfonylureas or metformin in 2003. Although we were not able to differentiate between type 1 and type 2 diabetes, nor did we assess oral agent monotherapy versus combination therapy, we found that use of TZDs, sulfonylureas, and metformin did not differ based on race/ethnicity or other demographic variables such as sex, insurance status, poverty status, or having a usual source of health care.

Comparison of cytochrome P450 2C9 genotyping methods and implications for the clinical laboratory.

STUDY OBJECTIVE: To compare the accuracy, speed, and cost of two methodologies used for genotyping known variants in the cytochrome P450 (CYP) 2C9 metabolizing enzyme gene. DESIGN: Comparative study. SETTING: University research center. SAMPLES: Fifteen-milliliter mouthwash samples collected from 253 subjects participating in a warfarin pharmacogenomic study. INTERVENTION: Genotyping for the isoleucine-to-leucine change at codon 359 (Ile359Leu [*3] polymorphism) was performed by using the Pyrosequencing and polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods in all 253 samples. Genotyping for the arginine-to-cysteine change at codon 144 (Arg144Cys [*2] polymorphism) was performed by using Pyrosequencing in all samples and by PCR-RFLP in a random subset of 136 samples. MEASUREMENTS AND MAIN RESULTS: Comparisons of genotyping success rates, time efficiency, and cost analyses were conducted for Pyrosequencing and PCR-RFLP at each variant site. Pyrosequencing and PCR-RFLP produced similar success rates on the first genotyping attempt for the Arg144Cys variant (93.3% vs 90.4%, respectively) and the Ile359Leu variant (83.8% vs 79.1%, respectively). With Pyrosequencing, genotyping 96 samples for either polymorphism could be performed in 1 hour. In contrast, genotyping 96 samples by RFLP took 10 hours for the Arg144Cys variant and 20 hours for the Ile359Leu variant. Total cost/sample for Arg144Cys genotyping was dollars 1.90 with PCR-Pyrosequencing and dollars 3.14 with PCR-RFLP. Total cost/sample for Ile359Leu genotyping was dollars 1.88 with PCR-Pyrosequencing and dollars 10.18 with PCR-RFLP CONCLUSION: Compared with RFLP, genotype determination by Pyrosequencing is a more time-efficient, cost-effective, and robust method for CYP2C9 genotyping. Because of its wide applicability and ease of use, Pyrosequencing is a promising technology for future pharmacogenomic investigations.