Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

Precision Medicine at the University of Alabama at Birmingham: Laying the Foundational Processes Through Implementation of Genotype-Guided Antiplatelet Therapy.

Precision medicine entails tailoring treatment based on patients' unique characteristics. As drug therapy constitutes the cornerstone of treatment for most chronic diseases, pharmacogenomics (PGx), the study of genetic variation influencing individual response to drugs, is an important component of precision medicine. Over the past decade investigations have identified genes and single-nucleotide polymorphisms (SNPs) and quantified their effect on drug response. Parallel development of point-of-care (POC) genotyping platforms has enabled the interrogation of the genes/SNPs within a timeline conducive to the provision of care. Despite these advances, the pace of integration of genotype-guided drug therapy (GGTx) into practice has faced significant challenges. These include difficulty in identifying SNPs with sufficiently robust evidence to guide clinical decision making, lack of clinician training on how to order and use genotype data, lack of clinical decision support (CDS) to guide treatment, and limited reimbursement. The University of Alabama at Birmingham's (UAB) efforts in precision medicine were initiated to address these challenges and improve the health of the racially diverse patients we treat.

Integration of genetic, clinical, and INR data to refine warfarin dosing.

Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy.

BACKGROUND: Although multiple reports have documented the influence of CYP2C9 and VKORC1 variants on warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance and individual proportion of time spent in target INR range (PPTR) is limited. Moreover the potential benefit of genotype-guided dosing implemented after initiation of therapy in a racially diverse population has not been explored. Herein we present the influence of CYP2C9 and VKORC1 C1173T on warfarin response during the first 30 days of therapy. METHODS: Warfarin dose was empirically determined in 250 African Americans 271 European Americans. The influence of CYP2C9 and VKORC1 on rate of INR increase, anticoagulation maintenance, risk of over-anticoagulation, and change in dose over 30 days was evaluated after adjustment for socio-demographic, lifestyle and clinical factors. Possession of variant VKORC1 (+/- variant CYP2C9) genotype was associated with a more rapid attainment of target INR and higher frequency of dose adjustments. Patients possessing variant genotypes spent less time in target range. However adjustment for rate of INR increase rendered the association non-significant. European Americans (but not African Americans) possessing variant VKORC1 (+/- variant CYP2C9) genotype had a higher risk of over-anticoagulation. Neither CYP2C9 nor VKORC1 influenced the risk of minor hemorrhage. CYP2C9 and VKORC1 explained 6.3% of the variance in dose change over the first 30 days of therapy demonstrating that the usefulness of genotype-guided dosing may extend beyond first day of therapy. CONCLUSION: The benefit of genotype-based dose prediction may extend beyond first few days of therapy. Whether genotype-guided dosing will decrease the risk of over-anticoagulation, improve anticoagulation control and most importantly improve outcomes for chronic warfarin users remains to be proven.

Estimation of the warfarin dose with clinical and pharmacogenetic data.

BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base. METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators. RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week). CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin.

The association of CYP2C9 and VKORC1 1173C/T genotype and risk of hemorrhage among African Americans and European Americans is presented. This association was evaluated using Cox proportional hazard regression with adjustment for demographics, comorbidity, and time-varying covariates. Forty-four major and 203 minor hemorrhages occurred over 555 person-years among 446 patients (60.6+/-15.6 years, 50% men, 227 African Americans). The variant CYP2C9 genotype conferred an increased risk for major (hazard ratio (HR) 3.0; 95% confidence interval (CI): 1.1-8.0) but not minor (HR 1.3; 95% CI: 0.8-2.1) hemorrhage. The risk of major hemorrhage was 5.3-fold (95% CI: 0.4-64.0) higher before stabilization of therapy, 2.2-fold (95% CI: 0.7-6.5) after stabilization, and 2.4-fold (95% CI: 0.8-7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in risk for major (HR 1.7; 95% CI: 0.7-4.4) or minor (HR 0.8; 95% CI: 0.5-1.3) hemorrhage. The variant CYP2C9 genotype is associated with an increased risk of major hemorrhage, which persists even after stabilization of therapy.

Valproate protein binding following rapid intravenous administration of high doses of valproic acid in patients with epilepsy.

OBJECTIVE: To characterize protein binding in patients with epilepsy who achieve transient high (>150 mg/L) total plasma concentrations following rapid valproate infusion at very high doses. METHODS: Patients with epilepsy (n = 40) were administered 20 or 30 mg/kg loading doses (6 or 10 mg/kg/min) of undiluted valproate sodium injection. Total and unbound valproic acid (VPA) concentrations were used to assess VPA binding to plasma albumin. One- and two-binding site models were explored in a nonlinear mixed effects population analysis framework. The relative importance of weight, age, sex, race and enzyme-inducing comedications on the binding site association constant (K) was examined using the likelihood ratio test. Intersubject and intrasubject variabilities were characterized using exponential or proportional error models. RESULTS: Optimal characterization of the data was achieved using the one-binding site model. Population binding parameter estimates (standard error) for number of binding sites (N) and K were 1.98 (0.0865) and 15.5 [2.28 (1/mM)], respectively. No significant covariates were identified for VPA protein binding. The intersubject and intrasubject coefficients of variation were 32% and 14%, respectively. CONCLUSIONS: A one-binding site model without any significant covariates for binding constants optimally described VPA protein binding. As the estimated dissociation constant (1/K, 64.5 microm or 9.3 mg/L) was within the therapeutic range (5-15 mg/L) for unbound VPA concentrations, protein binding was nonlinear. Although the range of unbound fraction and VPA concentrations were much higher than previous studies, the dissociation constant was consistent with historical data in normal healthy adults and epilepsy patients receiving lower doses.

Racial differences in the prevalence of Factor V Leiden mutation among patients on chronic warfarin therapy.

We report the prevalence of Factor V Leiden (FVL) in European American and African American patients on warfarin therapy residing in Alabama. METHODS.: Detailed history was obtained and FVL genotype was determined for 288 patients enrolled in a prospective cohort: Pharmacogenetic Optimization of Anticoagulation Therapy. Racial differences in genotype frequency were assessed by the Chi-square statistics and HWE assumptions by G-statistics. Race-specific analysis for the association between site of thromboembolism and the presence of FVL mutation was assessed using logistic regression. RESULTS.: The overall heterozygote (GA genotype) frequency was 4.9%. No patient was found to be homozygous (AA) for the variant allele. The prevalence of GA was higher in European American (8.6%) compared to African American (1.4%) patients (p=0.004). The FVL genotype frequency was significantly different across race for venous thromboembolic events (p=0.014) but not for arterial thromboembolic events (p=0.20). Multivariable race-specific analysis highlights the contribution of FVL mutation to the risk of venous thromboembolic events in European American (p=0.03) but not in African American patients (p=0.95). European American patients with the GA mutation were approximately 6.3 times more likely to have experienced a venous, rather than arterial thromboembolic event. CONCLUSION.: In Alabama, among patients on warfarin, the GA genotype is more prevalent in European Americans compared to African Americans. In European Americans, but not in African Americans, the GA genotype was more prevalent in patients with venous compared to arterial thromboembolic events.

Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.

Obesity is a major health problem facing the developed and developing world. Efforts by individuals, health professionals, educators, and policy makers to combat the escalating trend of growing obesity prevalence have been multifaceted and mixed in outcome. Various dietary supplements have been marketed to reduce obesity. These products have been suggested to accomplish this by decreasing energy intake and energy absorption, and/or increasing metabolic rate. Ephedra, one such supplement, was banned from sale in the US market because of concerns about adverse events. Another substance, Citrus aurantium, which contains several compounds including synephrine alkaloids, has been suggested as a safe alternative. This review examines the evidence for safety and efficacy of C. aurantium and synephrine alkaloids as examined in animal studies, clinical weight loss trials, acute physiologic studies and case reports. Although at least three reviews of C. aurantium have been published, our review expands upon these by: (i) distinguishing and evaluating the efficacy of C. aurantium and related compounds; (ii) including results from previously unreviewed research; (iii) incorporating recent case reports that serve to highlight, in an anecdotal way, potential adverse events related to the use of C. aurantium and related compounds; and (iv) offering recommendations to guide the design of future trials to evaluate the safety and efficacy of C. aurantium. While some evidence is promising, we conclude that larger and more rigorous clinical trials are necessary to draw adequate conclusions regarding the safety and efficacy of C. aurantium and synephrine alkaloids for promoting weight loss.

Efficacy of rapid IV administration of valproic acid for status epilepticus.

Although not approved by the US Food and Drug Administration for the treatment of status epilepticus (SE), valproic acid (VPA) is an emerging option for this purpose. The authors reviewed 63 patients (30 men) with SE treated with IV VPA (average dose, 31.5 mg/kg). Analysis of demographic, clinical, and treatment information indicated an overall efficacy of 63.3% and favorable tolerance of rapid administration.

Neurotoxicity following addition of intravenous valproate to lamotrigine therapy.

Reversible neurotoxic symptoms were observed in three adult patients with absence status epilepticus on lamotrigine (LTG) therapy after administration of an IV bolus followed by oral valproic acid (VPA). Neurotoxicity was likely related to elevated serum LTG levels, as improvement correlated with discontinuing or reducing LTG dosage.

The safety of rapid valproic acid infusion.

PURPOSE: The recommended rate of administration of valproic acid injection is 20 mg/min. Drug delivery at this rate may be inadequate for expeditious control of seizures. The safety of rapid infusion of valproic acid has not been established, and this study was designed to explore the effects of rapid infusion in patients with acute seizures. METHODS: Twenty patients with acute repetitive seizures received 20 mg/kg loading doses of valproic acid. Infusion rates ranged from 33.3 to 555 mg/min (median, 200 mg/min). Sixteen patients had received previous or concomitant antiepileptic drugs, with inadequate seizure control. Heart rate, blood pressure, and respiratory rate were measured before infusion and at frequent intervals for 1 hour after infusion. Patients were also observed for changes in level of alertness and signs of local irritation. RESULTS: No patient exhibited a decline in level of consciousness or respiratory function. Two patients with significant contributing factors exhibited declines in blood pressure requiring vasopressors. No significant local irritation was reported. Although efficacy was not a measured end point, seizures were abolished in all patients. CONCLUSIONS: Infusion of valproic acid at rates between 33 and 555 mg/min is well tolerated. No serious adverse effects attributable to the rapid infusion of valproic acid were encountered, although valproic acid, along with other factors, may have contributed to the hypotension in two patients. Intravenous valproic acid is an option for the control of acute seizures.

Prediction of intra ocular lens power in 100 patients using the ophthasonic a scan unit.

The aim of this study was to determine the range of ametropias encountered by using the computerized Ophthasonic A-Scan. The SRK formula was used to compute the IOL power using axial length and keratometry as inputs. The accuracy of prediction of IOL power was calculated by noting the disparity between the expected post-operative refraction and the actual refraction obtained after one and a half months of IOL implantation. The results obtained were encouraging; the maximum deviation from the expected result being +/- 3.2 D.