Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia

Nelarabine is the prodrug of 9-β-arabinofuranosylguanine (ara-G) and is therapeutically classified as a purine nucleoside analog. Nelarabine is converted to ara-G by adenosine deaminase and transported into cells by a nucleoside transporter. Ara-G is subsequently phosphorylated to ara-G triphosphate (ara-GTP), thereby initiating the therapeutic effect by inhibiting DNA synthesis. Nelarabine has been extensively studied in regards to its pharmacokinetics, and the data have demonstrated that ara-GTP preferentially accumulates in malignant T-cells. Clinical responses to nelarabine have been demonstrated in various T-cell malignancies and appear to correlate with a relatively high intracellular concentration of ara-GTP compared to nonresponders. Therefore, this unique drug feature of nelarabine accounts for clinical utilization in treating adult and pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Neuropathy is the most predominant adverse effect associated with nelarabine and the incidence correlates with the dose administered. Myelosuppression has been observed, with thrombocytopenia and neutropenia as the most common hematologic complications. This article reviews the pharmacology, mechanism of action, and pharmacokinetic properties of nelarabine, as well as nelarabine’s clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies. The toxicity profile, dosage, and administration, and areas of ongoing and future research, are also presented

The Impact of Pharmacogenomics on Chemotherapeutic Drug Development and Use

Cancer therapy is largely dependent on general treatment guidelines, and patients undergoing chemotherapy often experience treatment failure with standard drugs. The development of individualized drug therapy through pharmacogenomics has the potential to enhance chemotherapy regimen selection and improve patient outcomes. Antineoplastic agents such as cetuximab and trastuzumab are effective in treating cancers possessing specific genetic biomarker characteristics. Patients need to undergo genetic testing before these agents are administered to ensure appropriate use. Cetuximab has been shown to improve outcomes in metastatic colorectal cancers and head and neck squamous cell carcinomas positive for EGFR. Trastuzumab has shown benefit in human epidermal growth factor receptor 2 (HER2) overexpressing cancers affecting the breast tissue and gastrointestinal tract. High costs associated with the development of targeted drugs and a lack of clinical studies exploring the effects genetic variations can have on drug therapy limit implementation of pharmacogenomics into routine practice. As drug therapy experts, pharmacists need to be aware of advances in the field of pharmacogenomics and facilitate the use of this new class of personalized drugs

Genetic Variations in a Cytochrome P450 Enzyme and the Effects on Clopidogrel Bioactivation and Metabolism

Clopidogrel, the top prescribed antiplatelet medication for individuals who have experienced a myocardial infarction or cerebral vascular accident or who have peripheral arterial disease, is administered orally as a prodrug. It relies on hepatic metabolism through cytochrome P450 enzymes for conversion to its active form. Current research shows that allelic variation m the gene coding for CYP2C19 is the main factor contributing to the variability of response associated with clopidogrel treatment. Through the promotion of genetic testing for variability in the CYP2C19 gene and competently interpreting test results, pharmacists have the opportunity to use these findings to significantly impact clopidogrel prescribing and dosing. By tailoring an individual\u27s dosing regimen, pharmacists can maximize the efficacy of clopidogrel for a patient according to his or her genotype

The Pharmacogenetics of Opioid Pain Management

High rates of interpatient variability in drug metabolism and drug response for nearly all medications lead to the hypothesis that assessment of an individual patient\u27s genotype with respect to their ability metabolize certain drugs can be a useful tool in predicting a patient\u27s responsiveness to certain medications. Evaluating patients using pharmacogenomics as a basis for assessment could allow pharmacists to decide which treatment options would be most efficacious in a given patient and, thereby, have significant impact in the clinical setting. This holds true especially in the case of prodrugs, which require in vivo activation to an active or more active form. Codeine is a prodrug whose clinical efficacy depends greatly on its metabolism to more active forms by both cytochrome P450 enzymes and uridine diphosphate glucuronyltransferase enzymes and is affected by the activity of transporters and the structure of its target receptor. Evaluation of a patient\u27s metabolic capacity concerning these enzymes, as well as any abnormalities in transporter activity or receptor structure, could indicate if the patient will receive adequate pain relief from a given dose of codeine

Improving the Tenure Committee's Review Efficiency with Embedded Dossier Functionality

Numerous manuscripts have been published addressing perceptions of the promotion and tenure process. Very little has been published on mechanism to improve the efficiency of dossier review or tools to assist the reviewer in understanding the comprehensive scope of the applicant’s experiences. An innovative dossier format was utilized to assess the hyperlinks and pop-up tool tips would enhance the reviewer efficiency when reviewing the applicant’s materials. Super scripted numbers at the end of the narrative’s sentences, in the same manner as a journal article, contained the embedded hyperlinks and pop-up tool tips. A majority of the reviewers found the embedded functionality in the dossier did enhance their efficiency in completing the review.   Type: Case Stud

An Interdisciplinary Experience focused on Pharmacogenetics: Engaging pharmacy and physician assistant students in conversations about antiplatelet therapy with respect to CYP2C19 genotype

Objective: The goals of the interdisciplinary laboratory were to educate and engage pharmacy and physician assistant (PA) students in a discussion focused on the collection, interpretation, and application of pharmacogenetic data. Design: Interdisciplinary teams participated in a one-hour, case-based discussion and provided a therapeutic recommendation using the Clinical Pharmacogenetics Implementation Consortium guidelines. Assessment: All students were surveyed before and after the laboratory on knowledge and application of pharmacogenetics and working in interdisciplinary teams. The interdisciplinary laboratory successfully enhanced the student’s knowledge about sample collection and interpretation of pharmacogenetic information. Additionally, the laboratory improved student confidence in working in interdisciplinary teams to apply pharmacogenetic information to clinical decision making. Furthermore, the majority of students indicated that the interdisciplinary laboratory is valuable and useful in healthcare curriculums. Conclusion: The laboratory highlighted the differences between pharmacy and PA education regarding PGt, and brought to light several important uncertainties: (1) What is the depth of PGt knowledge that healthcare practitioners need? (2) What are best practices for conveying PGt information?   Type: Case Stud

Pharmacogenetics: CYPs, NAT2 and 5-HTT Related to Antidepressants

Pharmacogenetics (PGt), the study of a gene\u27s influence on patient response to a drug, shows strong potential for explaining issues with efficacy related to antidepressant medications. Each year, antidepressants are one of the most commonly prescribed medications due to the millions of Americans affected by depression. Importantly, it is recognized that there is wide interpatient variability in drug response to antidepressants caused by genetic mutations, which can alter the pharmacodynamic (PD) and pharmacokinetic (PK) properties of various drugs used to treat depression. Proteins that are mainly involved in how patients respond to medications include receptors, drug-targeted proteins, drug transport proteins and drug-metabolizing enzymes. Specifically in depression, variations in the serotonin reuptake transporter (SERT-1 or 5-HTT), N-acetyltransferase (NAT2), cytochrome P450 (CYP) 2C19, 2D6, and 1A2 can affect the outcomes of patients receiving certain antidepressant medications. Utilizing PGt can help prevent the trial and error in prescribing antidepressants and lead to better patient outcomes in the treatment of depression. Pharmacists can utilize genetic information to help primary care physicians choose drug regimens that are more likely to benefit their patients. Although advances are being made in this subject matter, some major efforts of future research will evaluate the efficacy of drug regimens and the dosing of drugs based on patient genetics

Exploring a Laboratory Model of Pharmacogenetics as Applied to Clinical Decision Making

Objective: To evaluate a pilot of a laboratory model for relating pharmacogenetics to clinical decision making. Case Study: This pilot was undertaken and evaluated to help determine if a pharmacogenetics laboratory should be included in the core Doctor of Pharmacy curriculum. The placement of the laboratory exercise in the curriculum was determined by identifying the point in the curriculum where the students had been introduced to the chemistry of deoxyribonucleic acid (DNA) as well as instructed on the chemistry of genetic variation. The laboratory included cytochrome P450 2C19 genotyping relative to the *2 variant. Twenty-four students served as the pilot group. Students provided buccal swabs as the source of DNA. Students stabilized the samples and were then provided instructions related to sample preparation, polymerase chain reaction, and gel electrophoresis. The results were reported as images of gels. Students used a reference gel image to compare their results to. Students then applied a dosing algorithm to make a "clinical decision" relative to clopidogrel use. Students were offered a post laboratory survey regarding attitudes toward the laboratory. Twenty-four students completed the laboratory with genotyping results being provided for 22 students (91.7%). Sixteen students were wild-type (*1/*1), while six students were heterozygous (*1/*2). Twenty-three students (96%) completed the post laboratory survey. All 23 agreed (6, 26.1%) or strongly agreed (17, 73.9%) that the laboratory "had relevance and value in the pharmacy curriculum" Conclusion: The post pilot study survey exploring a laboratory model for pharmacogenetics related to clinical decision making indicated that such a laboratory would be viewed positively by students. This model may be adopted by colleges to expand pharmacogenetics education.   Type: Case Stud

Exploring a Laboratory Model of Pharmacogenetics as Applied to Clinical Decision Making

Objective: To evaluate a pilot of a laboratory model for relating pharmacogenetics to clinical decision making. Case Study: This pilot was undertaken and evaluated to help determine if a pharmacogenetics laboratory should be included in the core Doctor of Pharmacy curriculum. The placement of the laboratory exercise in the curriculum was determined by identifying the point in the curriculum where the students had been introduced to the chemistry of deoxyribonucleic acid (DNA) as well as instructed on the chemistry of genetic variation. The laboratory included cytochrome P450 2C19 genotyping relative to the *2 variant. Twenty-four students served as the pilot group. Students provided buccal swabs as the source of DNA. Students stabilized the samples and were then provided instructions related to sample preparation, polymerase chain reaction, and gel electrophoresis. The results were reported as images of gels. Students used a reference gel image to compare their results to. Students then applied a dosing algorithm to make a "clinical decision" relative to clopidogrel use. Students were offered a post laboratory survey regarding attitudes toward the laboratory. Twenty-four students completed the laboratory with genotyping results being provided for 22 students (91.7%). Sixteen students were wild-type (*1/*1), while six students were heterozygous (*1/*2). Twenty-three students (96%) completed the post laboratory survey. All 23 agreed (6, 26.1%) or strongly agreed (17, 73.9%) that the laboratory "had relevance and value in the pharmacy curriculum" Conclusion: The post pilot study survey exploring a laboratory model for pharmacogenetics related to clinical decision making indicated that such a laboratory would be viewed positively by students. This model may be adopted by colleges to expand pharmacogenetics education.   Type: Case Stud

Introducing Pharmacogenetics and Personalized Medicine via a Weblog

to freshmen pharmacy students’ knowledge base. Methods: Incoming freshmen pharmacy students were invited by email to enroll in a one semester-hour, elective, on-line blog-based course entitled “Personal Genome Evaluation”. The course was offered during the students’ first semester in college. A topic list related to PGt and PM was developed by a group of faculty with topics being presented via the blog once or twice weekly through week 14 of the 15 week semester. A pre-course and post-course survey was sent to the students to compare their knowledge base relative to general information, drug response related to PGt, and PM. Results: Fifty-one freshmen pharmacy students enrolled in the course and completed the pre-course survey and 49 of the 51 students completed the post-course survey. There was an increase in the students’ general, PGt and PM knowledge base as evidenced by a statistically significant higher number of correct responses for 17 of 21 questions on the post-course survey as compared to the pre-course survey. Notably, following the course, students had an increased knowledge base relative to “genetic privacy”, drug dosing based on metabolizer phenotype, and the breadth of PM, among other specific points. Conclusions: The study indicated that introducing PGt and PM via a blog format was feasible, increasing the students’ knowledge of these emerging areas. The blog format is easily transferable and can be adopted by colleges/schools to introduce PGt and PM