Joseph D. Ma

Evaluation of in vivo P-glycoprotein phenotyping probes: a need for validation.

Drug transporters are involved in clinically relevant drug-drug interactions. P-glycoprotein (P-gp) is an efflux transporter that displays genetic polymorphism. Phenotyping permits evaluation of real-time, in vivo P-gp activity and P-gp-mediated drug-drug interactions. Digoxin, fexofenadine, talinolol and quinidine are commonly used probe drugs for P-gp phenotyping. Although current regulatory guidance documents highlight methodologies for evaluating transporter-based drug-drug interactions, whether current probe drugs are suitable for phenotyping has not been established, and validation criteria are lacking. This review proposes validation criteria and evaluates P-gp probes to determine probe suitability. Based on these criteria, digoxin, fexofenadine, talinolol and quinidine have limitations to their use and are not recommended for P-gp phenotyping.

Pharmacogenomics: bridging the gap between science and practice.

OBJECTIVE To educate pharmacists about principles and concepts in pharmacogenomics, clinical applications of pharmacogenomic information, and the social, ethical, and legal aspects of pharmacogenomics and to describe a Centers for Disease Control and Prevention (CDC)-supported pharmacogenomics education program for pharmacists and other health professionals. DATA SOURCES Primary literature from PubMed, recommendations from the Food and Drug Administration and Evaluation of Genomic Applications in Practice and Prevention Working Group, prescribing information, websites of government agencies and professional organizations, and relevant textbooks. STUDY SELECTION Not applicable. DATA EXTRACTION Not applicable. DATA SYNTHESIS Principles and concepts of pharmacogenomic nomenclature, polymorphism types, and systematic approach to understanding polymorphisms were reviewed. Drug therapy for select therapeutic areas that highlight the applicability of pharmacogenomics are presented, including abacavir, selective serotonin reuptake inhibitors, tamoxifen, and warfarin. Challenges of translating pharmacogenomics into clinical practice included ethical, social, legal, and economic issues. We have developed a pharmacogenomics education program to disseminate evidence-based pharmacogenomics information and provide a resource for health professionals, including pharmacists. CONCLUSION Pharmacists play a critical role in the education of patients and health professionals in the area of pharmacogenomics.

Clinical Application of Pharmacogenomics

The purpose of this review is to discuss the clinical application of pharmacogenomics for select drug therapies (eg, proton pump inhibitors [PPIs], codeine, and carbamazepine) and to highlight limitations and challenges that preclude implementation of pharmacogenomics into clinical practice. Genetic polymorphisms of cytochrome P450 (CYP) enzymes and the presence of the human leukocyte antigen (HLA)-B*1502 allele influence drug disposition and/or response. A portion of PPI pharmacokinetic and pharmacodynamic variability can be explained by CYP2C19 genotype. However, conflicting evidence exists related to Helicobacter pylori cure rates based on CYP2C19 genotype. For codeine, adverse drug reactions in neonates through breast-feeding from CYP2D6 ultra-rapid metabolizers have been reported. However, there is lack of conclusive evidence regarding the overall influence of CYP2D6 polymorphisms on codeine efficacy and toxicity. Although CYP2C19 and CYP2D6 genotyping tests are available, clinical utility remains low. The presence of the HLA-B*1502 allele is associated with carbamazepine-induced Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN). Pharmacogenomic testing is required prior to initiating carbamazepine in high-risk patients. Lack of sufficient resources, provider knowledge, and ethical, legal, and social issues are several limitations and challenges to implementing pharmacogenomic testing in clinical practice.

Epothilones: a novel class of microtubule-stabilizing drugs for the treatment of cancer

Microtubule-targeted anticancer drugs are effective in treating various cancers but are limited in use due to development of resistance and unacceptable toxicities. The epothilones are a novel class of microtubule-stabilizing anticancer drugs and may have a role in treating taxane-resistant cancers. Revised and updated data from several clinical studies for ixabepilone were recently published and subsequently resulted in ixabepilone becoming the first epothilone approved as monotherapy or in combination for treatment of locally advanced or metastatic breast cancer. BMS-310705, patupilone, KOS-862, KOS-1584 and ZK-EPO are epothilones that have been developed. Although peripheral sensory neuropathy and neutropenia are the dose-limiting toxicities for ixabepilone, these dose-limiting toxicities are ixabepilone specific. This review will discuss the current preclinical, clinical pharmacokinetic and pharmacodynamic, efficacy and toxicity data of the epothilones.

Maribavir Pharmacokinetics and the Effects of Multiple-Dose Maribavir on Cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-Acetyltransferase-2, and Xanthine Oxidase Activities in Healthy Adults

ABSTRACT Maribavir (1263W94, VP-41263) is an oral anticytomegalovirus agent under clinical development. The pharmacokinetics and safety of maribavir and the effects of maribavir on the activities of cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) were evaluated in a randomized, double-blind, placebo-controlled study. Twenty healthy subjects received a five-drug phenotyping cocktail of caffeine (CYP 1A2, NAT-2, XO), warfarin plus vitamin K (CYP 2C9), omeprazole (CYP 2C19), dextromethorphan (CYP 2D6), and midazolam (CYP 3A) 4 days before and after 7 days of treatment with maribavir at 400 mg twice daily (16 subjects) or placebo (4 subjects) for 10 days. Maribavir did not affect the CYP 1A2, CYP 2C9, CYP 3A, NAT-2, or XO activities. Bioequivalence was not demonstrated for CYP 2C19 and CYP 2D6, suggesting a decrease or inhibition of CYP 2C19 and CYP 2D6 activities. The pharmacokinetics of maribavir following a single dose and after 10 days of treatment were similar, with minimal accumulation at steady state. Maribavir was safe and well tolerated. Taste disturbance was the most frequently reported adverse event. These results will further guide evaluation of the drug interaction potential and clinical development of maribavir.

Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk.

Azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine (TG) are thiopurine drugs. These agents are indicated for the treatment of various diseases including hematologic malignancies, inflammatory bowel disease (IBD), rheumatoid arthritis, and as immunosuppressants in solid organ transplants. Thiopurine drugs are metabolized, in part, by thiopurine methyltransferase (TPMT). TPMT displays genetic polymorphism resulting in null or decreased enzyme activity. At least 20 polymorphisms have been identified, of which, TPMT *2, *3A, *3B, *3C, and *4 are the most commonly studied. These polymorphisms have been associated with increased myelosuppression risk. TPMT genotyping may be useful to predict this risk.

HLA-B*5701 testing to predict abacavir hypersensitivity

Abacavir is a nucleoside reverse transcriptase inhibitor used for combination antiretroviral therapy for treating human immunodeficiency virus (HIV) infection. An adverse effect from abacavir is a treatment-limiting hypersensitivity reaction, which can be severe and potentially life-threatening. Abacavir-induced hypersensitivity reaction has been associated with the presence of the major histocompatibility complex class I allele HLA-B*5701. A screening test for the HLA-B*5701 allele can assist clinicians to identify patients who are at risk of developing a hypersensitivity reaction to abacavir.

Genetic polymorphisms of cytochrome P450 enzymes and the effect on interindividual, pharmacokinetic variability in extensive metabolizers.

Genetic polymorphisms of cytochrome P450 (CYP) enzymes are one of the factors that contribute to the pharmacokinetic (PK) variability of drugs. PK variability is observed in the bimodal distribution between extensive metabolizers (EMs) and poor metabolizers (PMs). PK variability may also exist between individuals genotyped as homozygous EMs and heterozygous EMs. This may carry implications for drug dosing and drug response (e.g., risk of therapeutic failure or drug toxicity). Studies have reported significant PK differences between homozygous and heterozygous EMs. Some literature suggests that this distinction may be of clinical relevance. Due to study design limitations and data that are either sparse or conflicting, generalizations regarding the potential impact of the CYP genotype, within EMs, are difficult. Optimally designed clinical trials are needed. This review evaluates the potential impact of CYP genetic polymorphisms on interindividual PK variability of drugs within an EM population.

A Train-the-Trainer Approach to a Shared Pharmacogenomics Curriculum for US Colleges and Schools of Pharmacy

Objective. To assess pharmacy faculty trainers’ perceptions of a Web-based train-the-trainer program for PharmGenEd, a shared pharmacogenomics curriculum for health professional students and licensed clinicians. Methods. Pharmacy faculty trainers (n=58, representing 39 colleges and schools of pharmacy in the United States and 1 school from Canada) participated in a train-the-trainer program consisting of up to 9 pharmacogenomics topics. Posttraining survey instruments assessed faculty trainers’ perceptions toward the training program and the likelihood of their adopting the educational materials as part of their institution’s curriculum. Results. Fifty-five percent of faculty trainers reported no prior formal training in pharmacogenomics. There was a significant increase (p<0.001) in self-reported ability to teach pharmacogenomics to pharmacy students after participants viewed the webinar and obtained educational materials. Nearly two-thirds (64%) indicated at least a “good” likelihood of adopting PharmGenEd materials at their institution during the upcoming academic year. More than two-thirds of respondents indicated interest in using PharmGenEd materials to train licensed health professionals, and 95% indicated that they would recommend the program to other pharmacy faculty members. Conclusion. As a result of participating in the train-the-trainer program in pharmacogenomics, faculty member participants gained confidence in teaching pharmacogenomics to their students, and the majority of participants indicated a high likelihood of adopting the program at their institution. A Web-based train-the-trainer model appears to be a feasible strategy for training pharmacy faculty in pharmacogenomics.

The effect of oral pleconaril on hepatic cytochrome P450 3A activity in healthy adults using intravenous midazolam as a probe.

Pleconaril is a viral capsid inhibitor under evaluation for treatment of infections caused by rhinoviruses and enteroviruses. This study evaluated the effect of pleconaril on hepatic cytochrome P450 (CYP) 3A activity as assessed by intravenous (IV) midazolam. Healthy adults received oral pleconaril 400 mg 3 times daily for 16 doses. Single‐dose, IV midazolam 0.025 mg/kg was administered before and during pleconaril administration. Midazolam and pleconaril plasma concentrations were assayed by LC/MS/MS. Bioequivalence was assessed by least squares geometric mean ratios (LS‐GMR) with 90% confidence intervals (90% CIs) for the measured midazolam pharmacokinetic parameters. Sixteen subjects were enrolled, and 14 subjects completed the study. Pleconaril decreased midazolam AUC0‐∞ 28% and increased systemic clearance 39%. LS‐GMR (90% CI) were 0.718 (0.674–0.765) and 1.392 (1.307–1.483), respectively. Plasma pleconaril concentrations steadily increased over time. Observed changes in midazolam AUC0‐∞ and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.