Showing papers in "Clinical Pharmacology & Therapeutics in 2012"

Pharmacogenomics Knowledge for Personalized Medicine

Abstract: The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug responses. It provides clinically relevant information, including dosing guidelines, annotated drug labels, and potentially actionable gene-drug associations and genotype-phenotype relationships. Curators assign levels of evidence to variant-drug associations using well-defined criteria based on careful literature review. Thus, PharmGKB is a useful source of high-quality information supporting personalized medicine-implementation projects.

Anti‐TNF Monoclonal Antibodies in Inflammatory Bowel Disease: Pharmacokinetics‐Based Dosing Paradigms

Abstract: Crohn's disease and ulcerative colitis are chronic inflammatory disorders resulting from immune dysregulation. Patients who fail conventional medical therapy require biological treatment with monoclonal antibodies (mAbs). Although mAbs are highly effective for induction and maintenance of clinical remission, not all patients respond, and a high proportion of patients lose response over time. One factor associated with loss of response is immunogenicity, whereby the production of antidrug antibodies accelerates mAb clearance. However, other factors related to patient and disease characteristics also influence the pharmacokinetics of mAbs. These factors include gender, body size, concomitant use of immunosuppressive agents, disease type, serum albumin concentration, and the degree of systemic inflammation. Because it is important to maintain clinically effective concentrations to provide optimal clinical response and drug exposure is affected by patient factors, a better understanding of the pharmacology of mAbs will ultimately result in better patient care.

Operational implementation of prospective genotyping for personalized medicine: The design of the Vanderbilt PREDICT project

Abstract: The promise of "personalized medicine" guided by an understanding of each individual's genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant information. We describe the operational implementation of prospective genotyping linked to an advanced clinical decision-support system to guide individualized health care in a large academic health center. This approach to personalized medicine entails engagement between patient and health-care provider, identification of relevant genetic variations for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most of whom were scheduled for cardiac catheterization, were genotyped on a multiplexed platform that included genotyping for CYP2C19 variants that modulate response to the widely used antiplatelet drug clopidogrel. These data are deposited into the electronic medical record (EMR), and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.

Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey.

Abstract: To develop a benchmark measure of US physicians' level of knowledge and extent of use of pharmacogenomic testing, we conducted an anonymous, cross-sectional, fax-based, national survey. Of 397,832 physicians receiving the survey questionnaire, 10,303 (3%) completed and returned it; the respondents were representative of the overall US physician population. The factors associated with the decision to test were evaluated using χ(2) and multivariate logistic regression. Overall, 97.6% of responding physicians agreed that genetic variations may influence drug response, but only 10.3% felt adequately informed about pharmacogenomic testing. Only 12.9% of physicians had ordered a test in the previous 6 months, and 26.4% anticipated ordering a test in the next 6 months. Early and future adopters of testing were more likely to have received training in pharmacogenomics, but only 29.0% of physicians overall had received any education in the field. Our findings highlight the need for more effective physician education on the clinical value, availability, and interpretation of pharmacogenomic tests.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype

Abstract: Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.

Novel data-mining methodologies for adverse drug event discovery and analysis.

Abstract: An important goal of the health system is to identify new adverse drug events (ADEs) in the postapproval period. Datamining methods that can transform data into meaningful knowledge to inform patient safety have proven essential for this purpose. New opportunities have emerged to harness data sources that have not been used within the traditional framework. This article provides an overview of recent methodological innovations and data sources used to support ADE discovery and analysis.

The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy

Abstract: Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A non-synonymous coding single-nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.

Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and carbamazepine dosing

Abstract: Human leukocyte antigen B (HLA-B) is responsible for presenting peptides to immune cells and plays a critical role in normal immune recognition of pathogens. A variant allele, HLA-B*57:01, is associated with increased risk of a hypersensitivity reaction to the anti-HIV drug abacavir. In the absence of genetic prescreening, hypersensitivity affects ~6% of patients and can be life-threatening with repeated dosing. We provide recommendations (updated periodically at http://www.pharmkgb.org) for the use of abacavir based on HLA-B genotype.

Physiologically based pharmacokinetics joined with in vitro-in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology.

Abstract: Classic pharmacokinetics (PK) rarely takes into account the full knowledge of physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent "system" information. PBPK is not a new concept, but it has shown a very rapid rise in recent years. This has been attributed to a greater connectivity to in vitro-in vivo extrapolation (IVIVE) techniques for predicting drug absorption, distribution, metabolism, and excretion (ADME) and their variability in humans. The marriage between PBPK and IVIVE under the overarching umbrella of "systems biology" has removed many constraints related to cutoff approaches on prediction of ADME. PBPK-IVIVE linked models have repeatedly shown their value in guiding decisions when predicting the effects of intrinsic and extrinsic factors on PK of drugs. A review of the achievements and shortcomings of the models might suggest better strategies in extending the success of PBPK-IVIVE to pharmacodynamics (PD) and drug safety.

Drug Absorption Interactions Between Oral Targeted Anticancer Agents and PPIs: Is pH-Dependent Solubility the Achilles Heel of Targeted Therapy?

Abstract: A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4).

High-Risk Prescribing and Incidence of Frailty Among Older Community-Dwelling Men

Abstract: Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men ≥70 years of age. High-risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men.

Adaptive licensing: taking the next step in the evolution of drug approval.

Abstract: Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL.

The genetic and epigenetic basis of type 2 diabetes and obesity.

Abstract: Type 2 diabetes (T2D) and obesity are complex disorders that constitute major public health problems. The evidence for familial aggregation of both T2D and obesity is substantial. To date, more than 150 genetic loci are associated with the development of monogenic, syndromic, or multifactorial forms of T2D or obesity. However, the proportion of overall trait variance explained by these associated loci is modest (~5-10% for T2D, ~2% for body mass index (BMI)). Some of the familial aggregation not attributable to known genetic variation, as well as many of the effects of environmental exposures, may reflect epigenetic processes. In this review, we discuss the evidence concerning the genetic contribution to individual risk of T2D and obesity, and explore the potential role of epigenetic mechanisms. We also explain how genetics, epigenetics, and environment are likely to interact to define the individual risk of disease.

Pharmacogenomics and individualized medicine: translating science into practice.

Abstract: Research on genes and medications has advanced our understanding of the genetic basis of individual drug responses The aim of pharmacogenomics is to develop strategies for individualizing therapy for patients, in order to optimize outcome through knowledge of the variability of the human genome and its influence on drug response Pharmacogenomics research is translational in nature and ranges from discovery of genotype-phenotype relationships to clinical trials that can provide proof of clinical impact Advances in pharmacogenomics offer significant potential for subsequent clinical application in individual patients; however, the translation of pharmacogenomics research findings into clinical practice has been slow Key components to successful clinical implementation of pharmacogenomics will include consistent interpretation of pharmacogenomics test results, availability of clinical guidelines for prescribing on the basis of test results, and knowledge-based decision support systems

LX4211, a Dual SGLT1/SGLT2 Inhibitor, Improved Glycemic Control in Patients With Type 2 Diabetes in a Randomized, Placebo-Controlled Trial

Abstract: Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

Best Practice in the Use of Physiologically Based Pharmacokinetic Modeling and Simulation to Address Clinical Pharmacology Regulatory Questions

Abstract: Physiologically based pharmacokinetic (PBPK) models are increasingly used by drug developers to evaluate the effect of patient factors on drug exposure. Between June 2008 and December 2011, the Office of Clinical Pharmacology at the US Food and Drug Administration (FDA) received 25 submissions containing PBPK analyses. This report summarizes the essential content of a PBPK analysis needed in a regulatory submission for the purpose of addressing clinical pharmacology questions.

Nrf2: A Potential Target for New Therapeutics in Liver Disease

Abstract: Nuclear erythroid 2-related factor 2 (Nrf2) is an oxidative stress-mediated transcription factor with a variety of downstream targets aimed at cytoprotection. Nrf2 has recently been implicated as a new therapeutic target for the treatment of liver disease. Here, we focus on the most common liver diseases-nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease, and drug-induced liver injury-and highlight areas in the development of these conditions where activation of Nrf2 may alleviate disease progression.

Off-Label Drug Use in Pediatric Patients

Abstract: INTRODUCTION Until recently, it was considered unethical or impossible to perform clinical trials of new medicines in children. As a consequence, many medicines used for treating children are insufficiently documented with regard to dosing, efficacy, and safety. The off-label use of drugs has been extensive in treating the pediatric population. This article gives an overview of the extent and types of off-label use of medicines in pediatric populations.

Optimizing drug outcomes through pharmacogenetics: a case for preemptive genotyping

Abstract: Routine integration of genotype data into drug decision making could improve patient safety, particularly if many relevant genetic variants can be assayed simultaneously before prescribing the target drug. The frequency of opportunities for pharmacogenetic prescribing and the potential adverse events (AEs) mitigated are unknown. We examined the frequency with which 56 medications with known outcomes influenced by variant alleles were prescribed in a cohort of 52,942 medical home patients at Vanderbilt University Medical Center (VUMC). Within a 5-year window, we estimated that 64.8% (95% confidence interval (CI): 64.4-65.2%) of individuals were exposed to at least one medication with an established pharmacogenetic association. Using previously published results for six medications with severe, well-characterized, genetically linked AEs, we estimated that 383 events (95% CI, 212-552) could have been prevented with an effective preemptive genotyping program. Our results suggest that multiplexed, preemptive genotyping may represent an efficient alternative approach to current single-use ("reactive") methods and may also improve safety.

Physiologically based pharmacokinetic (PBPK) modeling in children.

Abstract: This review summarizes the present status of physiologically based pharmacokinetic (PBPK) modeling and simulation (M&S) and its application in support of pediatric drug research. We address the reasons that PBPK is suited to the current needs of pediatric drug development and pharmacotherapy in light of the evolution in pediatric PBPK methodologies and approaches, which were originally developed for the purpose of toxicologic evaluation. Also discussed is the current degree of confidence in using PBPK to support pediatric drug development and registration and the key factors essential for robust results and broader adoption of pediatric PBPK M&S.

Understanding the Critical Disposition Pathways of Statins to Assess Drug–Drug Interaction Risk During Drug Development: It's Not Just About OATP1B1

Abstract: The use of statins is widespread across disease areas because many patients have comorbidities. Given that these drugs have become common as comedications, it is essential to have an understanding of the potential risks of drug-drug interactions (DDIs) between statins and candidate drugs in development. Although the hepatic uptake transporter organic anion-transporting polypeptide 1B1 (OATP1B1) is known to play a substantial role in statin-related DDI risk, other transporters and metabolizing enzymes can also be involved. Consequently, a holistic approach to risk assessment is required, tailored to each statin. Using evidence from pharmacogenetics, DDIs, and literature on absorption, distribution, metabolism, and elimination (ADME) in humans, this review identifies pathways that contribute the most to, and are therefore the most critical to, the disposition of each statin. It also provides an understanding of the expected theoretical maximum increase in systemic exposure if the disposition of a statin is inhibited. Finally, on a statin-by-statin basis, we propose in vitro inhibition studies that should be routinely conducted during drug development so as to better assess DDI risk.

Biologics-Based Therapy for the Treatment of Rheumatoid Arthritis

Abstract: Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. In RA, biologics reduce joint inflammation, limit erosive damage, decrease disability, and improve quality of life. Infections are the main risk associated with their use. Because of the high prices of biologics, their cost-effectiveness is a matter of debate. They are mainly coadministered with disease-modifying drugs such as methotrexate when the latter are found to achieve insufficient disease control on their own.

Ketamine as a Novel Antidepressant: From Synapse to Behavior

Abstract: Recent reports of a rapid antidepressant effect of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, even in treatment-resistant populations, have spurred translational therapeutic and neuroscience research aimed at elucidating ketamine's mechanism of action. This article provides a concise overview of research findings that pertain to the effects of low-dose ketamine at the cellular, neurocircuitry, and behavioral levels and describes an integrated model of the action of ketamine in the treatment of depression.

Regulatory experience with physiologically based pharmacokinetic modeling for pediatric drug trials.

Abstract: Physiologically based pharmacokinetic (PBPK) approaches that incorporate the developmental physiology and ontogeny of cytochrome P450 (CYP) enzymes may have value in the design of pediatric trials. Four recent submissions to the US Food and Drug Administration (FDA) incorporated different PBPK applications to pediatric drug development.Further testing of PBPK models for three drugs showed that these models generally under predicted drug clearance. PBPK modeling may have potential for improving pediatric trials through the learn-and-confirm approaches utilized in current regulatory submissions.

Alanine Aminotransferase: A Clinical and Regulatory Tool for Detecting Liver Injury–Past, Present, and Future

Abstract: Assay of the serum activity of the enzyme alanine aminotransferase (ALT) has become the primary screening tool for detecting acute liver injury. But what does an elevated value mean? Not what it is too often mistakenly believed to indicate. It is not a test of liver function. It does not necessarily predict worse effects to come (in a given person). It is not a valid measure of severity of liver injury or dysfunction. It is too unspecific to be reliable in screening for relatively rare effects on the liver. Although these are substantial limitations, ALT is a very useful biomarker if understood and used properly. It is important to consider how and why these erroneous concepts came to have such wide acceptance, and how elevations of ALT activity for evaluating patients and subjects under study might be interpreted better.

The 1200 patients project: creating a new medical model system for clinical implementation of pharmacogenomics.

Abstract: The paradigm of individualized drug therapy based on genetics is an ideal that is now potentially possible. However, translation of pharmacogenomics into practice has encountered barriers such as limited availability and the high cost of genetic testing, the delays involved, disagreements about interpretation of results, and even lack of understanding about pharmacogenomics in general. We describe our institutional pharmacogenomics-implementation project, “The 1200 Patients Project,” a model designed to overcome these barriers and facilitate the availability of pharmacogenomic information for personalized prescribing. Clinical Pharmacology & Therapeutics (2012); 92 4, 446–449. doi:10.1038/clpt.2012.117

Economic and technological drivers of generic sterile injectable drug shortages.

Abstract: Over the past few years, an increasing number of critically needed medicines have been in short supply. Using economic theory to frame the drug-shortage problem, this paper explores why and how manufacturing-quality problems could combine with other economic and technological factors to result in shortages of generic sterile injectable drugs. The fundamental problem we identify is the inability of the market to observe and reward quality. This lack of reward for quality can reinforce price competition and encourage manufacturers to keep costs down by minimizing quality investments. The US Food and Drug Administration's (FDA's) need to use its regulatory flexibility, on behalf of patients, to avoid shortages of medically necessary drugs may further strengthen the incentive to "push the envelope" on quality. These dynamics may have produced a market situation in which quality problems have become sufficiently common and severe to result in drug shortages.

Transporter-mediated drug--drug interactions involving OATP substrates: predictions based on in vitro inhibition studies.

Abstract: Transporter-mediated drug–drug interactions (DDIs) are among the most important of the clinically relevant pharmacokinetic DDIs. We investigated the validity of a static prediction of area under the plasma concentration-time curve (AUC) ratios (AUCRs; AUC(with inhibitor)/AUC(control) using in vitro inhibition profiles, and selected the types of assumptions that improved the prediction accuracy with minimizing false-negative predictions. We used data from 58 DDI studies involving 12 substrates of hepatic organic anion–transporting polypeptides (OATPs). With original assumptions regarding the maximal increase in intestinal availability, maximum unbound concentration at the inlet to the liver, and inhibition of only the hepatic uptake process, the predicted AUCRs were comparable to those reported within a two/threefold error margin in 44/52 studies, whereas in 16 studies, the predictions were judged to be falsenegatives. When the inhibitory effects on both hepatic uptake and efflux/metabolisms were considered, the overall prediction accuracy became worse, although the false-negative prediction decreased to 11 studies. This illustrates that if appropriate assumptions are selected, unnecessary clinical DDI studies can be reasonably avoided.

The UCSF-FDA TransPortal: A Public Drug Transporter Database

Abstract: Drug transporters play a key role in the absorption, distribution, and elimination of many drugs, and they appear to be important determinants of therapeutic and adverse drug activities. Although a large body of data pertaining to drug transporters is available, there are few databases that inform drug developers, regulatory agencies, and academic scientists about transporters that are important in drug action and disposition. In this article, we inform the scientific community about the UCSF-FDA TransPortal, a new and valuable online resource for research and drug development.

The Role of Physiologically Based Pharmacokinetic Modeling in Regulatory Review

Abstract: During regulatory review of clinical pharmacology data in new drug applications and biologics license applications, questions are routinely asked about how intrinsic factors (e.g., organ dysfunction, age, and genetics) and extrinsic factors (e.g., drug-drug interactions) might influence dose-response and exposure-response and about the impact of these individual factors on the efficacy and safety of the candidate compound. Physiologically based pharmacokinetic (PBPK) modeling and simulation is one of the tools that can be used to address these critical questions.