Jeffry Florian

Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil.

Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug‐induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J–Tpeak) and late repolarization (global Tpeak–Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug‐related cardiac electrophysiology.

Improving the Assessment of Heart Toxicity for All New Drugs Through Translational Regulatory Science

Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo “thorough QT” studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J−Tpeak), and late repolarization (Tpeak−Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.

A Modeling and Simulation Approach to Characterize Methadone QT Prolongation Using Pooled Data From Five Clinical Trials in MMT Patients

Pharmacokinetic (PK)‐pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate‐corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration–time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1–3% of patients would have ΔQTcF >60 ms, and 0.3–2.0% of patients would have QTcF >500 ms at doses of 160–200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.

U.S. Food and Drug Administration Approval: Obinutuzumab in Combination with Chlorambucil for the Treatment of Previously Untreated Chronic Lymphocytic Leukemia

On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11–0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy–designated drug to receive FDA approval. Clin Cancer Res; 20(15); 3902–7. ©2014 AACR.

Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development

During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure‐matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies’ trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmax and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti‐infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.

Direct‐acting antiviral drugs for the treatment of chronic hepatitis C virus infection: Interferon free is now

Chronic hepatitis C (CHC) is a global, serious, and life‐threatening disease. Virologic response at 12 weeks post‐treatment (SVR12) signifies a durable virologic response and is currently the primary efficacy endpoint used in registrational trials. This change led to more rapid clinical development and earlier approvals of highly effective and well‐tolerated therapies, facilitating access to those in need. Hepatitis C virus (HCV) infection is a therapeutic area where mathematical modeling has proven helpful in understanding the drug mechanism and characterizing viral kinetics to inform therapy decisions. The availability of direct‐acting antivirals (DAAs) provides various treatment options for HIV/HCV coinfected patients, but the complexity of predicting and managing drug–drug interactions presents a unique challenge. Real‐world experience or noninterventional studies can provide insight regarding the safety and use of therapeutics that may not be readily available from traditional clinical trials. This article provides a brief overview of the development of promising drugs for the treatment of CHC.

Does an Increase in Serum Creatinine always Reflect Renal Injury? The Case of Stribild®

Single tablet, once-daily HIV treatment regimens offer patient convenience, the potential for increased adherence, and fewer patient-related dosing errors[1] . Stribild® (manufactured and marketed by Gilead Sciences; referred to as applicant in this report), a 4-drug fixed-dose combination (FDC) tablet, is approved for the treatment of HIV-1 infection in treatment-naïve adult patients. Stribild® contains elvitegravir (an integrase strand transfer inhibitor), cobicistat (an inhibitor of cytochrome P450 enzymes), and the nucleoside/nucleotide reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF).

Don't Get Boxed In: Commentary on the Visual Inspection Practices to Assess Exposure‐Response Relationships From Binary Clinical Variables

B plots are a quick and convenient way of displaying groups of data graphically. Typical box plots are highlighted by 5 key components: a boxed region consisting of the lower quartile, median, and upper quartile, and outer whiskers that, depending on methods used, may represent the lowest and highest observation or the lowest/highest observations within 1.5 of the interquartile (25th-75th) range. Because of the ease in constructing box plots and the convenience in representing several groups of data at once, box plots are commonly used in clinical pharmacology to assess the impact of extrinsic/ intrinsic factors (eg, sex, genetic polymorphisms, race, presence/absence of concomitant medications) on exposure (or, to a lesser extent, pharmacokinetic parameters). Another common use of box plots is to assess differences in effectiveness or adverse event occurrence relative to exposure. In these analyses, the original clinical measures are assigned as binary clinical outcomes (eg, yes or no, 1 or 0). Examples of binary clinical outcomes include occurrence of major bleeding episodes for anticoagulants, complete tumor response for oncology therapeutics, pain relief for analgesics, and reduction of pathogen levels below a prespecified limit for antivirals. In fact, continuous clinical variables are often converted to a binary response because of their ease of interpretation and utility as a clinical end point. The analysis of categorical data in this manner will often serve as a first step in deciding on the utility of additional analyses. For exposureresponse analysis (ER), box plots are commonly used to visually identify if different responses (eg, event vs nonevent) are associated with different exposures. Initial exposure–response evaluation for these binary variables typically includes the following 2 steps to determine the need for further quantitative analysis:

Knowledge management for efficient quantitative analyses during regulatory reviews

Knowledge management comprises the strategies and methods employed to generate and leverage knowledge within an organization. This report outlines the activities within the Division of Pharmacometrics at the US FDA to effectively manage knowledge with the ultimate goal of improving drug development and advancing public health. The infrastructure required for pharmacometric knowledge management includes provisions for data standards, queryable databases, libraries of modeling tools, archiving of analysis results and reporting templates for effective communication. Two examples of knowledge management systems developed within the Division of Pharmacometrics are used to illustrate these principles. The benefits of sound knowledge management include increased productivity, allowing reviewers to focus on research questions spanning new drug applications, such as improved trial design and biomarker development. The future of knowledge management depends on the collaboration between the FDA and industry to implement data and model standards to enhance sharing and dissemination of knowledge.

Trial geography, pharmacogenetics, and global drug development

Drug development is increasingly global. The benefits of multiregional trials include worldwide evaluation of safety and efficacy. However, clinical practice, environmental, and genetic factors can vary across geographic regions, significantly influencing trial outcomes within a specific geographic region or the global population relative to the United States (US). Genomic technologies and research discoveries continue to advance at a remarkable pace, offering opportunities to explore intrinsic factors that could account for regional variability in drug pharmacokinetics or response.