Entity

Time filter

Source Type

Silver Spring, MD, United States

Couderc J.-P.,University of Rochester | Garnett C.,Office of Clinical Pharmacology | Garnett C.,Center for Drug Evaluation and Research | Li M.,Center for Drug Evaluation and Research | And 5 more authors.
Annals of Noninvasive Electrocardiology | Year: 2011

Thorough QT (TQT) studies are designed to evaluate potential effect of a novel drug on the ventricular repolarization process of the heart using QTc prolongation as a surrogate marker for torsades de pointes. The current process to measure the QT intervals from the thousands of electrocardiograms is lengthy and expensive. In this study, we propose a validation of a highly automatic-QT interval measurement (HA-QT) method. We applied a HA-QT method to the data from 7 TQT studies. We investigated both the placebo and baseline-adjusted QTc interval prolongation induced by moxifloxacin (positive control drug) at the time of expected peak concentration. The comparative analysis evaluated the time course of moxifloxacin-induced QTc prolongation in one study as well. The absolute HA-QT data were longer than the FDA-approved QTc data. This trend was not different between ECGs from the moxifloxacin and placebo arms: 9.6 ± 24 ms on drug and 9.8 ± 25 ms on placebo. The difference between methods vanished when comparing the placebo-baseline-adjusted QTc prolongation (1.4 ± 2.8 ms, P = 0.4). The differences in precision between the HA-QT and the FDA-approved measurements were not statistically different from zero: 0.1 ± 0.1 ms (P = 0.7). Also, the time course of the moxifloxacin-induced QTc prolongation adjusted for placebo was not statistically different between measurements methods. ©2011, Wiley Periodicals, Inc. Source


McCance-Katz E.F.,University of California at San Francisco | McCance-Katz E.F.,San Francisco General Hospital | Sullivan L.E.,Yale University | Nallani S.,Office of Clinical Pharmacology
American Journal on Addictions | Year: 2010

Drug interactions are a leading cause of morbidity and mortality. Methadone and buprenorphine are frequently prescribed for the treatment of opioid addiction. Patients needing treatment with these medications often have co-occurring medical and mental illnesses that require medication treatment. The abuse of illicit substances is also common in opioid-addicted individuals. These clinical realities place patients being treated with methadone and buprenorphine at risk for potentially toxic drug interactions. A substantial literature has accumulated on drug interactions between either methadone or buprenorphine with other medications when ingested concomitantly by humans. This review summarizes current literature in this area.© American Academy of Addiction Psychiatry. Source


Jiang X.-L.,University of Florida | Zhao P.,Office of Clinical Pharmacology | Barrett J.S.,Childrens Hospital of Philadelphia | Lesko L.J.,University of Florida | Schmidt S.,University of Florida
CPT: Pharmacometrics and Systems Pharmacology | Year: 2013

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that undergoes extensive phase I and II metabolism. To better understand the kinetics of this process and to characterize the dynamic changes in metabolism and pharmacokinetics (PK) between children and adults, we developed a physiologically based PK (PBPK) model for APAP integrating in silico, in vitro, and in vivo PK data into a single model. The model was developed and qualified for adults and subsequently expanded for application in children by accounting for maturational changes from birth. Once developed and qualified, it was able to predict clinical PK data in neonates (0-28 days), infants (29 days to 2 years), children (2 to 12 years), and adolescents (12-17 years) following intravenous and orally administered APAP. This approach represents a general strategy for projecting drug exposure in children, in the absence of pediatric PK information, using previous drug-and system-specific information of adults and children through PBPK modeling. © 2013 ASCPT. Source


Madabushi R.,Office of Clinical Pharmacology | Cox D.S.,Glaxosmithkline | Hossain M.,Glaxosmithkline | Boyle D.A.,Glaxosmithkline | And 4 more authors.
Journal of Clinical Pharmacology | Year: 2011

The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of argatroban in pediatric patients and derive dosing recommendations. An open-label multicenter trial was conducted in pediatric patients (n = 18 from birth to 16 years). A population modeling approach was used to characterize pharmacokinetics and pharmacodynamics of argatroban in pediatric patients. Simulations were performed to derive a dosing regimen for pediatric patients. The estimated clearance of argatroban in pediatric patients was 2-fold lower than that in healthy adults. Body weight was significant predictor of argatroban clearance. The clearance in a typical 20-kg pediatric patient was 3.1 L/h. In 4 patients with elevated serum bilirubin levels, the estimated clearance was 0.6 L/h. Effect on activated plasma thromboplastin time (aPTT) was found to be concentration dependent. Simulations suggested that a starting dose of 0.75 μg/kg/min in pediatric patients was comparable in performance to 2.0 μg/kg/min approved in adults for attaining target aPTT and risk for bleeding. A dose increment step size of 0.25 μg/kg/min was suitable for titration. The PK/PD of argatroban was reasonably characterized in pediatrics. Plasma concentration-aPTT relationship was used to derive a safe starting dose and titration scheme for the first time in pediatric patients and was incorporated into the US prescribing information for argatroban. © 2011 The Author(s). Source


Wang Y.,Office of Clinical Pharmacology | Lee J.Y.,Office of Clinical Pharmacology | Michele T.,Center for Drug Evaluation and Research | Chowdhury B.A.,Center for Drug Evaluation and Research | Gobburu J.V.,Office of Clinical Pharmacology
International Journal of Clinical Pharmacology and Therapeutics | Year: 2012

Objective: Indacaterol is a long-acting β-agonist (LABA) approved by FDA in 2011 at a dose of 75 μg once daily for the treatment of chronic obstructive pulmonary disease (COPD). During the review process for indacaterol approval, data were reanalyzed by FDA to evaluate the validity of the model-based conclusions regarding dose selection. Methods: The same dose-response model applied by the sponsor was used to analyze a subset of the original data. Model predictions were compared with observed data to evaluate the model. Subgroups were created to visualize the relationship between key model parameters and covariates. The Emax model structure was evaluated for a meta-analysis. Results: Patient-level analyses showed that the model-based claim of additional benefit of 150 μg over 75 μg for more severe patients is not supported by the data. Mis-specified covariate model structures for key parameters contributed to this inconsistency. The assumed Emax model structure is not supported by the study-level data and the study-level analysis overestimates the incremental difference between two adjacent doses. Conclusions: Even though model-based drug development is highly desirable, thorough model evaluation and justification is necessary to ensure the validity of related decisions. Source

Discover hidden collaborations