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1.  Population Pharmacodynamic Modeling of Exenatide after Two-week Treatment in STZ/NA Diabetic Rats 
Journal of pharmaceutical sciences  2013;102(10):10.1002/jps.23682.
The purpose of this study is to investigate the effect of exenatide on glycemic control following two administration routes in a streptozotocin/nicotinamide (STZ/NA)-induced diabetic rat model and to develop a pharmacodynamic model to better understand disease progression and the action of exenatide in this experimental system. Two groups of STZ/NA-induced diabetic rats were treated for two weeks with 20 µg/kg/day of exenatide, either by continuous SC infusion or twice daily SC injections. Disease progression was associated with slower glucose utilization. Fasting blood glucose was significantly reduced by 30 mg/dL in both treatment groups at the end of two weeks. A subsequent IV glucose tolerance test (IVGTT) confirmed an improved glucose tolerance in both treatment groups; however, overall glycemic control was similar between groups, likely due to the relatively low and short-term drug exposure. A population indirect response model was successfully developed to simultaneously describe STZ/NA-induced disease progression, responses to an IVGTT, and exenatide effects on these systemic challenges. The unified model includes a single set of parameters, and the cumulative area under the drug-receptor concentration curve was used as a unique driving force to account for systemic effects long after drug elimination.
PMCID: PMC3808969  PMID: 23897494
type 2 diabetes; exenatide; pharmacokinetics; pharmacodynamics; mathematical modeling
2.  Interspecies Modeling and Prediction of Human Exenatide Pharmacokinetics 
Pharmaceutical research  2012;30(3):751-760.
To develop a model-based approach for interspecies scaling of the preclinical pharmacokinetics of exenatide and to predict concentration-time profiles in humans.
A target-mediated drug disposition (TMDD) model was simultaneously fit to concentration-time profiles of exenatide over a wide range of intravenous (IV) and subcutaneous (SC) doses obtained from mice, rats, and monkeys. Allometric relationships were incorporated into the model to scale parameters based on species body weight. Human pharmacokinetic profiles following IV and SC administration were simulated using the final model structure and parameter estimates and compared to clinical data.
The final model provided a good simultaneous fit to all animal data and reasonable parameter estimates. Exenatide receptor binding affinity and baseline receptor concentrations were species-dependent. Absorption parameters from rat provided the best prediction of exenatide SC absorption in humans, but good predictions could also be obtained using allometric scaling of preclinical absorption parameters.
A TMDD model combined with allometric scaling was successfully used to simultaneously describe preclinical data for exenatide from three animal species following both IV and SC administration. The majority of model parameters could be shared among the animal species and further used for projecting exenatide behavior in humans.
PMCID: PMC3732180  PMID: 23229855
allometric scaling; nonlinear absorption; nonlinear pharmacokinetics; target-mediated drug disposition; therapeutic proteins
3.  Physiologically Based Pharmacokinetic Model of Amphotericin B Disposition in Rats Following Administration of Deoxycholate Formulation (Fungizone®): Pooled Analysis of Published Data 
The AAPS Journal  2011;13(2):255-264.
The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration–time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability–surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration–time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation- and disease-related factors in AmB pharmacokinetics and pharmacodynamics.
PMCID: PMC3085707  PMID: 21431453
amphotericin B; interspecies scaling; physiologically based pharmacokinetic model; tissue distribution
4.  Interspecies Scaling of Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Type I Interferons 
Pharmaceutical research  2010;27(5):920-932.
To develop an integrated mechanism-based modeling approach for the interspecies scaling of pharmacokinetic (PK) and pharmacodynamic (PD) properties of type I interferons (IFNs) that exhibit target-mediated drug disposition (TMDD).
PK and PD profiles of human IFN-β1a, IFN-β1b, and IFN-α2a in humans, monkeys, rats, and mice from nine studies were extracted from the literature by digitization. Concentration-time profiles from different species were fitted simultaneously using various allometric relationships to scale model-specific parameters.
PK/PD profiles of IFN-β1a in humans and monkeys were successfully characterized by utilizing the same rate constant parameters and scaling the volume of the central compartment to body weight using an allometric exponent of 1. Concentration and effect profiles of other IFNs were also well described by changing only the affinity of the drug to its receptor. PK profiles in rodents were simulated using an allometric exponent of −0.25 for the first-order elimination rate constant, and no receptor-binding was included given the lack of cross-reactivity.
An integrated TMDD PK/PD model was successfully combined with classic allometric scaling techniques and showed good predictive performance. Several parameters obtained from one IFN can be effectively shared to predict the kinetic behavior of other IFN subtypes.
PMCID: PMC3176922  PMID: 20232116
allometry; interferon; nonlinear pharmacokinetics; receptor binding; target-mediated drug disposition
5.  TheViral MetaGenome Annotation Pipeline(VMGAP):an automated tool for the functional annotation of viral Metagenomic shotgun sequencing data 
Standards in Genomic Sciences  2011;4(3):418-429.
In the past few years, the field of metagenomics has been growing at an accelerated pace, particularly in response to advancements in new sequencing technologies. The large volume of sequence data from novel organisms generated by metagenomic projects has triggered the development of specialized databases and tools focused on particular groups of organisms or data types. Here we describe a pipeline for the functional annotation of viral metagenomic sequence data. The Viral MetaGenome Annotation Pipeline (VMGAP) pipeline takes advantage of a number of specialized databases, such as collections of mobile genetic elements and environmental metagenomes to improve the classification and functional prediction of viral gene products. The pipeline assigns a functional term to each predicted protein sequence following a suite of comprehensive analyses whose results are ranked according to a priority rules hierarchy. Additional annotation is provided in the form of enzyme commission (EC) numbers, GO/MeGO terms and Hidden Markov Models together with supporting evidence.
PMCID: PMC3156399  PMID: 21886867
J. Craig Venter Institute; metagenomic annotation; viral annotation
6.  The JCVI standard operating procedure for annotating prokaryotic metagenomic shotgun sequencing data 
Standards in Genomic Sciences  2010;2(2):229-237.
The JCVI metagenomics analysis pipeline provides for the efficient and consistent annotation of shotgun metagenomics sequencing data for sampling communities of prokaryotic organisms. The process can be equally applied to individual sequence reads from traditional Sanger capillary electrophoresis sequences, newer technologies such as 454 pyrosequencing, or sequence assemblies derived from one or more of these data types. It includes the analysis of both coding and non-coding genes, whether full-length or, as is often the case for shotgun metagenomics, fragmentary. The system is designed to provide the best-supported conservative functional annotation based on a combination of trusted homology-based scientific evidence and computational assertions and an annotation value hierarchy established through extensive manual curation. The functional annotation attributes assigned by this system include gene name, gene symbol, GO terms, EC numbers, and JCVI functional role categories.
PMCID: PMC3035284  PMID: 21304707
J. Craig Venter Institute; prokaryotic shotgun metagenomics; environmental sequencing; functional annotation; Global Ocean Sampling; Sargasso Sea
7.  The minimum information about a genome sequence (MIGS) specification 
Nature biotechnology  2008;26(5):541-547.
With the quantity of genomic data increasing at an exponential rate, it is imperative that these data be captured electronically, in a standard format. Standardization activities must proceed within the auspices of open-access and international working bodies. To tackle the issues surrounding the development of better descriptions of genomic investigations, we have formed the Genomic Standards Consortium (GSC). Here, we introduce the minimum information about a genome sequence (MIGS) specification with the intent of promoting participation in its development and discussing the resources that will be required to develop improved mechanisms of metadata capture and exchange. As part of its wider goals, the GSC also supports improving the ‘transparency’ of the information contained in existing genomic databases.
PMCID: PMC2409278  PMID: 18464787

Results 1-7 (7)