David LeBlond

Purdue University, ウェストラファイエット, Indiana, United States

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Publications (10)50.27 Total impact

  • Linas Mockus · David LeBlond · Gintaras Reklaitis
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    ABSTRACT: Every pharmaceutical product that is approved and released to the public is shaped by countless decisions made at the research and clinical stages of development. The efficacy and safety of these products depends on the quality of these decisions. In this paper we examine how modern probability tools might be used to raise the quality of such decisions. Specifically we are arguing for the greater use of Bayesian probability tools in pharmaceutical product development decision making. A case study on a novel Bayesian treatment of shelf life determination for lyophilized parenteral is presented.
    No preview · Article · Dec 2014 · Computer Aided Chemical Engineering
  • David LeBlond · Linas Mockus
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    ABSTRACT: A compendial standard is a function of data generated by one or more quality testing procedures. Since the data are sampled from an underlying distribution, the probability of passing a compendial test (Pa) can be expressed as a function of the distribution's model parameters. Applying Bayesian methodology to such a function, we show how to compute the posterior distribution of Pa and other quantities of interest. We apply this methodology to the USP<905> compendial standard and illustrate the importance of considering interbatch variance. We show that the operating characteristics of this Bayesian approach depend on the underlying model parameters almost exclusively through the population Pa and use this to develop a simple univariate procedure to determine the number of batches needed for a process qualification. We note some advantages of this Bayesian approach compared to current approaches. To show the simplicity of the approach and encourage its use, example R and WinBUGS code are provided.
    No preview · Article · Aug 2014 · Statistics in Biopharmaceutical Research
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    ABSTRACT: The role of Fc glycans on clearance of IgG molecule has been examined by various groups in experiments where specific glycans have been enriched or the entire spectrum of glycans was studied after administration in pre-clinical or clinical pharmacokinetic (PK) studies. The overall conclusions from these studies are inconsistent, which may result from differences in antibody structure or experimental design. In the present study a well-characterized recombinant monoclonal IgG1 molecule (mAb-1) was analyzed from serum samples obtained from a human PK study. mAb-1 was recovered from serum using its ligand cross-linked to Sepharose beads. The overall purity and recovery of all isoforms were carefully evaluated using a variety of methods. Glycans were then enzymatically cleaved, labeled using 2-aminobenzamide and analyzed by normal phase high performance liquid chromatography. The assays for recovering mAb-1 from serum and subsequent glycan analysis were rigorously qualified at a lower limit of quantitation of 15 μg/mL, thus permitting analysis to day 14 of the clinical PK study. Eight glycans were monitored and classified into two groups: (1) the oligomannose type structures (M5, M6 and M7) and (2) fucosylated biantennary oligosaccharides (FBO) structures (NGA2F, NA1F, NA2F, NA1F-GlcNAc and NGA2F-GlcNAc). We observed that the oligomannose species were cleared at a much faster rate (40%) than FBOs and conclude that high mannose species should be carefully monitored and controlled as they may affect PK of the therapeutic; they should thus be considered an important quality attribute. These observations were only possible through the application of rigorous analytical methods that we believe will need to be employed when comparing innovator and biosimilar molecules.
    Full-text · Article · Jul 2012 · mAbs
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    Teresa A Ellis · Jinhe Li · David Leblond · Jeffrey F Waring
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    ABSTRACT: Alzheimer's disease (AD), which is characterized by a degeneration of neurons and their synapses, is one of the most common forms of dementia. CSF levels of amyloid β(42) (Aβ(42)) have been recognized as a strong candidate to serve as an AD biomarker. There are a number of commercial assays that are routinely employed for measuring Aβ(42); however, these assays give diverse ranges for the absolute levels of CSF Aβ(42). In order to employ CSF Aβ(42) as a biomarker across multiple laboratories, studies need to be performed to understand the relationship between the different platforms. We have analyzed CSF samples from both diseased and nondiseased subjects with two different widely used assay platforms. The results showed that different values for the levels of CSF Aβ(42) were reported, depending on the assay used. Nonetheless, both assays clearly demonstrated statistically significant differences in the levels of Aβ(42) in CSF from AD relative to age-matched controls (AMC). This paper provides essential data for establishing the relationship between these assays and provides an important step towards the validation of Aβ(42) as a biomarker for AD.
    Full-text · Article · May 2012 · International Journal of Alzheimer's Disease
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    ABSTRACT: The use of von Frey filaments, originally developed by Maximilian von Frey, has become the cornerstone for assaying mechanical sensitivity in animal models and is widely used for human assessment. While there are certain limitations associated with their use that make comparisons between studies not straightforward at times, such as stimulus duration and testing frequency, von Frey filaments provide a good measurement of mechanosensation. Here we describe the application of von Frey filaments to testing in animal models, specifically with respect to determining changes in sensory thresholds in a pain state using the Dixon up-down method. In a literature survey, we found that up to 75% of reports using this method analyze the data with parametric statistical analysis and of those that used nonparametric analysis, none took into account that mechanical sensation is perceived on a logarithmic scale (Weber's Law) when calculating efficacy. Here we outline a more rigorous analysis for calculating efficacy and ED(50)'s from von Frey data that incorporates Weber's Law. We show that this analysis makes statistical and biological sense and provide a specific example of how this change affects data analysis that brings results from animal models more in line with clinical observations. PERSPECTIVE: This focus article argues that analyzing von Frey paw withdrawal threshold data obtained by using the Dixon up-down method without considering Weber's Law is inappropriate. An analysis method that incorporates how mechanical sensation is perceived and how its application brings results from animal models more in line with clinical data is presented.
    No preview · Article · Apr 2012 · The journal of pain: official journal of the American Pain Society
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    ABSTRACT: β-amyloid peptide (Aβ) is associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Aβ levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aβ production or Aβ clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aβ are consistent between sampling intervals to determine whether Aβ can be used as a pharmacodynamic biomarker for drug candidates. Previous studies have produced seemingly conflicting observations for the intrasubject stability of CSF Aβ levels; we attempt to reconcile these conflicting observations. The current study examined the Aβ levels in CSF collected with various sampling frequencies from three clinical studies conducted in healthy young or elderly subjects at the same investigative site for the purpose of designing future studies. The results suggest that CSF sampling frequency and/or sampling volume contributes to intrasubject variability in CSF Aβ levels, and that lowering the CSF sampling frequency may help minimize this effect. These results will help guide clinical trial design for Alzheimer's disease therapy.
    Full-text · Article · Nov 2011 · Alzheimer's & dementia: the journal of the Alzheimer's Association

  • No preview · Article · Jul 2011 · Alzheimer's and Dementia

  • No preview · Article · Jul 2011 · Alzheimer's and Dementia
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    ABSTRACT: As stipulated by ICH Q8 R2 (1), prediction of critical process parameters based on process modeling is a part of enhanced, quality by design approach to product development. In this work, we discuss a Bayesian model for the prediction of primary drying phase duration. The model is based on the premise that resistance to dry layer mass transfer is product specific, and is a function of nucleation temperature. The predicted duration of primary drying was experimentally verified on the lab scale lyophilizer. It is suggested that the model be used during scale-up activities in order to minimize trial and error and reduce costs associated with expensive large scale experiments. The proposed approach extends the work of Searles et al. (2) by adding a Bayesian treatment to primary drying modeling.
    Full-text · Article · Mar 2011 · AAPS PharmSciTech
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    ABSTRACT: Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. The DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA damage and has critical roles in DNA repair. Inhibition of PARP potentiates the activity of DNA-damaging agents such as temozolomide, topoisomerase inhibitors and radiation in both in vitro and in vivo preclinical models. Recently, several PARP inhibitors have entered clinical trials either as single agents or in combination with DNA-damaging chemotherapy. Because PARP inhibitors are not cytotoxic, a biomarker assay is useful to guide the selection of an optimal biological dose. We set out to develop an assay that enables us to detect 50% PAR reduction in human tumors with 80% power in a single-plate assay while assuring no more than a 10% false-positive rate. We have developed and optimized an enzyme-linked immunosorbent assay (ELISA) to measure PARP activity that meets the above-mentioned criterion. This robust assay is able to detect PAR levels of 30-2000 pg/ml in both tumor and peripheral blood monocyte samples. In a B16F10 mouse syngeneic tumor model, PARP inhibitor ABT-888 potentiates the effect of temozolomide in suppressing tumor growth, and PARP activity is greatly reduced by ABT-888 at efficacious doses. In summary, the ELISA assay described here is suitable for biomarker studies in clinical trials of PARP inhibitors.
    No preview · Article · Nov 2008 · Analytical Biochemistry