The absorption models can predict the following three BCS (Biopharmaceutics Classification Scheme) classes of compounds: class I, high solubility and high permeability; class III, high solubility and low permeability; class IV, low solubility and low permeability. The absorption models overpredict the absorption of class II, low solubility and high permeability compounds because dissolution is the rate-limited step of absorption.
IntroductionDrugs that prolong the QT interval on the electrocardiogram present a major safety concern for pharmaceutical companies and regulatory agencies. Despite a range of assays performed to assess compound effects on the QT interval, QT prolongation remains a major cause of attrition during compound development. In silico assays could alleviate such problems. In this study we evaluated an in silico method of predicting the results of a rabbit left-ventricular wedge assay.MethodsConcentration–effect data were acquired from either: the high-throughput IonWorks/FLIPR; the medium-throughput PatchXpress ion channel assays; or QSAR, a statistical IC50 value prediction model, for hERG, fast sodium, L-type calcium and KCNQ1/minK channels. Drug block of channels was incorporated into a mathematical differential equation model of rabbit ventricular myocyte electrophysiology through modification of the maximal conductance of each channel by a factor dependent on the IC50 value, Hill coefficient and concentration of each compound tested. Simulations were performed and agreement with experimental results, based upon input data from the different assays, was evaluated.ResultsThe assay was found to be 78% accurate, 72% sensitive and 81% specific when predicting QT prolongation (>10%) using PatchXpress assay data (77 compounds). Similar levels of predictivity were demonstrated using IonWorks/FLIPR data (121 compounds) with 78% accuracy, 73% sensitivity and 80% specificity. QT shortening (<−10%) was predicted with 77% accuracy, 33% sensitivity and 90% specificity using PatchXpress data and 71% accuracy, 42% sensitivity and 81% specificity using IonWorks/FLIPR data. Strong quantitative agreement between simulation and experimental results was also evident.DiscussionThe in silico action potential assay demonstrates good predictive ability, and is suitable for very high-throughput use in early drug development. Adoption of such an assay into cardiovascular safety assessment, integrating ion channel data from routine screens to infer results of animal-based tests, could provide a cost- and time-effective cardiac safety screen.
Experimental design (Box, G. E. P.; Hunter, W. G.; Hunter, J.
S. Statistics
for
Experimenters; Wiley: New York, 1978 and
Carlson, R. Design
and Optimisation in Organic
Synthesis;
Elsevier: Amsterdam, 1992) is an established and proven
methodology for product and process improvement in the
pharmaceutical industry. This paper presents a step-by-step
approach to optimisation of a synthetic transformation using a
central composite experimental design, in conjunction with
automated on-line HPLC. Highly predictive models for the
reaction were obtained using a commercially available software
package. [There are many commercially available DOE packages. The software package we used was Design-Expert 5 (DX-5) ().] These mathematical models were
interrogated to examine the effect on yield and quality under a
variety of reaction conditions or constraints. The synergy of
experimental design and automation is also discussed.
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