Zebrafish offer a nonclinical model for the high-throughput screening of drug compounds, including toxicity assessment, with resolution at the cellular level in living vertebrate organisms.  These small, freshwater, tropical fish share genetic and biochemical similarity to humans, in addition to similar organ system development.  Vertebrate disease models (e.g., Parkinson’s, epilepsy, wound repair) are available , as are 3-D image resolution and data analysis capabilities.  Live-imaging options, unparalleled in other vertebrate organisms, are possible using the transparent larvae.  Furthermore, live-cell microscopy can provide views of the inner complexity and workings at the cellular level.  For purposes of disease modeling, researchers can create and screen genetic mutants in the zebrafish that are linked to human immune diseases.  Neurological assessments using the live, transparent, zebrafish larvae allow visualization of the mechanisms of myelination.  In conclusion, the zebrafish preclinical model owes much of its popularity to the transparent nature and relevant ease of imaging of vertebrate larvae.  Optimization of data analyses for these varied indications is ongoing.

Source:  Genetic Engineering and Biotechnology News

Preclinical models are developed to test lead compounds for toxicity and efficacy.  This report  1) explores novel preclinical models (in vivo, in vitro, in silico, and systems biology) that show promise to expedite and improve the target validation, lead optimization, and toxicity screening timelines, and 2) discusses the various advantages and disadvantages of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) screening techniques.  In addition, the report provides an outlook for preclinical testing over the next decade.  It focuses on more than 60 companies that are involved in using or developing ADMET technologies to advance preclinical research and provides an update on how new models and systems have been employed to accelerate the discovery and development process.

Scope of this report

•  Understand the basis of ADMET testing and why it is a necessary and important component of preclinical research
•  Up-to-date information on the preclinical models and systems currently used in drug discovery and development.
•  Evaluation of the key recent developments and activities of companies who are developing and licensing new ADMET technologies.
•  Identification of existing models and how new ones are being developed to improve productivity and knowledge.

Source:  Business Insights

To verify the availability of pharmacokinetic parameters in cynomolgus monkeys, hepatic availability (Fh) and the fraction absorbed (Fa) multiplied by intestinal availability (Fg) were evaluated to determine their contributions to absolute bioavailability (F) after intravenous and oral administrations. These preclinical results were compared with those for humans using 13 commercial drugs for which human pharmacokinetic parameters have been reported.  In addition, in vitro studies of these drugs, including membrane permeability, intrinsic clearance, and p-glycoprotein affinity, were performed to classify the drugs on the basis of their pharmacokinetic properties.

In the present preclinical study, monkeys had a markedly lower F than humans for 8 of 13 drugs.  Although there were no obvious differences in Fh between humans and monkeys, a remarkable species difference in FaFg was observed.  These results suggest that first-pass intestinal metabolism is greater in cynomolgus monkeys than in humans, and that bioavailability in cynomolgus monkeys after oral administration may be unsuitable for predicting pharmacokinetics in humans.  A rough correlation was also observed between in vitro metabolic stability and Fg in humans.

Key: F (bioavailability), Fa (fraction absorbed), Fg (intestinal availability), Fh (hepatic availability).

Drugs examined: amitriptyline, dexamethasone, digoxin,  hydrochlorothiazide, ibuprofen,  lithium carbonate, midazolam, nifedipine,  propranolol, quinidine,  tacrolimus, timolol, and verapamil.

Source: Drug Metabolism and Disposition

Seventh Wave Laboratories now offer a battery of  gastrointestinal (GI) preclinical models (TIM) to help clients to assess the behavior of oral medications.  The in vitro models are licensed from TNO, a Dutch contract research organization.  The TIM system has proven useful in solving specific needs in formulation development and pharmacokinetics.

By accurately simulating the conditions in the human GI tract, the TIM system gives insight into the release, solubility, and availability for absorption of pharmaceuticals.  This state-of-the-art, validated system has a much higher predictive value than regular dissolution tests.  The computer-regulated model can simulate various physiologic states and helps scientists to determine the bioaccessibility of active compounds and predict resultant blood concentration after single or repeated intake of various dosage forms.

Sources:  Outsourcing-Pharma.com and ScientistLIVE