Ricerca offers a comprehensive array of preclinical assessments

The ability to identify early on those compounds most likely to stand up to the scrutiny of the IND process is a critical part of drug development. Ricerca provides custom integrated in vitro and in vivo metabolism studies to support medicinal chemistry lead optimization programs, IND-enabling toxicology and pharmacokinetics studies, and clinical metabolism requirements.

Whether you need a single, focused study or a total package to support an IND submission, Ricerca is here to help. Over 120 laboratories at our Ohio site provide a full range of chemistry and biology services. Following are key preclinical assays provided by Ricerca

Cytotoxicity

Only one in ten drug candidates make it through the development process. One-third of these failures are due to unacceptable toxicity levels. A cytotoxicity assay is a rapid and cost-effective tool to sort out the likely failures before a compound is entered into the costly development process and to help choose the optimal candidate. Ricerca's in vitro cytotoxicity assays use a selection of cell lines tailored to specific drug leads. With this method we can evaluate a group of qualified lead compounds and identify those most likely to succeed.
 

Solubility

Aqueous solubility is an important determinant of the bioavailability and usefulness of a drug candidate. Nephelometry (light scattering) is an accepted technique to rapidly determine the apparent solubilities of a large number of lead compounds.
 

Permeability

Assessment of the intestinal permeability of compounds intended for oral administration plays an important role in selecting candidates for drug development. Ranking a series of lead compounds in order of absorption potential facilitates compound selection and optimization. Ricerca uses a comparison of apparent permeabilities through Caco-2 or MDCK monolayer cultures (Artusson and Borchardt, Pharm. Res. 1997, 14, 1655-1657). These absorption models are also useful for understanding any absorption issues associated with compounds further advanced in development, including those involved with active transport mechanisms.
 

Metabolic stability

The metabolic stability of a drug candidate is an important consideration in determining its potential for human use. The metabolism of the drug in the body, the half-life of the drug in the body, and whether it forms metabolites are important parameters to assess the bioavailability, toxicity, and dosing potential for drug-drug interaction of a compound.

Ricerca's metabolic stability assays are designed to quickly determine whether a compound is metabolized by hepatic drug metabolizing enzymes. Adding time points to the assay allows the determination of the metabolic rate, measured as the "intrinsic" clearance rate. Coupled with permeability data, these assays can weed out compounds with unacceptable pharmacokinetic properties. Same site in vivo pharmacokinetic studies, medicinal chemistry, radiolabel synthesis, LC-MS/MS, and metabolite ID expertise are available to confirm bioavailability and clearance predictions and identify metabolites.
 

Protein binding

As a criterion in an ADMET discovery lead evaluation program, the degree of binding of a compound to plasma proteins can provide important indications about the compound's efficacy and its potential for drug-drug interactions. A rapid technique to determine plasma protein binding is ultrafiltration centrifugation.
 

CYP450 Inhibition

Many drug-drug interactions involve cytochrome P450 (CYP) inhibition. In the U.S. FDA Guidance for Industry, it is recommended that the ability of a new drug entity to inhibit CYP isozymes be assessed. Making this evaluation prior to drug candidate selection can reduce the odds of failure during the development process. An accepted method to accomplish this goal is to measure the inhibitory activity of drug leads on individual isozymes of human cDNA expressed CYP.
 

CYP450 Induction

In the U.S. FDA Guidance for Industry: "Drug Metabolism/ Drug Interaction Studies in the Drug Development Process: Studies In Vitro", it is recommended that the ability of a new drug entity to induce cytochrome P450 isozymes be assessed. One method to accomplish this goal is to treat human hepatocyte cultures with the test article and to measure the expression and the activity of the individual isozymes compared to controls. Carrying out this assay during the discovery phase is one fast and cost-effective means of eliminating leads with low potential for success.
 

Interspecies comparison

The interspecies comparison study is conducted in order to highlight the potential metabolic differences between the species and aid in the selection of the best species to conduct subsequent in vivo toxicology and pharmacokinetic studies.
 

Metabolite identification

Ricerca conducts on-site metabolite and standards synthesis, including radiolabeled compounds. Sophisticated analytical tools employed by experienced metabolism chemists will facilitate structure modifications and help to design appropriate toxicokinetic and pharmacokinetic studies.