The FDA has published an updated Guidance Agenda – new and revised draft guidances CDER is planning to publish during calendar year 2012.   Guidances of particular interest to nonclinical pharmaceutical toxicologists may include:


• Endocrine Disruption Potential of Drugs: Non Clinical Evaluation

• Integrated Summary of Safety


• Food-Effect Bioavailability and Fed Bioequivalence Studies—Bioavailability and Bioequivalence Studies for Orally Administered Drug Products Submitted in New Drug Applications General Consideration

Electronic Submissions
• Providing Regulatory Submissions in Electronic Format – General Considerations
• Providing Regulatory Submissions in Electronic Format – Study Data
• Providing Regulatory Submissions in Electronic Format – Standardized Study Data


SourceU.S. Food and Drug Administration

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High-throughput ADME Screening Technologies

Posted by cdavenport on Monday Apr 16, 2012 Under ADME, Drug Safety, Regulatory

High throughput (HT) Absorption, Distribution, Metabolism, and Excretion (ADME) screening technology is the current push from Big Pharma to be outsourced through contract research organizations (CROs).  Shifting also is the ADME regulatory emphasis; the FDA has released a draft guidance (17 Feb 2012) that includes specific wording around what needs to be done with respect to transporter drug-drug interactions (both efflux and influx).  The guidance will start to drive significant changes in how ADME screening is performed.  Two assays that are routinely being utilized in pharma are the Caco-2 cell-based assay and the PAMPA (parallel artificial-membrane permeation) assay.  As currently practiced, predictive ADME screening is made even more difficult given the variety of transport mechanisms available.  In toxicology screens (ADME-tox), however, one is not looking for altered aspects of the drug, which is generally initially unknown, but changes in known, endogenous parameters.  Thus ADME-tox lends itself more easily to HT platforms.  New platforms for high throughput ADME screening are available, and discussed in this article.

Source:  Drug Discovery and Development

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Dried Blood Spot Analysis: Preclinical Pros and Cons

Posted by cdavenport on Tuesday Jan 25, 2011 Under ADME, EMA, FDA, Techniques

Both advantages and challenges exist for use of dried blood spots during preclinical drug development.   Advantages include small sample volumes coupled with easy shipment and storage.  The amount of blood per spot varies (10 to 100 μL), but use of 15 to 20 μL seems to be most common.  With larger blood spots, although multiple analyses are possible from each spot, the spots are less homogeneous.  For this reason, it is suggested to have 3-4 smaller spots (of 20 μL or less) which are more homogeneous, thus increasing inherent sample quality.

The small sample volumes required for dried blood spot analysis mean that fewer animals – and therefore less drug – are needed during preclinical studies relative to conventional blood analysis (milliliters of blood often required).  Blood samples spotted and dried on cards don’t need to be frozen, thereby simplifying the procedures for both sampling and shipping, with subsequent cost savings.  Provided a compound is stable in blood, which must be demonstrated for each compound, dried blood spot samples can be shipped in an envelope at room temperature.

In addition to the ethical and financial benefits, use of dried blood spot analysis can also improve preclinical data quality.  Typically, use of multiple small animals is necessary to generate drug concentration-time curves in typical pharmacokinetic and toxicology studies, due to insufficient blood volume per animal, thus introducing a potential source of undesirable variation in the data.  That source of variability can be eliminated with dried blood spot analysis.  The smaller volumes associated with the technique mean that serial sampling can be performed with each animal, thereby enhancing preclinical data quality.  In addition, some researchers have found that the relatively high stability of compounds in dried blood spots, especially prodrugs and their metabolites, is a key advantage of the technology.

Dried blood sample analysis has some drawbacks in that analysis is more time-consuming than that required for liquid samples, but still includes liquid chromatography and tandem mass spectrometry.  The limit of resolution is not yet adequate for low-exposure drugs (e.g., pg/mL), and components of the cards on which spots are collected can interfere with some analyses.  Some researchers have determined that the additional time necessary for analysis is a detriment to the speed required in discovery-phase research.  In some organizations, the decision to use dried blood spots is currently being made on a program-by-program basis as drug candidates move from discovery into early-stage development.  One holdup has been the impracticality of switching late-stage compounds with a long history of analyses in plasma over to dried blood spot analysis.  The pharmacokinetic values obtained from liquid plasma and from dried blood are not directly comparable, and “bridging” studies are required to switch between matrices.  “Even though you can generate an in vitro number for converting between blood and plasma, it doesn’t always work,” Neil Spooner, director of bioanalytical science and development at GlaxoSmithKline in Ware, England said.

Perhaps the most pressing detriment to use of dried blood spots is the need for improved automation, although some automation is available.  Fully automated techniques are generally available for fluid samples, thus enabling high throughput analysis of thousands of samples.  Direct analysis methods for dried blood spots, which bypass the need to create a paper punch, are under development.

To date, it is undetermined how global regulatory bodies will respond to data obtained from dried blood spot analysis.  Some feel that the European Union may be more accepting than the Federal Drug Administration (FDA).  The FDA declined to comment citing “insufficient experience with the technology.”  Although international guidelines state that kinetics can be measured in blood, plasma, or serum, specific US guidelines for use of dried blood spot analyses are absent.  Richard M. LeLacheur, vice president at PharmaNet USA, a contract research organization in Princeton, N.J., says “As the comfort level, regulatory experience, and infrastructure grow, people will realize it’s not a big leap to go into dried blood spots, and the benefits are worth it.”

Source: Chemical & Engineering News

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Drug Pharmacokinetic Comparison between Humans and Monkeys

Posted by cdavenport on Thursday Jan 21, 2010 Under ADME, Drug Safety

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

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