Can A New Lead Drug Be Developed? Ask Manufacturing, Early and Ofte

Manufacturing's input is critical where questions of solubility, stability and delivery are concerned.

By Duane B. Lakings, Ph.D., Drug Safety Evaluation Consulting, Inc.

A good deal has been written lately about the “attrition rates” of new drug discoveries. A growing number of promising new leads ultimately prove to be too insoluble or unstable to be formulated. This problem is evident in the declining rate of new drug approvals. Today, fewer drugs and biologicals make it from Phase I to the marketplace, and half of Phase I drugs are likely to fail late in Phase III, according to FDA.

Many pharmaceutical companies now conduct biological research studies to determine a compound’s therapeutic potential. These tests include ADMET, or preliminary assessments of metabolism, pharmacokinetics, and toxicology, which indicate leads with the “best” properties for further development.

Such studies answer important questions: Is the lead with the highest biological potency now ready to be developed? Should additional studies be conducted, and if so, which experiments should be run and by whom?

But the chemical properties of new leads should also be evaluated early in the selection process. Manufacturing professionals, who are not typically involved during the critical transition between discovery and preclinical development, have the expertise needed to evaluate these chemical properties — specifically, solubility, stability and delivery.

If manufacturing is part of the developability assessment team, each drug candidate lead can be analyzed fully, and both its “biological” and “chemical” attributes and drawbacks determined. Sometimes, all leads will have one major drawback. Sometimes, they’ll have two or more, signaling the need to “go back to the drawing board” until the right lead is found.

Manufacturing’s input is particularly important in evaluating new leads for solubility, stability and delivery. Studying each of these areas requires well-characterized analytical chemistry methods that can quantify each lead’s performance in collected samples. If the leads are structurally similar, a single method may be used to evaluate more than one lead. Normally, analytical chemists, like those in manufacturing, can select a method based on the structure of a compound and can choose which leads may be assayed by the same method.

Once assays are available, the “chemical” drug-like properties of discovery leads can be evaluated. A major problem with many leads is that they are relatively lipophilic, since the active sites of most pharmacological targets are also lipophilic and leads must have some lipophilic characteristics in order to diffuse effectively across membranes and interact with targets.

However, drug leads must also have hydrophilic properties in order to reach the membrane and the target, and they should be soluble in the surrounding aqueous medium.

In order for leads to be administered orally, the compound should show aqueous solubility over a range of pHs; the stomach (the site for dissolution) is acidic, the upper GI tract (the primary site of absorption) is acidic to neutral, and blood (the primary transporter of the lead to the target) is maintained at pH 7.4. Leads with limited aqueous solubility over this pH range will most likely have poor and variable absorption.

For other routes of delivery, the desired pH range is narrower but, for most routes, will include neutral pH. Since many organic compounds are least soluble in water at neutral pH, the team must consider closely whether any lead will be soluble enough in water to be delivered.

Another “problem” with many discovery leads is that they have limited stability, both prior to being administered and while in the body and being transported to the site of pharmacological action. If leads are degraded prior to reaching the target, the desired pharmacology may not be obtained or the response may be insufficient or too brief to effectively mediate the disease. Thus, sufficient stability in administration vehicles and in stimulated gastric fluids should be another primary developability assessment attribute for discovery leads. Leads with stability problems will also be difficult to formulate and may have insufficient shelf life for marketing.

A third area where manufacturing groups can be of assistance in evaluating discovery leads is in drug delivery. Many in vitro systems are available for determining the extent of delivery across various membrane types, including the GI tract, lung, blood-brain barrier (BBB), skin, and eye. Using the defined analytical chemistry methods, the ability of discovery leads to diffuse across membranes can be evaluated.

Any drug developability assessment team should include representatives from manufacturing. A cross-disciplinary approach will allow the team to evaluate new drug leads, not only from a biological standpoint, but based on their solubility, stability and delivery. Leads that pass a multidisciplinary team’s muster have a much greater chance of clearing nonclincal and clinical evaluations, and actually making it to market.



About the Author

Duane B. Lakings, Ph.D., is president of Drug Safety Evaluation Consulting, Inc. (Elgin, Texas; www.dseconsulting.com). He has over 25 years experience in characterizing candidates as potential therapeutic agents and assists biotechnology and pharmaceutical companies with their drug discovery and development programs. He can be reached via email at dblakings@dseconsulting.com

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