It Takes a Team to Develop a Prodrug Program

Just as it takes a team to efficiently develop analogs, a successful prodrug program depends highly on quick evaluation of prodrug candidates by a team. For big pharma, a prodrug solution to the lack of developability of drug candidates has been an act of last resort, or, when applied to an agent going off patent, an effort to maintain market exclusivity. This was not always the case. In the 1960s, the Parke Davis Company developed a number of very successful prodrugs, as did a concerted effort by the Upjohn Company in the mid-1960s to the mid-1970s.

In most companies, a prodrug program is only initiated when a specific problem is identified and the effort is only maintained while the immediate need presents itself. Because the effort is initiated in response to a specific problem area, after more traditional methods of overcoming the barrier to developability are exhausted, the development of the drug candidate is delayed and made more complex by the need for additional toxicology and ADME studies. Thus, a prodrug solution to a problem is often viewed negatively by management. What if a prodrug solution to a developing problem is proposed early?

Imagine the scenario where a discovery team appears to be going down the path leading directly to a series of leads/candidates having clear drugability issues. Would it not make sense to raise the question in the development team of a prodrug solution in the event that other strategies do not work? If implemented early, would a prodrug solution be any more expensive than normal analog development? The answer is probably no. If a prodrug becomes the NCE, some issues in its development may add some additional burden to the drug metabolism and toxicology staff. However, this approach may be less financially burdensome in the long run than the added expense of a significant time delay in development, if the prodrug strategy is implemented six months after the problem/barrier is identified.

When the need for a prodrug solution presents itself, who should constitute the "prodrug team"? First, it is important to identify the cause or etiology of the drugability problem and to identify the strengths and weaknesses of this team as it relates to the general prevailing knowledge of the prodrug concept. The views expressed here are based on experience as a prodrug researcher and the knowledge gained from being a consultant to big and small pharma over the last 30+ years and is inherently biased by these experiences.

First the etiology of the drugability problem must be identified with some degree of certainty. Is it solubility, permeability (from either the intrinsic properties of the drug candidate or due to the drug being an efflux candidate), presystemic metabolism, or poor pharmacokinetic properties? Or is it a combination of more than one property? Identification of the etiology is not easy and, sometimes, a property such as limited aqueous solubility, can mask other underlying problems and lead to flawed approaches. There is a greater chance that the true cause of the problem is accurately identified if the decision to pursue a prodrug solution is made by a team constituted of medicinal chemists, ADME specialists, toxicologists and pharmaceutical formulation scientists, with input from marketing. If the right experiments are performed and the etiology or causes are identified, the probability of success is greatly enhanced.

Once the problem/cause/s are identified, what prodrug solution should be applied? Precedent easily identifies some solutions, while others require greater creativity.

The medicinal chemist brings to the table the ability to synthesize complex molecules as well as highly developed observation skills. However, they are sometimes put off by the perceived trivial nature of some prodrug chemistry and are often naive when it comes to issues of the safety and reversibility of possible promoieties.

The pharmacologist and molecular biologist must test prodrugs with the view that they might not be active per se, so it takes a different mindset in reviewing data from various screens. That is, receptor based screens will not tell the whole story, while cell-based and in vivo screens are likely to be more meaningful.

The drug metabolism, ADME and early PK specialists often perform in vitro metabolism and permeability studies and small animal PK studies on prodrugs. However, they must be conscious of the limitations of the in vitro screens and the over-interpretation of studies performed in mice/rats in relation to eventual human studies. Drug metabolism and early PK specialists often help identify the problem/s with the parent molecules and have sufficient knowledge to suggest possible prodrugs, but often do not have the capability to synthesize possible prodrug candidates.

Toxicologists often are not supportive of prodrug programs, because it makes their work more demanding. They not only must be concerned about the active drug, but must also address toxicology questions related to the prodrug and its breakdown products. See earlier questions raised about formaldehyde production and the role of pivalic acid in depleting carnitine levels

The presence of a formulation scientist on the team is critical. Their role is to make sure that any testing of the prodrug uses realistic formulations that can be scaled to human use and that issues, such as chemical stability, are addressed up front. For example, prodrugs proposed and moved into development can be so chemically unstable that they will never be developed as an approvable entity. If properly trained with a strong physical/chemical background, the formulation scientist is critical to the success of a prodrug program.

While bench scientists often do not appreciate the role played by marketing, marketing specialists can play a very important role as part of this team. For example, if an injectable prodrug is needed for a specific product, it is important to know if a reconstitutable lyophilized product would be acceptable or if a ready-to-use solution is required. This may be dictated by the disease being treated or by competitor products. If a ready-to-use solution is needed, then that will dictate what promoiety or chemistry can be applied. Prodrugs, by their very nature, tend to be more or less chemically unstable. This can present a problem for the formulation scientists. Therefore, the type of formulation needed, often dictated by marketing and patient acceptability issues, may require a greater and more creative effort.

The formula for a successful prodrug effort is teamwork. Such a team is difficult to put together on an as-needed basis. Big pharma companies have recently shifted toward a paradigm where specialty prodrug teams have been constituted to work with discovery teams to identify prodrug strategies immediately when the need begins to present itself. That is, prodrug strategies are becoming an integral part of the drug discovery paradigm. There are also small companies whose business plan/strategy is to design prodrug solutions, both as a conduit for new drug candidates and/or as CROs, to help big and small pharma solve drugability problems.

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