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Molecular Relatives: Prodrugs

Posted on May 19th, 2016 by in Pharma R&D


I’m an avid sailor, and on our boat we have an amazing device known as a water-maker. It is probably one of the most useful pieces of equipment on board for long cruises, as it takes in sea water, and, through a process of reverse osmosis, provides potable drinking water. It occurred to me that this is somewhat similar to a prodrug, which is only pharmacologically active after metabolism.

Are prodrugs just a poor relation in the drug family, simply the same drug dressed up to look different? I can’t agree with that assessment, and I really believe that they have a huge role to play in improving our pharmaceutical offerings.

Prodrugs are sometimes confused with generic drugs, but they are very different. The FDA defines a generic drug as being “… identical–or bioequivalent–to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use” (1). This is clearly different from a prodrug, which requires some type of in vivo enzymatic and/or chemical transformation in order for the active parent drug to be released.

I was surprised to learn that the concept of prodrugs is actually not that new. Although there could be others, I found reference to one introduced in 1899 by Schering – methenamine (2). This was a bit of a shock, as I assumed it was a relatively modern concept. A more contemporary example of a prodrug would be Horizant ® (gabapentin enacarbil), used to treat adults with moderate-to-severe primary RLS (Restless Legs Syndrome) (3). Among other possible benefits, the use of this prodrug allows for once daily dosing.

There are a number of reasons to consider developing a prodrug, which all have direct patient benefits (2):

  1. Improve formulation and administration. By using prodrugs, it may be possible to reduce the number of tablets or capsules required to have the same therapeutic benefit.
  2. Enhance permeability and absorption. Not only can this be beneficial for orally administered drugs, but it can also improve the absorption of transdermal and ocular drugs.
  3. Change the distribution profile. There are few examples of prodrugs in this category, but clearly if drugs can be delivered site-selectively, then there can be great patient benefits.
  4. Protect from rapid metabolism and excretion. The effectiveness of drugs can be diminished both by the first-pass effect through the gastrointestinal tract and liver as well as by extensive excretion. Prodrugs may be designed to avoid both of these effects.
  5. Overcome toxicity problems. Site-selective drug delivery and activation may reduce the toxic effects of drugs, therefore enhancing patient benefit.
  6. Manage the life-cycle. A prodrug may be classified as a new chemical entity and thereby receive patent protection. Furthermore, the development of a prodrug can be less expensive and faster.

Building on the last point above, one contributory factor to the lower cost and faster development of a prodrug, in some cases, can be the use of the 505(b)(2) route for filing an application for approval with the FDA. This type of filing is “an application that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference” (4). Thus, where the parent drug has already been registered, it may be possible to rely on some of the data already generated for that drug. This can reduce both time and development costs for the prodrug.

Prodrugs are a cornerstone of drug development, and they are an excellent route where some aspect of the parent drug needs improvement. While some regard prodrugs as simply a marketing tool to replace drugs going off patent, I would contend that there is an emerging trend for prodrug development in areas of significant unmet medical need. This is exemplified by a press release in January of this year regarding a submission to the FDA for tenofovir alafenamide, a prodrug of tenofovir, for the treatment of HIV (5). So prodrugs don’t seem to me to be a poor relation at all!



  2. Huttunen KM, Raunio H, Rautio J. Prodrugs – from Serendipity to Rational Design. Pharmacological Reviews. 2011; 63:750-771.

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