Prodrugs: Some Thoughts and Current Issues

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ABSTRACT:

The prodrug approach to resolving formulation, delivery, and toxicity limitations on problematic drugs has had its proponents and detractors. Over the last 10 years or so, about 20% of all new small molecule NCEs have been prodrugs—a number that will surprise some. As chemists begin to explore new chemical spaces, larger and more complex molecules present greater drug delivery challenges. Prodrugs provide a means of solving these challenges, but also have their limitations. Prodrugs are becoming an integral part of the drug discovery paradigm in some large pharma companies, and a number of small biotech companies have been built around the design and application of prodrugs to improve drug candidates. Some issues facing the area of prodrug research and the commercialization of prodrugs are discussed.

Section snippets

INTRODUCTION

“Drugs need to be designed with delivery in mind” is a quote that I have attributed to the late Professor Takeru Higuchi; it was said during an afternoon coffee break at the University of Kansas sometime during the mid-1970s. Today, while exploring chemical spaces and complexities not seen in earlier generations of drug molecules, our medicinal chemistry colleagues are making the task of delivery more and more challenging. While new and novel formulation approaches have helped us meet some of

A HISTORICAL PERSPECTIVE

The terms “pro-drug” and “pro-agent” were coined by Adrien Albert who, in a footnote to some later work, acknowledged that “predrug” might have been a more appropriate term. He used the terms to describe agents that must undergo transformation to the active ingredient prior to exhibiting their pharmacological action. Albert suggested that this process could be done in a foresighted manner to overcome restrictions of the parent, active drug, such as limited solubility, toxicity, etc. Various

WHAT HAVE YOU DONE FOR ME LATELY?

From 2000 to 2008, 236 new molecules were approved worldwide.7., 8., 9., 10., 11., 12., 13., 14., 15. Of these, 191, or 81%, were small molecular weight drugs (NCEs); the other 19% were either new biological entities or larger molecular weight drugs, mostly polypeptides. Of the 191 NCEs, 24, or 12.6%, were clearly identified as prodrugs, while another 10 (an additional 5.2%) may be considered prodrugs. This latter group consists mainly of molecules that are antivirals or anticancer drugs that

COMPANIES WITH PRODRUGS AS THEIR PRIMARY PRODUCT FOCUS

While Interx was one, if not the earliest, of the new wave of biotech/drug delivery companies to embrace prodrugs, the companies listed in Table 5 seem to promote research and development of prodrugs as a part of their primary business strategy. Included in Table 5 is ProQuest, a company spun-off from the University of Kansas with number of prodrug platform technologies. ProQuest was purchased by Guilford and, through a series of acquisitions, is now a part of Eisai. ProQuest, in collaboration

COMPANIES WITH PRODRUG CANDIDATE(S)

Many biotech companies have drug candidates in early discovery to late development that are prodrugs. A partial listing of these companies can be found in Table 6. Medium-to-large companies with considerable effort in the prodrug area are listed in Table 7. Again, this information was gleaned mainly from personal contacts and the appearance of a number of prodrugs studies listed in the Investigational Drugs Database (IDDB). Not listed in this table are a number of Japanese companies that also

PRODRUGS IN CLINICAL TRIALS

Table 8 contains information on prodrugs in clinical trials. If one just types the word “prodrug” into < clinicaltrials.gov >, the NIH-sponsored clinical trails database, a total of 64 hits are seen. Many of these trials do not involve new prodrugs undergoing Phase I–III studies, but are mainly clinical trials of approved prodrugs for new indications or in combination with another drug. Only 15 or so of the 64 trials did appear to involve studies with NCE prodrugs.

This listing is not

CONCERNS ABOUT THE ATTITUDE OF THE USPTO TOWARD PRODRUG PATENT APPLICATIONS AND WHETHER THE FDA CLASSIFIES A PRODRUG AS AN NCE

I would like to express some frustration with the attitude of the USPTO toward prodrug patent applications. From personal experience and in reviewing some examples of litigation by generic and patent- trolling companies, it appears as though the argument is being made by the USPTO and generic companies attempting to invalidate approved patents that any prodrug manipulation should be considered obvious. This is particularly the case when someone applies a previously successful prodrug approach

THE FDA NOT PROVIDING NCE STATUS TO FOSAPREPITANT SHOULD BE A CONCERN TO ALL PRODRUG RESEARCHERS

A new and recent disturbing issue involving prodrugs concerns a challenge by Actavis Elizabeth LLC to the grant of NCE status to lisdexamfetamine (see Tab. 1 for the structure), a novel prodrug of dexamphetamine marketed by Shire but discovered by New River. Shire claims that lisdexamfetamine, unlike dexamphetamine from tablets, delivers dexamphetamine only after oral administration and is not readily broken down into dexamphetamine if recovered from the tablet and injected or attempts are made

CONCLUSIONS

In writing this commentary on prodrugs, I hope that I have raised the reader’s consciousness on the future and some of the issues facing the area of prodrug research and the commercialization of prodrugs.

ACKNOWLEDGMENTS

I would like to thank all my former students and colleagues who have contributed to our knowledge of prodrugs. I apologize if my information on various companies is less than up-to-date, as specific information on companies utilizing prodrugs and prodrugs in clinical trials is not easy to obtain and verify. I hope the readers will forgive me for any errors or oversights.

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