Benefits of Utilizing the 505(b)(2) Pathway for Prodrugs

By Rachel Rozakis, PharmD, Clinical Pharmacologist II 

Over the past decade, at least 30 prodrugs have been approved by the US Food and Drug Administration (FDA). It is likely that prodrugs will continue to be important in drug development well into the future. There are many potential pharmacological benefits to using prodrugs as an alternative to parent drug molecules that may lead to a safer and more efficacious drug product. Utilizing the 505(b)(2) pathway for a prodrug strategy has the potential to not only lead to better therapeutic options but can be beneficial from a regulatory standpoint as well. If a prodrug falls under the 505(b)(2) pathway, previously conducted studies on the drug may be utilized. This can potentially expedite the approval process and reduce costs. In contrast, drugs using the 505(b)(1) pathway can take far longer to be approved and at significantly greater expense. Therefore, when possible, the 505(b)(2) pathway for prodrugs can remove major barriers that the original, parent drugs faced in the development process.

What is a Prodrug?

Prodrugs are compounds that are pharmacologically inactive at the time of administration. After a prodrug has entered the body, it undergoes metabolism to reach its active parent drug form. Prodrugs may be activated by various enzymes or processes within the body, depending on the prodrug’s chemical structure. For example, many prodrugs are designed to include an ester group, which when cleaved off by enzymes (or esterases), results in the creation of the drug’s active therapeutic form. A parent drug with limitations in its pharmacokinetic (PK) profile, such as poor solubility, inefficient delivery to the target site, or rapid elimination, can prevent the drug from reaching its full therapeutic potential. Modification of the parent drug into a prodrug can help improve important PK properties, including its absorption, distribution, metabolism, and excretion (ADME). The optimization of these properties can lead to increased bioavailability, safety, and efficacy. Both traditional and modern approaches have been used to optimize ADME properties for prodrugs. Traditional approaches include altering the physicochemical properties of the drug and modern approaches include utilizing transporters and protein expression in the body.

Benefits of the 505(b)(2) Pathway for Prodrugs

For eligible compounds, a 505(b)(2) strategy can remove certain barriers that developers face in the drug development process, often resulting in time and cost savings. When compounds are the result of a modification to an innovator drug (such as prodrugs), developers may rely on external data and leverage relevant information from prior investigations rather than conducting new studies when utilizing the 505(b)(2) pathway. Not only can this regulatory pathway alleviate some of the costs and time associated with a traditional new drug application (NDA), but a 505(b)(2) program can also eliminate the need for most nonclinical studies and extensive safety and efficacy tests. Specifically, a well-defined 505(b)(2) program can often save one to two years of pre-clinical research and five to ten years of clinical research. A prodrug that goes through the 505(b)(2) pathway may also be eligible for three, five, or even seven years of marketing exclusivity, depending on its level of similarity to a parent compound and/or if it is considered an orphan drug. A prodrug of a previously approved parent drug would be an excellent candidate for a 505(b)(2) development approach. The 505(b)(2) process has many advantages for suitable drug candidates and should be considered by drug developers with prodrug programs.

Prodrug Benefits

Prodrug modifications can remove unwanted drug properties or they can add or retain advantageous drug properties in terms of bioavailability, efficacy, or safety. There are many advantages of prodrugs. Some specific benefits of prodrug development include:

• Increased solubility
• Increased lipophilicity
• Selective targeting to site
• Protection from rapid elimination
• Patient compliance

Increased Solubility

Many drugs are poorly absorbed in an aqueous environment, which can lead to low oral bioavailability. The addition of a polar molecule (e.g., certain esters and amide groups) can help a drug be better absorbed, and therefore allow it to reach the target tissue in a high enough concentration to be effective.

Increased Lipophilicity

Lipophilicity is also an important property for drug molecules because travel through lipophilic membranes in the body is essential for absorption and distribution. For example, the addition of a lipophilic moiety to a drug can help it pass through the blood brain barrier if the drug needs to reach the brain to be effective.

Selective Targeting to Site

Ideally, a drug would find its way to the appropriate target site without spending much time elsewhere in the body. To help achieve this, prodrugs can be designed to be released in specific organs or tissues where they will be the most efficacious. Different methods may be employed to achieve selective targeting, such as designing a prodrug to target specific transporters or activating enzymes in the body. Selective targeting not only improves efficacy, but also improves safety by reducing toxicity and side effects. This is especially true for chemotherapy drugs which often damage healthy cells. Chemotherapeutic agents that remain inactive until delivery at a tumor are less likely to have off-target toxicity.

Protection From Rapid Elimination

Enzymes in the body can rapidly metabolize some drugs, causing them to be eliminated before an adequate therapeutic effect has taken place. For example, metabolism via enzymes in the digestive system can lead to accelerated drug clearance. A more prolonged duration of action can be achieved through prodrugs that prevent rapid metabolism, thus extending the half-life of a parent compound. Drugs with adequate exposure times also may require less frequent dosing.

Patient Compliance

Many of the prodrug benefits listed above can directly or indirectly play a positive role in patient compliance. For example, prodrug solubility modifications that improve taste or odor in orally administered drugs or decrease injection site pain in intravenously administered drugs can directly impact compliance. Additionally, selective targeting may indirectly improve compliance as patients are more likely to adhere to treatment regimens with fewer side effects. Lastly, prodrugs that require less frequent dosing can reduce the burden on patients.

Prodrug Applications

Prodrugs can be utilized in a variety of diseases and applications. Some examples include using prodrugs for the treatment of inflammatory bowel diseases, certain oncology therapies, and for transdermal drug delivery. Inflammatory bowel diseases: Prodrugs intended for the treatment of inflammatory bowel disease are designed to keep the drug intact as it passes through the stomach and into the small intestine and is ultimately hydrolyzed by bacteria in the colon to release the active compound. This approach can help treat localized diseases of the colon such as ulcerative colitis, which requires frequent dosing of anti-inflammatory agents. Oncology therapies: Similarly, oncology can also benefit from targeted drug delivery. Traditional chemotherapeutic agents are not only toxic but lack target specificity, which makes targeted drug delivery a much more appealing option. There are many existing prodrug approaches to targeted cancer therapy. Passive and active strategies can both improve patient outcomes by enhancing the localized delivery of a drug to the tumor. Passive strategies include utilizing abnormal properties of the tumor microenvironment (e.g., reduced pH or overexpression of certain surface receptors at the tumor) to deliver the prodrug to the tumor. Active strategies include activating prodrugs at the tumor site using enzymes or photodynamic therapy. The development of prodrugs for oncology indications continues to be an active area of research. Transdermal drug delivery: Transdermal drug delivery is also an area where prodrugs are of interest. This is due to the unique challenges associated with the delivery of drugs transdermally through the top layer of the skin, which has multiple lipid and aqueous phases. Altered physicochemical properties of prodrugs can allow the drugs to be absorbed into the skin more efficiently and thus be delivered more effectively to the site of action and/or achieve systemic exposure. There are many other applications and therapeutic indications for prodrugs, including infectious diseases, central nervous system disorders, and opioid misuse. Because of their wide spectrum of utility in various therapeutic areas, prodrugs represent a key drug development strategy to consider.

Conclusions

Prodrugs are associated with many benefits including improved drug delivery, improved patient compliance, and more efficient ADME properties. Utilizing the 505(b)(2) pathway can allow prodrug programs to save significant time and expenses, allowing treatments to reach patients in a more streamlined manner. Allucent has extensive experience supporting 505(b)(2) development programs from both a strategic and operational perspective. Our approach is to match regulatory knowledge with scientific, clinical, nonclinical, and overall drug development expertise to find the right path for each 505(b)(2) program. Prodrug programs can benefit from Allucent’s 505(b)(2) consulting services which help guide drug developers through the 505(b)(2) regulatory pathway from start to finish. Contact one of Allucent’s 505(b)(2) experts today for help with your prodrug development program.