UHSP Pharmaceutical and Administrative Sciences Chair Receives $1.2 Million FDA Contract for Generic Drug Research

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Funding will support research to create an in vitro/in silico model to accelerate generic drug product development designed for oral cavity administration.

Dr. Giovanni Pauletti, Gustavus and Henry Pfeiffer Chair of Pharmaceutical and Administrative Sciences, professor of pharmaceutics and associate dean of graduate studies at the University of Health Sciences and Pharmacy in St. Louis (UHSP), has received a $1.2 million contract from the U.S. Food and Drug Administration (FDA). The funding will support Pauletti’s work to develop a computational tool with the potential to accelerate the development of generic forms of medications which are delivered through the oral cavity.

Over the past five years, Pauletti has been conducting research to examine how in vitro systems could be used in conjunction with pharmacokinetic modeling in drug development. Utilizing this three-year FDA contract, Pauletti will further extend his research by developing an in silico computer modeling and simulation platform with the capability to predict drug concentrations in human subjects for generic formulations after administration to the oral cavity without the use of clinical trials.

“Through in vivo studies, generic drug developers measure the blood levels of medications at various times in real people to ensure that the generic product is bioequivalent to the already approved innovator product,” Pauletti explained. “These studies take a significant amount of time and are very expensive, so what we’re hoping to do is evaluate bioequivalence though other types of studies with a combination of computer simulations informed by results from in vitro experiments. This approach will utilize mathematical equations that we would validate, and these equations will provide us with data similar to what in vivo studies would offer. If we’re successful, this may be a way to get certain drugs, including those that can be delivered through the oral cavity, on the market as generics without in vivo studies, which means more rapid access to generic products for patients.”

Making Medications More Readily Available

Pauletti’s contract comes from the FDA’s Office of Generic Drugs, which works to ensure—through its scientific and regulatory process—that the U.S. population has access to safe, effective and high-quality generic drugs. In recent years, the organization has been particularly focused on improving physiologically based pharmacokinetic models of drug absorption via complex routes of delivery, including administration via the oral cavity, nose, eye and lungs.

Most drug development outside of the United States focuses on generics, since this requires fewer resources, Pauletti pointed out. Rather than performing extensive clinical trials to determine the safety of existing drugs, generics researchers can rely on information gathered from other countries and scientists. This enables development of a generic version for the local market faster and cheaper. Depending on where the generic development is taking place, it may be the only opportunity that patients have to gain access to certain effective medications. In contrast, many companies based in the United States invest more resources for new drug development over generics. While patients benefit from the discovery of novel therapeutics, new drug development is a costly endeavor that many countries cannot afford.

 

Our tool is designed to allow for the optimization of drug formulations for rapid onset or limited absorption out of the oral cavity, depending on a patient’s needs. This is important as the FDA works to achieve its goal of making safe and effective generic medications more readily available to the public.

Dr. Giovanni Pauletti

“Oral cavity drug delivery continues to gain interest as an alternative to the conventional oral route of administration because of the enhanced drug absorption qualities it offers and its benefits for pediatric patients and those who are unable to swallow tablets,” Pauletti said. “This also includes fast dissolving pain medications that can carry a significant risk of abuse. Our tool is designed to allow for the optimization of drug formulations for rapid onset or limited absorption out of the oral cavity, depending on a patient’s needs. This is important as the FDA works to achieve its goal of making safe and effective generic medications more readily available to the public.”

Pauletti’s research is being aided by GastroPlus®’s physiologically based pharmacokinetic modeling platform from the software company Simulations Plus Inc. GastroPlus® is a mechanistically based simulation software package that simulates intravenous, oral, oral cavity, ocular, inhalation, dermal, subcutaneous, and intramuscular absorption, biopharmaceutics, pharmacokinetics and pharmacodynamics in humans and animals. Currently, Simulations Plus Inc. is the only company with a computational model for absorption of drugs in the oral cavity.

Using this novel simulation tool that is informed by results from in vitro experiments, Pauletti said researchers involved in generic development will be able to assess what needs to be fine-tuned in the drug formulation to create drug profiles that are most similar to the approved reference listed drug. “Our tool offers a standardized process for measuring generic drug formulations and can help inform decisions on whether the formulations meet the criteria and level of similarity the FDA wants for generic drugs,” he said. “We are excited to initiate this FDA-funded project in collaboration with our colleagues at Simulations Plus. The value of this partnership between academia and industry lies in its potential to accelerate translation of innovative discoveries into tangible patient benefits.”

Partnering to Facilitate Interactions

“This project is a combination of pharmaceutical sciences and engineering, but at the end of the day, it’s all designed to benefit the patient,” Pauletti explained. “We’re not making new molecules, we’re just learning how to deal with existing molecules in a more effective way, and this tool helps accelerate the process.” Pauletti’s research efforts are now underway and will continue until September 2023. His team is currently working to develop the system to compare computational predictions with real lab-generated data and information from clinical trials. This will assure the researchers that their predictions about a drug are appropriate for humans. At press time, his team was initiating the early laboratory experiments that will take six to nine months. The researchers are also developing technology to help transfer data into their computational predictions.

“What we hope to do is facilitate the interaction between the agencies and researchers,” Pauletti noted. “The idea is to provide researchers that developed generics with a tool that could help them to really assess some of their new formulations for generics, ahead of clinical trials. We have started to develop a consortium of different companies that are focusing on the development of generics to best understand what their needs are and how we can help. The final product that is developed under this contract will be really meaningful for both FDA as well as the end users in the companies that develop generics.”

Pauletti’s team includes student pharmacists in addition to seasoned researchers. While the COVID-19 pandemic has added complications to the process and restricted who can enter the laboratory, Pauletti noted that student pharmacists have been helping on the computational side of his research. This gives students hands-on experience with pharmacokinetics and the use of computer and simulation tools. “That helps them to gain insight into the contemporary pharmaceutical research component, and also provides them with opportunities to explore some of their future career paths, which for pharmacy is quite diverse,” he said. “We teach them pretty much the clinical routes, but the tools that they learn are certainly applicable also for industrial or research and development career paths.”

In addition to his role at UHSP, Pauletti is also a member of the International Pharmaceutical Federation (FIP). Pauletti has served in numerous roles at FIP since his years as a student in Switzerland. He is currently serving his second four-year term as the scientific secretary, a member of the cabinet who advises the president of FIP on all scientific affairs relevant to pharmacy and pharmaceutical sciences.

Reprinted with permission from the University of Health Sciences and Pharmacy in St. Louis. Additional reporting by Emily Jacobs, a freelance writer based in Toledo, Ohio.