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Cutting-Edge Pharmacokinetics for 505(b)(2) Programs: Can We Really Do That?

If you think regulatory pharmacokinetics requirements are just a box-checking exercise then you may be throwing away money and time on unnecessary studies. At Premier Consulting, we have always focused on innovative approaches for the most challenging drug development programs, but our cutting-edge pharmacokinetics strategies are getting attention from industry, academia, and the FDA.

We have often mentioned in our blogs that every 505(b)(2) product and its development program are unique. Nowhere is this more true than in the development of an optimal bridging strategy. Furthermore, we use our pharmacokinetic and statistical prowess to solve problems and avoid studies that seem inevitable to most clients and CROs.

Did you know that in many situations, a single-dose simulation can be used to avoid a multiple-dose study? The savings in time and cost are obvious. But when a study is required, our modeling can be used to determine the minimum sample size and to ensure the success of the study.

Here are some recent examples of what Premier Consulting’s team of Pharmacokinetics experts have achieved for our clients.

Case Study 1

Client A developed a drug-device 505(b)(2) combination product for continuous subcutaneous (SC) administration. Prior to Premier Consulting’s involvement, the FDA would not accept the results of the pivotal bridging study to an intravenously (IV) administered listed drug because the client had used a different device than their to-be-marketed product. The client then conducted a second pharmacokinetic study with the to-be-marketed device, but only 1 sample per subject was collected randomly over a range of several hours.

Although the FDA agreed that the pharmacokinetics were similar, a new bioequivalence (BE) study would be required in order to rely on the findings of efficacy and safety for the listed drug. At this point, the client approached Premier Consulting for a solution as it did not have the time or finances to conduct another pharmacokinetic study.

Premier Consulting’s pharmacokinetics team looked for ways to utilize the client’s existing data and determined that a model incorporating the data from both studies would be needed. Our team filled in the gaps with a graphical and analytical evaluation of both data sets. This approach required scientists with advanced pharmacokinetics in conjunction with a strong statistical background. Further, our team demonstrated that the observed variability of the client’s device function did not affect the relative or the systemic levels of drug compared with the listed drug and therefore posed no safety concern.

The FDA was suitably impressed by Premier Consulting’s approach.

Case Study 2

Client B developed a sclerosing agent for intralesional administration. Although the risk of inadvertent IV administration was low, the FDA requested that our client justify the safety of the product in the event that it was administered as an IV bolus.

Of course, it was not possible nor desirable to test the safety in a clinical study. Instead, our pharmacokinetics team sought to use the widely accepted nonlinear kinetic model for the drug. The simulation performed with success despite the variations and complexities in modeling nonlinear capacity limited kinetics involving different compartments for oral and IV administrations.

The FDA accepted the simulation report for the NDA filing. Once again, problem solved.

Case Study 3

To eliminate the food effects of an oral drug, Client C has developed two formulation prototypes. Separate BE studies were conducted for the 2 formulations compared to the listed drug in subjects under both fasted and fed conditions. Unfortunately, the two formulations resulted in systemic exposures that were significantly either higher or lower than that of the listed drug. Back to the drawing board?

Premier Consulting’s pharmacokinetics team had a better idea, and used population PK modeling to simultaneously fit combined data to identify the rate of absorption for each formulation. The “virtual” BE trial using the established population PK model of the proposed product was performed to identify the ratio of each formulation that could be combined to achieve BE to the listed drug.

The result was a formulation that can eliminate the food effect of the product, without needing to go through a laborious reformulation process.

The Importance of Pharmacokinetics and Statistics in 505(b)(2) Programs

There are as many examples of our innovative PK strategies as there are clients, because every 505(b)(2) program requires a different approach. Therefore, the value that Premier Consulting adds comes in many shapes and sizes. We have never been afraid to raise eyebrows if the approach saves time and money for our clients.

So what is so special about Premier Consulting’s pharmacokinetics team?

  • Combined backgrounds in pharmacokinetics and statistics are essential for identifying credible models
  • Specific experience with unique 505(b)(2) bridging strategies is necessary for finding innovative solutions
  • Enthusiasm for solving problems that others have declared to be too hard

These factors contribute to the think-out-of-the-box success of our team.

Did we mention that several members of our pharmacokinetics team trained at the FDA? Contact us to find efficient solutions for your development program. We welcome the challenge.


Ruth E. Stevens, PhD, MBA
Strategic Advisor