FDA releases draft guidance for physiologically based PK analyses

The US Food and Drug Administration (FDA) has issued draft guidance for industry on the use of physiologically based pharmacokinetic (PBPK) analyses for biopharmaceutics applications.

A PBPK analysis uses models and simulations combining physiology, population, and drug substance and product characteristics to mechanistically describe the pharmacokinetic or pharmacodynamic behaviors of a particular drug product, according to the FDA.

The idea behind using this technique is that it helps predict systemic drug exposure from oral drug products.

“When a sponsor submits a drug application, biopharmaceutics modeling could inform drug development of in vivo responses due to formulation alternations, which in turn supports clinically relevant decision making,” the agency advised. “In silico approaches, such as this, would ultimately reduce the long-term burden on both industry and regulators.”

The guidance document, issued 30 September 2020, offers industry some examples of high-level workflows and use cases. It applies only to orally administered, systemically active drug products. The FDA noted the guidance does not apply to locally active drug products, including orally delivered gastrointestinal drugs that reach the site of action before entering systemic circulation. The agency plans to consider PBPK analyses of locally acting drugs on a case-by-case basis.

The agency highlighted several regulatory uses of PBPK models for biopharmaceutics applications, specifically for supporting product quality. For example, the models could be used for development of clinically relevant dissolution specifications to aid in biopredictive dissolution method development. The agency is encouraging such development early on in product development, especially for products with dissolution as the rate-limiting step for absorption.

The FDA advised drug sponsors to incorporate dissolution profiles into the PBPK model and evaluate the predicted systemic exposure. That exposure should be comparable (plus or minus 10%) with the observed in vivo pharmacokinetic data. “To evaluate the method, we recommend that sponsors use observed in vivo PK data of formulations with different release rates,” the agency said in the draft guidance.

The agency also advised sponsors to consider relevant dissolution acceptance criteria, which is a way to identify and reject drug product batches that are not bioequivalent to the pivotal clinical drug product. A clinically relevant dissolution acceptance criterion can be wider than the average dissolution data of pivotal clinical batches, meaning a variation range of beyond plus or minus 10% for an extended-release drug product, according to the guidance.

The draft guidance also explores establishing clinically relevant drug product quality specifications outside of dissolution. Quality attributes can include drug substance quality attributes, excipient quality attributes, in-process quality attributes, and finished drug product attributes. Manufacturing process parameters to be considered include coating parameters and compression force.

Drug sponsors can also use PBPK analyses as a quality risk assessment for pre- and post-approval changes, the FDA said.

During the pre-approval stage, that could mean bridging clinical batches to the to-be-marketed product accounting for chemistry, manufacturing, and controls changes such as formulation, manufacturing process, and manufacturing site changes during development. In the post-approval stage, it could support biowaivers for post-approval changes.