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PBPK Modeling to Support Bioequivalence & Generic Product Approvals

We ended the year 2021 on high note when Dr. Eleftheria Tsakalozou (Staff Fellow, US FDA) delivered an impactful webinar on the hot topic of the utility of physiologically-based pharmacokinetic (PBPK) modeling to support bioequivalence (BE) assessment of complex and locally acting generics to members of the Simcyp consortia.

Bioequivalence is used to compare the relative bioavailability between of two preparations of the same drug. Bioavailability is the extent at which a drug enters its intended biological destination or systemic circulation. Bioequivalence studies are required when creating a generic drug, creating a new formulation, or switching manufacturing sites. Typically, bioequivalence is demonstrated via pharmacokinetic analysis after clinical trials.

Dr. Tsakalozou began her presentation by explaining the principles of BE for locally acting drug products, stating that the Agency may consider the use of ‘alternative scientifically valid methods’ for a drug that is intended to act locally. She continued by focusing on generic drug products and how mechanistic PBPK models can guide the establishment of clinically relevant product quality attributes (CQA), support the development of product specific guidances (PSGs), and provide a risk assessment following formulation changes.

PBPK models with mechanistic description of formulation CQA and enhanced population simulation capabilities can be used to support virtual BE (VBE) assessments. VBE is demonstrated using modeling and simulation in lieu of clinical studies to establish bioequivalence. PBPK models can be leveraged to predict local drug exposure by integrating knowledge on the characterization of a drug product, the physiology or pathophysiology at or near the site of action, and the population information of healthy volunteers or patients receiving the drug product and to establish a link with systemic exposure, if measurable. The webinar specifically outlined FDA’s approval of an Abbreviated New Drug Application (ANDA) for a generic diclofenac sodium topical gel, 1% (referencing Voltaren topical gel, 1%), where for the first time a VBE assessment leveraging dermal PBPK modeling and simulation supported by a totality of evidence approach resulting in the approval of the ANDA and discussed the lessons learned from this submission. The Simcyp Simulator’s MPML-MechDermA model (Figure 1) was used for this case example.


Figure 1. Simcyp’ s Multi-Phase Multi-Layer (MPML) MechDermA Model


Take home messages shared by Dr. Tsakalozou:

  • A dermal PBPK model for diclofenac sodium topical gel, 1% supported the ANDA approval
  • The developed model was used to bridge drug product quality attributes with local bioavailability and BE considerations for the test drug product
  • PBPK models can support development of a drug product prior to approval
  • Alternative BE approaches for product development and regulatory approval are achievable

The recording for this webinar is available here on YouTube. Dr. Tsakalozou also covered this topic at the September, 2021 FDA Office of Generics Workshop and in this peer-reviewed paper.

While this webinar focused on dermal generics, Simcyp has successfully demonstrated BE and supported dissolution specifications for a range of oral drug products such as tablet, capsule, suspension, etc.

The Simcyp platform also offers range of mechanistic models for assessing virtual BE for other delivery types, such as IV, long acting injectable, and intra-vaginal, intra-muscular. Additionally, VBE is now demonstrating its ability to extend BCS-based biowaivers beyond BCS Class I and III compounds in certain cases. VBE saves time, money, and gets safe drugs to patients faster than traditional bioequivalence methods. See this recent discussion between myself and Ellen Leinfuss at the 2021 AAPS annual meeting for further details on oral VBE case examples.

About the author

Nikunjkumar Patel, PhD
By: Nikunjkumar Patel, PhD

Nikunj has more than 11 years of experience in computer aided drug design and PKPD modelling including 8+ years of experience focusing on PBPK modelling. He joined Certara’s Simcyp division in 2011 and worked extensively on oral and dermal absorption PBPK Modelling and mechanistic cardiac safety risk assessment. He has a doctorate degree in Quantitative Systems Toxicology and Safety.

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