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. 在生产非专利药、新配方或更换生产地点时，需要进行生物等效性研究。通常情况下，生物等效性是通过临床试验后的药代动力学分析来证明的。
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. 此外，在某些情况下，VBE 还能将基于 BCS 的生物豁免扩展到 BCS I 类和 III 类化合物之外。与传统的生物等效性方法相比，VBE 可节省时间和金钱，并能更快地向患者提供安全的药物。See this recent discussion between myself and Ellen Leinfuss at the 2021 AAPS annual meeting for further details on oral VBE case examples.
