Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation

Debrief

FDA Public Workshop was hosted on May 19, 2016 by the US Food and Drug Administration (FDA) at its White Oak Campus in Silver Spring, MD. The workshop speakers were from the FDA, industry, and academia. The workshop was chaired by Dr. Liang Zhao, Director of Division of Quantitative Methods & Modeling Office of Research Standards Office of Generic Drugs.

The plenary sessions presenters were from FDA (Drs. John Duan, Xinyuan Zhang,  from industry (Drs. Filippos Kesisoglou (Merck), Jasmina Novakovic (Apotex ), Masoud Jamei  (Simcyp), Viera Lukacova (SimulationsPlus) and Thomas Eissing (Bayer Technology), and from academia (Dr. Gordon Amidon, University of Michigan).  Dr. Kathleen Uhl gave the opening remarks and Dr. Robert Lionberger gave the closing remarks.

A few Dr. Zhao’s presentation slides were on:

  • M&S Impact Various Regulatory Activities in OGD (4/1/15 to 4/1/16)
  • PBPK in Applications for Generics
  • Number of Compounds Assessed Using Absorption Modeling
  • PBPK Applications in NDA: Current Status
  • Drug labels with dosing recommendations informed by PBPK

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM505000.pdf

Dr. Duan’s presentation title was The Application of Mechanistic Oral Absorption Model in Biopharmaceutics Review”. Highlights of presentation were:

His presentation outline slide described an overview, covering

  • Patient first initiative in drug development
  • Biopharmaceutics Team growth
  • Predictions help decision making

Current status, covering

  • Current practice
  • Dissolution spec setting
  • Set clinically relevant product specs
  • Risk assessment

PBPK Future App

  • Meet the challenge
  • Information in regulatory submission
  • Product life cycle management

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM505003.pdf

Dr. Zhang’s presentation title was OGD Experience and Efforts on Oral Absorption Modeling and Simulation”. Highlights of presentation were:

Update on Absorption Modeling and Simulation in OGD

  • Innovative Model for Future Product Development

Case Examples:

  • Evaluate the impact of slow dissolution in a specific pH condition on BE (warfarin sodium tablets)
  • Evaluate the PPI impact on BE (prasugrel HCl tablets, fingolimod capsules)

Summary slides had following points:

  • OGD has routinely applied mechanism-based absorption modeling and simulation to address various issues raised in regulatory activities.
  • OGD is actively improving the science of predictions for oral solid dosage forms.
  • OGD is willing to collaborate with internal and external stakeholders to advance the application of mechanism-based absorption modeling and simulation in drug product development and regulatory review.

Dr. Kesisoglou’s presentation title was Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: An Industry Perspective”. A few presentation slides were on:

  • Current status of absorption modeling in formulation development
  • Case studies
    • Formulation development and achlorhydric simulations
    • Dissolution impact on PK and BE projections
    • Multimedia dissolution and BE projections
    • Projection of API form change and population simulations
    • Food effect projection for a BCS I compound
    • Absorption modeling-based IVIVC for IR tablet
    • Conclusions and future directions

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM503760.pdf

Dr. Novakovic’s presentation title was ”Modeling and Simulations for Development and Bioequivalence Evaluation of a Generic Drug Product”. Highlights of presentation were:

Roles of PBPK modeling and simulation

Early development

  • Reference List Drug (RLD) characterization;
  • Establishing Quality Target Product Profile (QTPP);
  • Formulation design and product development of to achieve bioequivalence

Life-cycle and Quality Risk Management (QRM)

  • Bio-indicative dissolution test conditions and clinically meaningful specification limits;
  • Bio-study waiver for the additional strengths and SUPAC;
  • Critical material attributes (CMA) and boundaries for a rate–controlling excipient;

Summary slide had the following points:

  • At early product development stage PBPK modeling is a proven toll to characterize RLD, facilitate product development to define formulation strategy and achieve bioequivalence;
  • During life-time cycle management, QRM is ensured by implementing adequate controlled strategies (i.e. test methods and specification limits);
  • Controlled strategy, established to ensure BE, is developed based on PBPK modeling;
  • PBPK Modeling and Simulation is a powerful but underused tool to facilitate development and ensure QRM of a generic drug product.

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM503762.pdf

Dr. Amidon’s  presentation title was ” Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence (BE) Evaluation ”.

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM503764.pdf

Dr. Jamei presentation title was ” Mechanistic Modeling and Simulation of Oral Drug Absorption: Opportunities and Challenges”. A few presentation slides were on:

Outline

IVIVE (in vitro-in vivo extrapolation )-Linked PBPK absorption modelling

Physiologically-based IVIVC (PB-IVIVC)

Bioequivalence and PBPK modelling

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM503765.pdf

Dr. Lukacova’s presentation title was ”Incorporating Mechanistic Modeling & Simulation to Assist with Formulation Development”. Highlights of presentation were:

Outline

  • Why Modeling & Simulation?
  • Overview of Mechanistic Simulation Models
  • Predicting in vivo absorption & PK

Applications in Generic Product Development

  • Generating IVIVCs
  • Performing virtual bioequivalence trials and establishing dissolution specifications
  • Understanding food effects

A successful biowaiver case study

Conclusions

Summary slide was:

  • A mechanistic, physiologically-based absorption/PK model was constructed in GastroPlus and validated across three dose levels (50, 100, and 300 mg) using in vivo data collected from tablets manufactured with non-particle-engineered API.
  • Parameter sensitivity analysis showed that mean particle size would be the main property that determines whether formulations are likely to be bioequivalent, regardless of dose.
  • Virtual bioequivalence trial simulations showed that, for a sufficiently powered study, the population-derived Cmax and AUC values would be bioequivalent between the tablets manufactured with non-particle-engineered (NPE) vs. new-particle-engineered (PE) API, regardless of the dose.
  • Regulatory agencies approved the sponsor’s biowaiver application

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM503766.pdf

Dr. Eissing’s  presentation title was ” PK-Sim for Mechanistic Oral Absorption Modeling and Simulation and More”. A few presentation slides were on:

  • Introduction: PBPK modeling with PK-Sim & MoBi
  • Oral absorption and dissolution modeling
    • Concept
    • Examples
    • Implementation

 

  • Examples shown for how to model different formulations and their oral absorption in PK-Sim/MoBi to better understand PK
  • PK-Sim is a PBPK tool with a focus on flexibility and transparency, together with MoBi leaving a lot of room for problem specific solutions

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM503767.pdf

Dr. Kesisoglou’s presentation title was ”OrBiTo: Innovative Tools for Oral Biopharmaceutics”. Highlights of presentation were:

Overview

  • Programme vision, mission and objectives
  • Members of the OrBiTo consortium
  • OrBiTo Work Packages
    • Aims and deliverables
    • Highlights of progress to date
  • Integration of dissolution in PBPK models

Objective slide described:

  • Define the critical physicochemical, formulation and physiological factors that determine oral drug product performance.
  • Develop both experimental and theoretical models which can be used to robustly predict the in vivo performance of formulated drug products.
  • Fully leverage industrial knowledge and experience through pooling existing physicochemical, in vitro characterization, preclinical and clinical data to assess the reliability of currently available prediction methods and to underpin the development of new modelling and simulation tools.

Physicochemical tools – Understanding the API

Objective

  1. Provide a range of in vitro physico-chemical tools and in silico models that can assess the API’s key molecular properties important for in vivo performance, including excipient interactions
  2. Provide the information gained by use of tools, defined in objective 1, for a subset of the OrBiTo database to establish a Drug Development Decision Tree, expanding the DCS and facilitating drug formulation selection and optimising the dosage form design process
  3. Integrate knowledge and results obtained from physico-chemical studies and models in WP1 with “In vitro tools – understanding the formulation” (WP2).
  4. Serve as physico-chemical parameter input for integrated modelling and predictive tools developed in WP4 (PBPK modelling).

http://www.fda.gov/downloads/Drugs/NewsEvents/UCM503769.pdf


 

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