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Translational Modeling Strategies for Orally Administered Drug Products: Academic, Industrial and Regulatory Perspectives

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Abstract

During non-clinical and clinical development of a new molecular entity (NME), modeling and simulation (M&S) are routinely used to predict the exposure and pharmacokinetics (PK) of the drug compound in humans. The basic methodology and output are generally understood across all functional disciplines. However, this understanding is mostly restricted to traditional methods such as those in simplified kinetic models and void of adequate mechanistic foundation to address questions beyond the observed clinical data. In the past two decades, alternative and more mechanistic methods, particularly for describing absorption, distribution, excretion and metabolism (ADME) of drugs have been developed and applied under the general umbrella of physiologically-based pharmacokinetic (PBPK) methods. Their mechanistic nature gives the ability to ask many other questions which were not traditionally asked and provide some logically and evidenced-based potential answers. Whilst traditional PK methods are mainstream and understood by most scientists, mechanistic absorption models alongside other PBPK approaches are still deemed eclectic, despite making significant strides in the fundamental science as well as regulatory acceptance. On November 3rd, a short course was held at the annual American Association of Pharmaceutical Scientists (AAPS) meeting in San Antonio, Texas. The different talks were tailored to provide a basis or rationale for the subject, introduction to fundamental principles with historical perspective, a critique of the state-of-the-art, examples of successful application of the methods across different phases of the drug development process and the specific standards these mechanistic models should meet to be fully reliable from a regulatory perspective.

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Abbreviations

AAPS:

American association of pharmaceutical scientists

ADME:

Absorption, distribution, metabolism and excretion

API:

Active pharmaceutical ingredient

AUC:

Area under the curve

BCS:

Biopharmaceutics classification system

BDDCS:

Biopharmaceutics drug disposition classification system

BE:

Bioequivalence

Cmax :

Maximal concentration

CMC:

Chemistry, manufacturing and controls

CMC:

Critical micellar concentration

CRDPS:

Clinically relevant drug product specifications

CYP:

Cytochrome P450

DDI:

Drug-drug interaction

DMPK:

Drug Metabolism and Pharmacokinetics

EMA:

European Medicines Agency

ER:

Extended-release

FaSSIF:

Fated state simulated intestinal fluid

FeSSIF:

Fed state simulated intestinal fluid

HFHC:

High-fat, high-calorie

HFLC:

High-fat, low-calorie

HPβCD:

hydroxypropyl-β-cyclodextrin

IR:

Immediate-release

IVIVC:

In vitro-in vivo correlation

IVIVP:

In vitro-in vivo prediction

IVIVR:

In vitro-in vivo relation

LFLC:

Low-fat, low-calorie

M&S:

Modeling and simulation

MR:

Modified-release

NDA:

New drug approval

NME:

new molecular entity

PBBM:

Physiologically-based biopharmaceutics modeling

PBPK:

Physiologically-based pharmacokinetic(s)

PCDPD:

Patient centric drug product development

PK:

Pharmacokinetics

QbD:

Quality by Design

QC:

Quality control

SmPC:

Summary of product characteristics

U.S. FDA:

United States Food & Drug Administration

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Author information

Authors and Affiliations

  1. Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

    Sandra Suarez-Sharp

  2. Simulations Plus, Inc., 42505 10th Street West, Lancaster, California, USA

    Sandra Suarez-Sharp & Michael B. Bolger

  3. Swedish Medical Products Agency, Uppsala, Sweden

    Anders Lindahl

  4. Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA

    Tycho Heimbach

  5. Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK

    Amin Rostami-Hodjegan

  6. Certara, Princeton, New Jersey, USA

    Amin Rostami-Hodjegan

  7. Janssen Research & Development, LLC, San Diego, California, USA

    Siladitya Ray Chaudhuri

  8. Drug Delivery & Disposition, Department of Pharmaceutical & Pharmacological Sciences, KU Leuven, Herestraat 49, Box 921, Gasthuisberg, 3000, Leuven, Belgium

    Bart Hens

  9. Research Foundation Flanders (FWO-Vlaanderen), Brussels, Belgium

    Bart Hens

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  1. Sandra Suarez-Sharp
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Correspondence to Bart Hens.

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Suarez-Sharp, S., Lindahl, A., Heimbach, T. et al. Translational Modeling Strategies for Orally Administered Drug Products: Academic, Industrial and Regulatory Perspectives. Pharm Res 37, 95 (2020). https://doi.org/10.1007/s11095-020-02814-y

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