Model‐Informed Drug Development for Long‐Acting Injectable Products: Summary of American College of Clinical Pharmacology Symposium

Sharan, Satish; Fang, Lanyan; Lukáčová, Viera; Chen, Xiaomei; Hooker, Andrew C.; Karlsson, Mats O.

doi:10.1002/cpdd.928

Cited by 11 publications

(8 citation statements)

References 53 publications

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“…Moreover, a recent study of Mahdi et al (61) illustrates the use of TCAT™ modeling, in combination with in vitro experiments, to support the choice of the suitable solvent for rifampicin subcutaneous delivery in the treatment of skin tuberculosis. The attempts to use MIDD for the development of long-acting injectables have been summarized in the report of Sharan et al (62).…”

Section: Application Of Pbpk/pbbm Modeling In Formulation Developmentmentioning

confidence: 99%

The emerging role of physiologically-based pharmacokinetic/biopharmaceutics modeling in formulation development

Cvijić¹,

Ignjatović²,

Parojčić³

et al. 2021

Arhiv za farmaciju

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Computer-based (in silico) modeling & simulation tools have been embraced in different fields of pharmaceutics for a variety of applications. Among these, physiologically-based pharmacokinetic/biopharmaceutics modeling (PBPK/PBBM) emerged as a particularly useful tool in formulation development. PBPK/PBBM facilitated strategies have been increasingly evaluated over the past few years, as demonstrated by several reports from the pharmaceutical industry, and a number of research and review papers on this subject. Also, the leading regulatory authorities have recently issued guidance on the use of PBPK modeling in formulation design. In silico PBPK models can comprise different dosing routes (oral, intraoral, parenteral, inhalation, ocular, dermal etc.), although the majority of published examples refer to modeling of oral drugs performance. In order to facilitate the use of PBPK modeling tools, a couple of companies have launched commercially available software such as GastroPlus™, Simcyp™ PBPK Simulator and PK-Sim®. This paper highlights various application fields of PBPK/PBBM modeling, along with the basic principles, advantages and limitations of this approach, and provides relevant examples to demonstrate the practical utility of modeling & simulation tools in different stages of formulation development.

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Section: Application Of Pbpk/pbbm Modeling In Formulation Developmentmentioning

confidence: 99%

The emerging role of physiologically-based pharmacokinetic/biopharmaceutics modeling in formulation development

Cvijić¹,

Ignjatović²,

Parojčić³

et al. 2021

Arhiv za farmaciju

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“…There is currently a growing interest in using LA formulations for the treatment of HIV infection, as indicated by the recent approval of LA cabotegravir, rilpivirine, and lenacapavir 1 . Upon intramuscular or subcutaneous administration, LA formulations form a depot from which the drug is slowly released to keep sustained plasma concentrations for days or months 2 . Patients may benefit from the use of an injectable treatment to reduce confidentiality concerns, avoid pill fatigue, and improve therapy adherence.…”

Section: Introductionmentioning

confidence: 99%

Development of a physiologically‐based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs

Bettonte,

Berton,

Battegay

et al. 2024

CPT Pharmacom & Syst Pharma

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There is growing interest in the use of long‐acting (LA) injectable drugs to improve treatment adherence. However, their long elimination half‐life complicates the conduct of clinical trials. Physiologically‐based pharmacokinetic (PBPK) modeling is a mathematical tool that allows to simulate unknown clinical scenarios for LA formulations. Thus, this work aimed to develop and verify a mechanistic intramuscular PBPK model. The framework describing the release of a LA drug from the depot was developed by including both the physiology of the injection site and the physicochemical properties of the drug. The framework was coded in Matlab® 2020a and implemented in our existing PBPK model for the verification step using clinical data for LA cabotegravir, rilpivirine, and paliperidone. The model was considered verified when the simulations were within twofold of observed data. Furthermore, a local sensitivity analysis was conducted to assess the impact of various factors relevant for the drug release from the depot on pharmacokinetics. The PBPK model was successfully verified since all predictions were within twofold of observed clinical data. Peak concentration, area under the concentration‐time curve, and trough concentration were sensitive to media viscosity, drug solubility, drug density, and diffusion layer thickness. Additionally, inflammation was shown to impact the drug release from the depot. The developed framework correctly described the release and the drug disposition of LA formulations upon intramuscular administration. It can be implemented in PBPK models to address pharmacological questions related to the use of LA formulations.

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“…Currently, marketed LAI products mainly include those for the treatment of chronic conditions, such as antipsychotic drugs, hormonal contraceptives, cancer drugs, etc 1–3 . LAIs pose unique challenges for conducting bioequivalence (BE) studies and thus for development of generic drugs, mainly due to costly and lengthy in vivo BE studies 4 . Model‐integrated evidence (MIE) has been increasingly applied for generic drug development and assessment, especially for complex drug products for which in vivo BE studies are challenging to conduct 5 .…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] LAIs pose unique challenges for conducting bioequivalence (BE) studies and thus for development of generic drugs, mainly due to costly and lengthy in vivo BE studies. 4 Model-integrated evidence (MIE) has been increasingly applied for generic drug development and assessment, especially for complex drug products for which in vivo BE studies are challenging to conduct. 5 MIE has the potential to help overcome the challenges in LAIs (e.g., they can provide more efficient study designs to demonstrate BE).…”

Section: Introductionmentioning

confidence: 99%

Establishing the suitability of model‐integrated evidence to demonstrate bioequivalence for long‐acting injectable and implantable drug products: Summary of workshop

Gong

Zhang

Yoon

et al. 2023

CPT Pharmacom & Syst Pharma

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On November 30, 2021, the US Food and Drug administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop titled “Establishing the Suitability of Model‐Integrated Evidence (MIE) to Demonstrate Bioequivalence for Long‐Acting Injectable and Implantable (LAI) Drug Products.” This workshop brought relevant parties from the industry, academia, and the FDA in the field of modeling and simulation to explore, identify, and recommend best practices on utilizing MIE for bioequivalence (BE) assessment of LAI products. This report summerized presentations and panel discussions for topics including challenges and opportunities in development and assessment of generic LAI products, current status of utilizing MIE, recent research progress of utilizing MIE in generic LAI products, alternative designs for BE studies of LAI products, and model validation/verification strategies associated with different types of MIE approaches.

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Model‐Informed Drug Development for Long‐Acting Injectable Products: Summary of American College of Clinical Pharmacology Symposium

Cited by 11 publications

References 53 publications

The emerging role of physiologically-based pharmacokinetic/biopharmaceutics modeling in formulation development

The emerging role of physiologically-based pharmacokinetic/biopharmaceutics modeling in formulation development

Development of a physiologically‐based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs

Establishing the suitability of model‐integrated evidence to demonstrate bioequivalence for long‐acting injectable and implantable drug products: Summary of workshop

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