In Vitro-In Vivo Correlation (IVIVC) Population Modeling for the In Silico Bioequivalence of a Long-Acting Release Formulation of Progesterone.

Elena M Tosca,Paolo Bettica,Maurizio Rocchetti,Giuseppe De Nicolao,Elena Pérez,Jaime Moscoso Del Prado,Conchi Nieto,Paolo Magni

doi:10.3390/pharmaceutics13020255

Elena M Tosca, Paolo Bettica + Show 6 more

Open Access

https://doi.org/10.3390/pharmaceutics13020255

Copy DOI

Abstract

Health authorities carefully evaluate any change in the batch manufacturing process of a drug before and after regulatory approval. In the absence of an adequate in vitro–in vivo correlation (Level A IVIVC), an in vivo bioequivalence (BE) study is frequently required, increasing the cost and time of drug development. This study focused on developing a Level A IVIVC for progesterone vaginal rings (PVRs), a dosage form designed for the continuous delivery in vivo. The pharmacokinetics (PK) of four batches of rings charged with 125, 375, 750 and 1500 mg of progesterone and characterized by different in vitro release rates were evaluated in two clinical studies. In vivo serum concentrations and in vitro release profiles were used to develop a population IVIVC progesterone ring (P-ring) model through a direct differential-equation-based method and a nonlinear-mixed-effect approach. The in vivo release, , was predicted from the in vitro profile through a nonlinear relationship. was used as the input of a compartmental PK model describing the in vivo serum concentration dynamics of progesterone. The proposed IVIVC P-ring model was able to correctly predict the in vivo concentration–time profiles of progesterone starting from the in vitro PVR release profiles. Its internal and external predictability was carefully evaluated considering the FDA acceptance criteria for IVIVC assessment of extended-release oral drugs. Obtained results justified the use of the in vitro release testing in lieu of clinical studies for the BE assessment of any new PVRs batches. Finally, the possible use of the developed population IVIVC model as a simulator of virtual BE trials was explored through a case study.

Highlights

Introduction iationsChanges in the formulation composition, as well as in the batch manufacturing process, equipment, and site, are commonplace during various stages of drug development or after its regulatory approval
in vivo correlation (IVIVC) has been defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between an in vitro property of a dosage form and its in vivo response [3]
The aim of the present work was to establish a Level A IVIVC between the in vitro release of progesterone vaginal rings (PVRs) and the corresponding serum concentration profiles observed during clinical studies

Summary

Introduction

Changes in the formulation composition, as well as in the batch manufacturing process, equipment, and site, are commonplace during various stages of drug development or after its regulatory approval. If one or more of these changes occur, in vivo bioequivalence (BE). Studies in humans are required, increasing the development costs and time to market. An established in vitro–in vivo correlation (IVIVC) could be used to support biowaivers, thereby largely reducing the regulatory burden, leading to time and cost savings [1,2]. IVIVC has been defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between an in vitro property of a dosage form (e.g., drug dissolution or release profile) and its in vivo response (e.g., concentration–time profile) [3]. The Level A IVIVC, defined as a point-to-point relationship

Objectives

Methods

Results

Discussion

Conclusion