Combining biorelevant in vitro and in silico tools to investigate the in vivo performance of the amorphous solid dispersion formulation of etravirine in the fed state

Litou, Chara; Turner, David B.; Holmstock, Nico; Ceulemans, Jens; Box, Karl; Kostewicz, Edmund; Kuentz, Martin; Holm, René; Dressman, Jennifer B.

doi:10.1016/j.ejps.2020.105297

Cited by 16 publications

(5 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Litou et al also simulated the plasma profiles of a drug with significant precipitation observed in an in vitro biorelevant dissolution testing (USP Apparatus II). In that study, a simple first order precipitation equation was assumed in a commercial in silico model (Simcyp).…”

Section: Orally Administered Dds Formulationsmentioning

confidence: 99%

“…Furthermore, the effect of phase separation of the ASD formulations in the gastrointestinal fluid on drug permeation in the intestinal epithelium has also been discussed. 10 Litou et al 12 also simulated the plasma profiles of a drug with significant precipitation observed in an in vitro biorelevant dissolution testing (USP Apparatus II). In that study, a simple first order precipitation equation was assumed in a commercial in silico model (Simcyp).…”

Section: Orally Administered Dds Formulationsmentioning

confidence: 99%

See 1 more Smart Citation

In Silico Modeling Approaches Coupled with In Vitro Characterization in Predicting In Vivo Performance of Drug Delivery System Formulations

Kambayashi

2023

Mol. Pharmaceutics

View full text Add to dashboard Cite

Optimization of the in vivo performance of dosage forms in humans is essential in developing not only conventional formulations but also drug delivery system (DDS) formulations. Although animal experiments are still useful for these formulations, in silico approaches have become increasingly important for DDS formulations with regard to species-specific differences in physiology that can affect the in vivo performance of dosage forms between animals and humans. Furthermore, it is also important to couple in vitro characterizations with in silico models to predict in vivo performance in humans precisely. In this review article, I summarized in vitro−in silico approaches to predicting the in vivo performance of oral DDS formulations (amorphous solid dispersions, lipid-based formulations, nanosized formulations, cyclodextrins-based formulations, sustained release products, enteric coat products, and orally disintegrating tablets) and parenteral DDS formulations (cyclodextrins-based formulations, liposomes, and inhaled formulations).

show abstract

Section: Orally Administered Dds Formulationsmentioning

confidence: 99%

Section: Orally Administered Dds Formulationsmentioning

confidence: 99%

In Silico Modeling Approaches Coupled with In Vitro Characterization in Predicting In Vivo Performance of Drug Delivery System Formulations

Kambayashi

2023

Mol. Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…Dissolution experiments in Level II biorelevant media simulating the fasted and / or the fed state have proven more useful compared to the equilibrium solubility of the pure unformulated drug substance for identifying the "effective" solubility, modelling the dissolution experiments and forecasting the in vivo performance of bio-enabling formulations. In particular, two case example formulations were tested i.e., a nanosized [23] formulation of aprepitant and an amorphous solid dispersion (ASD) [24] of etravirine and the conclusions derived were the following:…”

Section: Into Pbpk Modelsmentioning

confidence: 99%

Oral biopharmaceutics tools: recent progress from partnership through the Pharmaceutical Education and Research with Regulatory Links collaboration

O’Dwyer

Box

Dressman

et al. 2021

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

Objectives To summarise key contributions of the Pharmaceutical Education and Research with Regulatory Links (PEARRL) project (2016–2020) to the optimisation of existing and the development of new biopharmaceutics tools for evaluating the in vivo performance of oral drug products during the development of new drugs and at the regulatory level. Key findings Optimised biopharmaceutics tools: Based on new clinical data, the composition of biorelevant media for simulating the fed state conditions in the stomach was simplified. Strategies on how to incorporate biorelevant in vitro data of bio-enabling drug products into physiologically based pharmacokinetic (PBPK) modelling were proposed. Novel in vitro biopharmaceutics tools: Small-scale two-stage biphasic dissolution and dissolution-permeation setups were developed to facilitate understanding of the supersaturation effects and precipitation risks of orally administered drugs. A porcine fasted state simulated intestinal fluid was developed to improve predictions and interpretation of preclinical results using in vitro dissolution studies. Based on new clinical data, recommendations on the design of in vitro methodologies for evaluating the GI drug transfer process in the fed state were suggested. The optimized design of in vivo studies for investigating food effects: A food effect study protocol in the pig model was established which successfully predicted the food-dependent bioavailability of two model compounds. The effect of simulated infant fed state conditions in healthy adults on the oral absorption of model drugs was evaluated versus the fasted state and the fed state conditions, as defined by regulatory agencies for adults. Using PBPK modelling, the extrapolated fasted and infant fed conditions data appeared to be more useful to describe early drug exposure in infants, while extrapolation of data collected under fed state conditions, as defined by regulators for adults, failed to capture in vivo infant drug absorption. Summary Substantial progress has been made in developing an advanced suite of biopharmaceutics tools for streamlining drug formulation screening and supporting regulatory applications. These advances in biopharmaceutics were achieved through networking opportunities and research collaborations provided under the H2020 funded PEARRL project.

show abstract

“…ASDs have been widely used in formulating poorly soluble drugs, and currently, more than 30 commercially available medicines are formulated using the ASD technology. , For these oral dosage forms, dissolution is the prerequisite for satisfactory absorption in the gastrointestinal tract. , However, the dissolution mechanism of ASDs remains elusive, and the dissolution performance depends on many factors related to formulation design and dissolution conditions. Once in contact with dissolution media, the hydrated ASDs may undergo drug crystallization or amorphous–amorphous phase separation while the drug and polymer are dissolving. , At the same time, drug crystallization or liquid–liquid phase separation may also occur spontaneously in the dissolution media that is often time supersaturated .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 For these oral dosage forms, dissolution is the prerequisite for satisfactory absorption in the gastrointestinal tract. 3,4 However, the dissolution mechanism of ASDs remains elusive, and the dissolution performance depends on many factors related to formulation design and dissolution conditions. Once in contact with dissolution media, the hydrated ASDs may undergo drug crystallization or amorphous−amorphous phase separation while the drug and polymer are dissolving.…”

Section: ■ Introductionmentioning

confidence: 99%

Water-Resistant Drug–Polymer Interaction Contributes to the Formation of Nano-Species during the Dissolution of Felodipine Amorphous Solid Dispersions

et al. 2022

View full text Add to dashboard Cite

Drug–polymer interactions are of great importance in amorphous solid dispersion (ASD) formulation for both dissolution performance and physical stability considerations. In this work, three felodipine ASD systems with drug loading ranging from 5 to 20% were prepared using PVP, PVP-VA, or HPMC-AS as the polymer matrix. The amorphization and homogeneity were confirmed by differential scanning calorimetry and powder X-ray diffraction. The intrinsic dissolution behavior of these ASDs was studied in 0.05 M HCl and phosphate-buffered saline (PBS) (pH 6.5). In 0.05 M HCl, PVP-VA ASDs with low drug loading (<15%) showed rapid dissolution accompanied with nano-species generation, while in the PVP system, rapid dissolution and nano-species generation were observed only when drug loading was less than 10%, and HPMC-AS ASDs always released slowly with no nano-species formation. In PBS, PVP-VA ASDs with drug loading less than 10% showed rapid dissolution accompanied with nano-species generation, while for PVP ASDs, rapid dissolution and nano-species generation were observed only when drug loading was 5%. However, 20% drug loading HPMC-AS ASDs exhibited rapid dissolution of felodipine and nano-species generation. When the drug loading was above the transition point of PVP-VA ASDs and PVP ASDs, the release rate was significantly lowered, and no nano-species was generated. To understand this phenomenon, drug–polymer interactions were studied using the melting point depression method and the Flory–Huggins model fitting. The Flory–Huggins interaction parameters (χ) for felodipine/HPMC-AS, felodipine/PVP, and felodipine/PVP-VA were determined to be 0.62 ± 0.07, −0.55 ± 0.20, and −1.02 ± 0.21, respectively, indicating the existence of the strongest attractive molecular interaction between felodipine and PVP-VA, followed by felodipine/PVP, but not in felodipine/HPMC-AS. Furthermore, dynamic vapor sorption further revealed that the molecular interactions between felodipine and PVP or PVP-VA were resistant to water. We concluded that water-resistant drug–polymer interactions in felodipine/polymer systems were responsible for the formation of nano-species, which further facilitated the rapid initial drug dissolution.

show abstract

Combining biorelevant in vitro and in silico tools to investigate the in vivo performance of the amorphous solid dispersion formulation of etravirine in the fed state

Abstract: Combining biorelevant in vitro and in silico tools to investigate the in vivo performance of the amorphous solid dispersion formulation of etravirine in the fed state..

Cited by 16 publications

References 39 publications

In Silico Modeling Approaches Coupled with In Vitro Characterization in Predicting In Vivo Performance of Drug Delivery System Formulations

In Silico Modeling Approaches Coupled with In Vitro Characterization in Predicting In Vivo Performance of Drug Delivery System Formulations

Oral biopharmaceutics tools: recent progress from partnership through the Pharmaceutical Education and Research with Regulatory Links collaboration

Water-Resistant Drug–Polymer Interaction Contributes to the Formation of Nano-Species during the Dissolution of Felodipine Amorphous Solid Dispersions

Contact Info

Product

Resources

About