Science Pool

Prediction of drug-induced liver injury (DILI) is challenging. Translation from animals to humans is poor and manifestation of DILI can be complex mechanistically. 

In this poster, we focus on:

• transcriptomics analysis of 128 compounds form the FDA Liver Toxicity Knowledge Base (68 associated with DILI and 60 not associated with DILI)
• the use of machine learning in accurately predicting DILI and providing an insight into the mechanism of toxicity

Read our poster to learn more about our research!

LEARN MORE

Evotec possesses a comprehensive drug discovery platform to support oligonucleotide-based drug discovery from in silico design to clinical translation. Oligonucleotides therapeutics have been emerging as novel therapeutic modality for a vast range of diseases constantly growing resulting in 15 drugs currently approved. Here, we show our ongoing effort to further expand this platform by employing the recently developed splintR-qPCR as a novel bio-analytical method for quantification of oligonucleotides in tissues and comparing it to LC/MS and bDNA in use in Evotec. Within an Evotec internal R&D proof of concept study, the splintR-qPCR was proven as valid and comparable method to bDNA and gold-standard LC/MS. The high sensitivity, throughput and low costs compared to LC/MS and bDNA assay place splintR-qPCR as pivotal method that will strengthen Evotec oligonucleotides expertise on PKPD modelling.

Download our poster here!

The Twin Screw Wet Granulation (TSWG) is a manufacturing process gaining increased attention in the pharmaceutical industry due to its versatility, scalable nature, and seamless integration into continuous manufacturing lines. Especially advantageous in early pharmaceutical development, where API quantity is limited, TSWG accommodates small batch sizes, facilitating later large-scale campaigns using the same equipment. 
A DoE study was conducted in order to assess the influence of the main process parameters on the characteristics of granules and tablets. A leading formulation containing a soluble drug, namely Niacin, was used, and the factors evaluated in the DoE were the screw design, the screw speed, the Liquid/Solid ratio (L/S), the feed rate and the screen type. 
The responses evaluated were referring to the process (e.g. torque), the granules (e.g. particle size distribution (PSD), density and flowability) and the tablets (e.g. tensile strength, friability and disintegration time). This study provides critical insights into optimizing TSWG processes, ensuring efficient granule and tablet outcomes.

Download the poster, which was presented at AAPS PharmSci360 2023, for comprehensive details on the influential process parameters and their impact on granulation and tablet characteristics in TSWG.

Download Now

This text underscores the significance of Orally Dispersible Tablets (ODTs) for enhancing treatment compliance, particularly for patients with swallowing difficulties. Co-processed excipients for fast-disintegrating tablets (CPE-ODT) offer a convenient solution, combining a soluble filler and superdisintegrant. These can be efficiently blended with active ingredients, lubricants, and compressed into tablets, streamlining the development process. Investigating the relationships among compaction stress, compact solid fraction, and mechanical strength is crucial for optimizing tablet composition and speeding up development. Striking a balance between inter-particle bonding strength and porosity is especially vital for ODTs, ensuring rapid disintegration with sufficient mechanical resistance for downstream processes. The study aims to establish a general pre-formulation screening method by generating compressibility, compactibility, and tablettability profiles of CPE-ODTs blended with varying drug amounts. These data offer valuable insights into the impact of drug load on compression behavior and key properties, such as friability and disintegration time, facilitating the efficient development of ODTs.

Download this poster presented at AAPS PharmSci360 2023 for comprehensive details on this formulation screening approach.

Download Now

This poster discusses the development of oral enteric dosage forms as a solution to bypass the acidic stomach environment. Coated hard-shell capsules are more time and cost-efficient in early pharmaceutical development than enteric tablets and pellets. The current study assesses acid-resistance and dissolution rate of not-banded gelatin and HPMC capsules, filled at two weights, and coated with an enteric polymer at four levels. The goal is to determine the minimum enteric polymer needed for gastro-resistance, compare gelatin and HPMC shells in the coating process, and examine the impact of filling level and curing step on dissolution profiles, with fixed coating parameters. This research is important for optimizing the coating process and advancing the understanding of factors influencing gastro-resistance in oral enteric dosage forms.

Download our poster presented at AAPS PharmSci360 2023 for in-depth insights into this critical aspect of pharmaceutical development.

Feel free to make questions to our experts!

Download the Poster Now

While simple combinations of dosage forms expedite access to First-in-human (FIH) studies, the demand for robust formulations and processes challenges quick development, particularly for tablet production. Early clinical phases face hurdles like dose uncertainty and limited active pharmaceutical ingredient availability. The study addresses these challenges by proposing a compressibility assessment method using small-scale experiments. The aim is to establish a pre-formulation screening approach based on compressibility data for active ingredients, utilizing round punches of varying diameters. By employing the smallest tooling, the study achieves a remarkable 75% reduction in the amount of active ingredient required for compressibility analysis.

Download our poster presented at AAPS PharmSci360 2023 to learn more

Download Now

Download

• The genotoxic potential is one of the major risks associated to potential pitfalls in drug development.
• True positive results in the genotoxicity screening observed during the Lead Optimization phase not always represent a showstopper, but need to be carefully characterized.
• In this scenario, the toxicologist could provide a strategy supporting the next IND enabling phase by adopting the most effective risk management to allow the highest success rate possible.
• The process proposed can be adapted to any scenario, and provides data supporting the risk assessment ensuring the lowest attrition and the ethical use of animals.

Download

Read our latest poster on Differentiated transcriptomic signatures detectable in primary human hepatocytes transduced by AAV-based vectors: A potential enabler for in vitro safety profiling.

Download

Hepatic transporter inhibition, mitochondrial dysfunction, and reactive metabolite formation are some of the most common mechanisms associated with intrinsic DILI. The cytochrome P450 (CYP450) superfamily of enzymes play an important role in phase 1 metabolism within the liver. For certain chemical entities, reactive metabolites may form with increased toxicity compared to the parent. These reactive metabolites may result in hepatotoxicity through the formation of reactive oxygen species, DNA damage, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. In our research the pan-specific CYP450 inhibitor, 1-aminobenzotriazole (1-ABT), was used in combination with high-content imaging to evaluate the effects of potential reactive metabolites on cell health parameters in hepatocytes. The endpoint assessed included nuclear features, glutathione (GSH) content, mitochondrial dysfunction, and reactive oxygen species (ROS) formation, as well as cellular ATP content. A calculated fold-shift in cell health features between the plus and minus 1-ABT dosing conditions was used to determine reactive metabolite formation. A panel of known DILI reference compounds associated with the formation of reactive metabolites were assessed through this HCI bioactivation assay within metabolically competent HepaRG cells, primary human hepatocytes (PHH) and primary mouse hepatocyte (PMH).

Download