Exploring ADME Tox: Navigating the Path to Drug Safety

Tom Chan (PhD), Sr Principal Scientist, Boehringer Ingelheim

Characterization of Divergent Metabolic Pathways in Elucidating an Unexpected, Slow-Forming, and Long Half-Life Major Metabolite of Iclepertin

Iclepertin is a glycine transporter inhibitor in Phase III development for the treatment of cognitive impairment associated with schizophrenia. Early metabolite identification studies associated with the first in human studies identified a single major circulating metabolite M530a, which was anticipated from preclinical studies. However, a second major circulating metabolite, M232, was uncovered only after multiple dose studies. This case study emphasizes the potential of missing slow forming and low clearance metabolites based on data from preclinical or single dose clinical studies and how in special cases such as this, a prudent, staged approach to metabolite identification, can help identify these metabolites prior to large-scale clinical trials.

Ritu Singh (PhD), Associate Director (Drug Metabolism & Pharmacokinetics), C4 Therapies

In Vitro Binding Assays to Assess Exposure of Bifunctional Degradation Activating Compounds (or BiDAC Degraders) in the Brain

An important step in the development of drugs targeted for central nervous system (CNS) activity involves the accurate determination of the extent of drug exposure to the brain. We have recently evaluated the TRANSIL Brain Absorption assay, a high-throughput matrix-free method that measures the affinity of drugs to porcine brain membranes to estimate their binding to brain tissue. The fraction unbound in the brain was determined for a few selected compounds using the ultracentrifugation and TRANSIL Brain Absorption methods and the calculated K_p,uu,brain values derived using the two methods were compared. The values derived from the fraction unbound using the TRANSIL Brain Absorption method were relatively higher than those calculated from the ultracentrifugation method. Correlating the unbound brain exposure to pharmacodynamic (PD) effect in vivo for select compounds showed that the PD effect was better explained by brain exposure based on the unbound fraction determined by the TRANSIL Brain Absorption method.

Francesco Rossignolo, Research Expert Discovery DMPK, Evotec

DMPK Developability Assessment in Transition from Discovery to Development

Identifying and progressing drug candidates with the best overall drug safety profile and establishing a well-characterized translational risk profile is key in reducing clinical attrition and costs associated with the development of new drugs. It is now recognized in the pharmaceutical industry that acceptable human PK parameters and minimized drug-drug interactions potential increase the probability of a promising candidate becoming a successful therapy. To support this, the nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) has evolved in recent years from being largely descriptive to a more quantitative and mechanistic understanding of the disposition of the drug candidate towards the optimization and confident prediction of key properties associated with human ADME and PK parameters.
The ONE Evotec organization has designed a framework of activities based on a tiered approach in which in vitro assays and in vivo models are used first for compounds of interest to “flag” potential issues and identify the overall best profile, followed by confirmation of findings in more relevant, or standard regulatory, in vitro and in vivo models.

Sravani Adusumalli (PhD), Associate Principal Scientist, Cyprotex

CYP46A1 Inhibition and Activation: An In Vitro High Throughput Screening Assay to Assess Possible Drug Interactions using FDA Approved Chemical Library

Cytochrome P450 46A1 (CYP46A1) is involved in the metabolism of cholesterol to 24-hydroxy cholesterol in the brain. It is mainly expressed in the brain and to a lesser extent in the endocrine tissues and retina. This enzyme’s inhibition and activation has been studied for therapeutic potential. CYP46A1 has not been extensively studied for drug interactions and evaluating this may provide insight to avoid any potential adverse reactions. We performed rapid and automated high throughput in vitro screening in a 384 well plate format with 2321 FDA approved drugs to identify any potential inhibitors or activators.

Josh Gillum, Senior Director, Evotec

Using Integration to Drive Efficiency and Reduce Risk in Drug Development

Outsourcing drug development in the biotech and pharmaceutical sectors is costly, resource-intensive, and laden with risks. Companies seeking new therapies often adopt a traditional model, engaging multiple vendors for the scientific data required to complete a clinical trial initiation dossier. This places the entire burden of risk and resource provision on the sponsoring company, compounding the complexities and expenses of drug development. Integrating these processes through a partnership-based model can markedly decrease resource allocation and risk, leading to time and cost savings. Additionally, integration enhances adherence to timelines, bolstering credibility with potential investors and the stock market.

Chris Strock (PhD), Vice President US ADMET Operations, Cyprotex

Title: Development of Comprehensive Multiplatform Mechanistic Assays and Tools for Organ Specific Tox Prediction

Abstract: Employing a diverse array of assay platforms and cutting-edge transcriptomics techniques, Cyprotex has crafted an extensive suite of assays tailored for forecasting organ-specific toxicity. Delve deeper into our innovative approach to toxicology prediction, augmented by the integration of Evotec’s renowned PanHunter software for pathway activation analysis, along with the power of Machine Learning for enhanced predictive capabilities.

Jonathan Jackson (PhD), Senior Principal Scientist, Pfizer

Title: Cholestatic Drug Induced Liver Injury: A Function of Bile Salt Export Pump Inhibition and Farnesoid X Receptor Antagonism

Abstract: This study investigated the relationship between the inhibition of the bile salt export pump (BSEP) and the activation of the bile acid (BA) compensatory mechanism in human liver cells. The researchers used two BSEP inhibitors, cyclosporine A (CsA) and troglitazone (Trog), in cultured human hepatocytes. They found that CsA treatment increased intracellular concentrations of bile acids triggering the activation of FXR-target genes resulting in the activation of the bile acid basolateral efflux compensatory mechanism. However, Trog having both BSEP inhibition and FXR antagonist properties prevented the activation of the compensatory mechanism leading to bile acid-induced cytotoxicity. These findings suggested BSEP inhibition initiates a bile acid feedback compensatory mechanism with the primary purpose of decreasing bile acid accumulation to prevent bile acid induced liver damage.

Read the publication here.

Seema Kumar (PhD), Senior Director DMPK, Pioneering Medicines

Drug Disposition Considerations for ADCs

Abstract: Antibody-drug conjugate (ADC) combines the high specificity and long half-life of monoclonal antibodies with the high potency of small-molecule drugs. ADC aims to selectively deliver cytotoxic drugs to targeted tumor tissues, thereby limiting systemic exposure and increasing the therapeutic index of small-molecule drugs. Due to its complex multi-component structure (combining the large and small molecule drug components) and inherently heterogenous nature, ADC poses unique challenges in characterization and understanding of its drug disposition. The talk will highlight some of these challenges.