Small Molecules and Biologics: Advanced ADME Strategies & Techniques

Speaker: Brian Ogilvie, PhD, BioIVT

Abstract: Carboxylesterases (CES) represent an important pathway of drug metabolism. However, the striking differences in terms of number of carboxylesterases and tissue distribution make interspecies extrapolation a challenge. Several factors affect biotransformation and efficacy of drugs that are metabolized by CES. CES-mediated clinical drug-drug interactions (DDI) should also be evaluated. The regulatory guidance recommends examining CES-mediated metabolism for drugs that do not undergo significant metabolism by CYP enzymes.

Speaker: Dr. Benoit Cox, Senior Scientist, UCB Biopharma

Abstract: Accurate prediction of drug-induced liver injury and drug clearance in human subjects remain 2 important gaps in preclinical drug development. Advanced human in vitro models with an increasing physiological relevance offer a promising avenue to address these questions. This work describes the development of a human liver-chip by combining 3D models from primary human hepatocytes, microwells and a microfluidic system. The model recapitulates key hepatic functions and proof-of-concept data is presented how the model can be deployed in drug discovery and development.

Speaker: Karissa Cottier, BioIVT

Abstract: Oligonucleotide therapies comprise a growing share of drugs in development due to their improved affinity, selectivity, and duration of action compared to small molecules. Optimization of their use in vitro is needed to facilitate therapeutic lead testing. In these studies, we refine the treatment of siRNA in HEPATOPAC, a long-term co-culture model containing micropatterned primary human hepatocytes. Knockdown and functional endpoints of ADME genes, as well as fatty liver disease-associated genes, were assessed in this model. Together, these demonstrate the utility of HEPATOPAC for generating siRNA mediated isogenic pairs for both ADME and target screening applications.

Speaker: Dr. Grant Churchill, Professor of Chemical Pharmacology, University of Oxford

Abstract: Clinical observations revealed that Tanganil, an over-the-counter drug approved only in France, relieved neurological symptoms in ataxia. Tanganil is a racemate of N-acetyl-leucine. As part of a drug development program by our startup biotech IntraBio, we investigated how acetylated L-leucine was effective but leucine itself was not. Using data and advice from BioIVT, we worked out that acetylation makes leucine a substrate for the monocarboxylate transporter. This combined with other work on the mechanism of action and a successful phase 3 clinical trial makes it likely that the N-acetyl-L-leucine will become an approved drug for rare and common neurological disorders.

Speaker: Marc Lecomte, PhD. Principal Scientist, NCE DMPK, Merck Healthcare KGaA

Abstract: This presentation will focus on drug-drug interactions preclinical studies from different projects at Merck. The presentation will discuss the importance of the study design to avoid producing results which are not fulfilling the goals of the study, in terms of drug-drug interaction assessment (CYP-induction and AOX inhibition in these cases). Dr. Lecomte will also discuss the importance to monitor the test item batches, impurity profile in this case, used when running drug-drug interaction preclinical studies.

Speaker: Maciej Czerwinski, PhD, Director, Consulting at BioIVT

Abstract: Antibody-drug conjugates (ADC) target tumor cells with therapeutic payloads taking advantage of monoclonal antibody (mAb) and differential expression of their antigens. The mAb-linked drug, typically cytotoxic small molecule, can be unconjugated and released into the plasma where it can contribute to drug-drug interaction potential of the ADC. The instability of ADC dictates that both the intact drug-linker-mAb construct, and its small molecule drug component alone, must be considered from the perspective of the ADC safety. Safety properties of the FDA-approved ADC, in nine out of twelve cases emphasized in boxed warnings, and ADME development strategies for ADC are presented.

Dr. Karissa Cottier will review culture techniques and applications for HEPATOPAC plates. The demonstration to include:

• Unpacking a HEPATOPAC kit
  
• Viewing HEPATOPAC islands in a 24-well and 96-well plates
• Changing media in a plate

Scott Heyward will discuss best practices to culture hepatocytes. The demonstration to include:

• Plating techniques
• Viewing plated hepatocytes
• Discussion of the range BioIVT hepatocyte products, characterization and lots

Dr. Michael Voice to discuss applications for BACTOSOMES and other recombinant enzymes in drug discovery programs. He will answer questions and review:

• Species and products available 
• Services including custom synthesis of new recombinant enzymes
• Benefits of BACTOSOMES versus other recombinant enzymes systems, and subcellular fractions

Louise Flower, BioIVT’s clinical site manager in Burgess Hill, UK, will answer your questions and discuss best practices for ethical sourcing of human biospecimens including:

• Considerations for regulatory submissions including:
  • Consent forms and protocols
  • Frequency of regulatory approvals
  • Surgical and postmortem collections
• Challenges of acquiring human biological specimens with special focus on:
  • Postmortem facial tissues
  • Normal brain and heart tissues
  • SSCLC

Dr. Goritsa Rakleova, Scientific & Product Development Manager at Fidelis Research, a BioIVT company, will answer your questions and discuss critical considerations in sourcing fresh tissues for research. She will discuss:

• Overcoming logical challenges to ensure integrity of biospecimens
• Preservation methods to increase the longevity and reliability of samples for future research
• Impact of research priorities on biospecimen availability and associated data
• Considerations for fresh vs. processed tissues
• BioIVT’s capabilities to provide fresh tissues