Perspectives on the evaluation and adoption of complex in vitro models in drug development: Workshop with the FDA and the pharmaceutical industry (IQ MPS Affiliate).

Complex in vitro models (CIVM) offer the potential to improve pharmaceutical clinical drug attrition due to safety and/ or efficacy concerns. For this technology to have an impact, the establishment of robust characterization and qualifi­cation plans constructed around specific contexts of use (COU) is required. This article covers the output from a workshop between the Food and Drug Administration (FDA) and Innovation and Quality Microphysiological Systems (IQ MPS) Affiliate. The intent of the workshop was to understand how CIVM technologies are currently being applied by pharma­ceutical companies during drug development and are being tested at the FDA through various case studies in order to identify hurdles (real or perceived) to the adoption of microphysiological systems (MPS) technologies, and to address evaluation/qualification pathways for these technologies. Output from the workshop includes the alignment on a working definition of MPS, a detailed description of the eleven CIVM case studies presented at the workshop, in-depth analysis, and key take aways from breakout sessions on ADME (absorption, distribution, metabolism, and excretion), pharmacology, and safety that covered topics such as qualification and performance criteria, species differences and concordance, and how industry can overcome barriers to regulatory submission of CIVM data. In conclusion, IQ MPS Affiliate and FDA scientists were able to build a general consensus on the need for animal CIVMs for preclinical species to better determine species concordance. Furthermore, there was acceptance that CIVM technologies for use in ADME, pharmacology and safety assessment will require qualification, which will vary depending on the specific COU.

Strategies to minimize CNS toxicity: in vitro high-throughput assays and computational modeling.

INTRODUCTION: Healthy functioning of the brain is dependent on the ability of the blood-brain barrier (BBB) and other central nervous system (CNS) barriers to protect the neurocompartments from potential disruptive and damaging xenobiotic agents. In vitro high-throughput (HT) screens and computational models that assess a compound's ability to pass through or disrupt the BBB have become important tools in the identification of new well-tolerated peripheral drugs and safer chemical products such as pesticides. Leveraging these HT in vitro assays and computational BBB tools together with the current understanding of brain penetration may enable the drug discovery community to minimize access of drug candidates into the CNS compartment. AREAS COVERED: This article reviews aspects of the most recent in vitro and computational approaches designed to provide an early assessment of a compound's ability to access the neurocompartment. This article also provides insight into using these tools to identify compounds that have restricted access to the neurocompartment. EXPERT OPINION: The development of safer peripheral-acting medicines and chemical products can be achieved through prospective design and early assessment with HT assays of the BBB in conjunction with computational models. Exclusion or significantly reduced access of a compound to the neurocompartment will increase the odds of identifying a compound with reduced CNS-related adverse drug reactions. A holistic approach to compound design and evaluation that incorporates prospective design principles (e.g., optimization of physicochemical properties), leverages HT in vitro assays and integrates the use of BBB computational models may yield the 'best-in-class' peripherally acting product.

Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.