Transpharmation is committed to improving the success of new drugs by offering translational models and transformative research services. For CNS targeted therapeutics, the disposition of a drug in the brain is a vital factor in understanding its efficacy and safety profile. With a combination of state-of-the-art techniques and extensive CNS development expertise, Transpharmation is able to provide support for critical lead selection and development decisions, thereby helping improve the quality of clinical candidates.

Models

    • Simultaneous collection of brain tissue and plasma from the same animal followed by LC-MS/MS bioanalysis of compound concentrations
    • Brain and plasma free-fraction determination using equilibrium dialysis
    • Useful for early-stage screening and lead selection programs, and can be combined with efficacy or POC studies
    • Industry accepted gold-standard model for determining unbound drug concentrations in specific brain regions over time
    • Combined drug and biomarker assessment enables PK-PD studies to establish robust dose-response profiles
    • In vitro and in vivo parameters are optimized for each compound to ensure accuracy and reliability of results which can be used to support development decisions.
    Quinidine graph (n=4)
    Figure 1. Mean + S.D. (n=4) unbound plasma and brain ECF concentrations of quinidine in Sprague-Dawley rats over time following i.v. administration of a loading dose and constant rate infusion of quinidine.
    Quinidine graph (n=5)
    Figure 2. Mean + S.D. (n=5) unbound plasma and CSF concentrations of quinidine in Sprague-Dawley rats over time following i.v. administration of a loading dose and constant rate infusion of quinidine.
    • ~150 beagle dogs of various ages are available for CSF and plasma sampling studies to evaluate drug delivery and exposure in a clinically relevant non-rodent species
    • Efficacy and safety profiles of new drugs can be further characterized by assessing drug or biomarker levels in CSF and plasma from the same animal over time
    • Aged dogs provide a natural and translational model for various age related conditions such as Alzheimer’s Disease progression, Osteoarthritis and Cancer
    • Collecting serial samples of CSF and plasma via surgically implanted catheters allows the determination of unbound drug delivery into the brain in awake rats
    • Reduced inter-animal variability improves quality and power of data over parallel sampling techniques
    • Studies can be performed in SAGE® ADME knockout rats to investigate how specific drug transporters affect the pharmacokinetics of drugs
    • Data rich study designs have demonstrated predictive validity in characterizing drug delivery into the brain 1
    1. Fan, J. et. al. Drug Metabolism Reviews.44(S1):138-139 (2012)
    • Non-survival sampling of cerebrospinal fluid from the cisterna magna of mice can be used to estimate free drug concentrations in the brain following drug administration
    • Can be combined with brain tissue harvesting and plasma collection to understand differences in drug exposure for CSF, brain and plasma
    • Also useful as an addition to efficacy or POC studies