In Vivo DMPK

The investigation of distribution to tissues and organs is an essential component to characterize and understand the pharmacokinetic (PK) behavior of a drug and is, thus, part of each non-clinical ADME program. Tissue Distribution/QWBA Quantitative whole body autoradiography (QWBA) is unique in its ability to assess the pattern and time course of drug distribution in a whole body picture. Using QWBA images, radioactive material (unchanged drug and its metabolites) can be visualized and quantified in tissues as well as organ substructures. The data generated may assist in relating adverse events (e.g., from histopathological findings in toxicology studies) to the presence or absence of drug-related material in the relevant tissue. In combination with results obtained from mass balance studies in preclinical species, QWBA distribution data provide input for dosimetry calculations and allow to predict radiological exposure in humans in preparation of radiolabeled mass balance studies (hADME) as required by regulatory authorities. NUVISAN has experience in conducting single and repeated dose QWBA studies with 14C- and 3H-radiolabeled compounds. Our smart and cost effective QWBA designs will evaluate exposure to drug-related material in blood and tissues (including the regional distribution within certain organs) and its elimination rates, localization at the site of action (e.g., dermal, tumor, or blood brain barrier penetration), placenta transfer as well as binding to melanin-containing tissues and structures. AME (Mass Balance, Metabolite Profiling And ID) Radiolabeled absorption, metabolism, and excretion (AME) studies in rodent and non-rodent species are important elements in non-clinical drug development, conducted to investigate the disposition of unchanged drug and total drug-related material (drug and metabolites), i.e., the metabolic fate of a drug. As such, data are crucial for safety and efficacy assessments of drug candidates. As a vital component of regulatory submissions, the main objective of each AME study is the determination of the maximum recovery of the radioactive dose in excreta (urine and feces) and potentially expired air (so called mass balance). Both animal mass balance and QWBA data are required for dosimetry calculations in order to calculate the appropriate radioactive dose in human mass balance (hADME) studies. We have many years of experience in conducting mass balance studies in rodent and non-rodent species. Our studies are set-up according to the 3R principle (replace, reduce, refine) delivering maximum information on your drug candidate while using lean and cost-effective designs. Excretion of radioactivity is analyzed in urine, feces, and - if required - in expired air and bile using liquid scintillation counting (LSC). Blood sampling in mass balance animals is aiming to verify exposure in plasma. Quantification of radioactivity in carcasses (e.g., in case of incomplete mass balance) and/or various tissues can be performed upon request. Our biotransformation team will generate metabolite profiles in virtually all matrices (except expired air) by off-line scintillation counting following chromatographic (UPLC) separation and fraction collection, which allows quantification of radioactive signals even in samples bearing very low levels of radioactivity. The elucidation of metabolite structures is carried out by high resolution mass spectrometry (HR-MS) according to your pre-defined quantitative thresholds in relation to the radioactive dose. Biliary Excretion The investigation of biliary excretion is usually performed as part of the rodent mass balance study using a radiolabeled drug candidate to characterize its excretion pathway and rate. This also includes the detection and identification of metabolites eliminated into bile. Once a substance has been excreted by the liver into bile and subsequently into the intestinal tract, it can be either eliminated from the body via feces or become subject to reabsorption. This process is known as enterohepatic circulation and its extent can profoundly influence the pharmacokinetics of a compound leading to a prolongation of its elimination half-life. The evaluation of such is therefore of particular relevance for safety and/or efficacy. NUVISAN offers designs to investigate hepatobiliary elimination in rodent, both to characterize the excretion pathways and metabolism of a drug candidate and to determine enterohepatic circulation of drug-related material.