In vivo DMPK

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Tissue Distribution/QWBA

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.

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.

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.

Milk excretion

Milk excretion studies aid the safety and efficacy assessment of drug candidates that are intended to be used by women of reproductive age and/or lactating women. The data is required to support the planning of human lactation studies and will allow dosimetry of radiation exposure. Our radioactive studies assess the transfer of a drug and/or its metabolites into rat milk (including generation of quantitative profiles of both in milk and plasma) as well as total radioactivity in plasma, blood, and milk.

PK in Genetically Modified Rodents

Genetically modified rodents can be useful models in assessing the in vivo function of drug-metabolizing enzymes and transporters or to overcome species differences in drug metabolism and disposition by using humanized mice. We can conduct DMPK studies in genetically modified mice and rats if required for your drug development program.

Placental Transfer

The use of drugs in pregnancy generally raises concerns regarding potential exposure in the fetus and possible adverse effects through their accumulation in fetal tissues and organs. Whether or not a compound is able to cross the placental barrier is an important assessment from the drug safety package. Such data are typically obtained from QWBA studies using pregnant rodents to determine the potential exposure and risk to the fetus.

Rodent/Non-rodent PK

The understanding of pharmacokinetics (PK) is a prerequisite for the success of a drug candidate. PK data in rodent and non-rodent species shed light on whether or not your compound has appropriate properties to qualify for preclinical pharmacology (efficacy) and safety studies. Our in vivo PK study portfolio offers a wide variety of study designs in various animal species. From assessment of basic PK properties for compound optimization and selection to more complex studies addressing special project needs, our experienced team will find the best approach for your research and drug development program.

By serial collection of microsamples, we can deliver a full PK profile in each individual animal with or without collection of excreta, even in mouse and rat.

Our analytical scientists and laboratory technicians have experience in quantifying analytes in a wide variety of matrices applying mass spectrometry.

 

SPECIES

Mouse, rat, dog, minipig, and genetically modified animals (mouse or rat)

 

DOSING ROUTES

Intravenous (bolus or infusion), oral, subcutaneous, intramuscular, intranasal, intratracheal, intraperitoneal, and topical

 

MATRICES

Blood, plasma, serum, urine, feces, bile, cerebrospinal fluid, broncho-alveolar lavage, and tissues

 

FAST TURNAROUND

We understand the relevance and importance of fast turnaround times in drug discovery for compound optimization and offer a discovery PK business model enabling rapid data delivery within 5 days after dosing.

 

REPORTS
We deliver standardized reports using NUVISAN templates or customized reports according to your specific needs and requirements. Whether it is a format ready to be uploaded into your internal database, an abbreviated or even submission-ready study report, you tell us how you would like to receive your DMPK data.

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(exploratory & GxP)

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Pharmacology

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& Patient Studies

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Supplies

Regulatory
Affairs

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Services

Corporate Project
Management

NUVISAN Overall Services along the Value Chain

API Manufacturig
(Non-GMP / GMP)

Formulation
Development

Pharmaceutical
Analysis

Bioanalysis
(Discovery and Regulated)

Biomarkers
(exploratory & GxP)

Translational
Pharmacology

Healthy Volunteers
& Patient Studies

Clinical Trial
Supplies

Regulatory
Affairs

Backend
Services

Corporate Project
Management