DMPK and ADME-Tox

 

DMPK (Drug Metabolism and Pharmacokinetics) and ADME-Tox (Absorption, Distribution, Metabolism, Excretion and Toxicity) 

Successful drug discovery requires a deep understanding of biological context coupled with knowledge and experience of the property space required to deliver safe, efficacious drugs; DMPK continues to be a key player in this success since the major sources of attrition – clinical efficacy and safety – are clearly linked to exposure in key tissues either on- or off-target.

Evotec and its wholly owned subsidiary Cyprotex offer a comprehensive and flexible range of in vitro and in vivo DMPK/ADME studies designed to cover the majority of activities in the hit-to-lead and lead optimisation phase through to candidate selection. We also offer in vitro metabolite profiling, structural elucidation and DDI (drug-drug interaction) studies for IND and NDA submissions during pre-clinical development and clinical stage projects.

There is realisation that evaluating toxicology earlier in a project reduces the risk of late-stage failure. As a consequence, human relevant cell-based models are being introduced in drug discovery to address this need. Cyprotex is leading the science in this field and have significant expertise in the latest techniques such as HCS, MEA and 3D cell-based models.

The scientific expertise and processes can be accessed as fee-for-services or as part of partially or fully integrated programmes. DMPK and ADME-Tox support will be provided to our partners in a variety of ways tailored to suit their specific project requirements.

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Synthesis, scale-up and synthetic route development

Integrated drug discovery

Through Evotec, our partners access expertise in a wide range of therapeutic areas. Our fully integrated drug discovery programs allow DMPK/ADME to be aligned seamlessly with chemistry, pharmacology and toxicology testing to reduce cycle time and enable improved decision making.  A combination of a portfolio of routine in vitro assays and the flexibility to address its partners’ requirements through customised solutions enables Evotec to offer a truly bespoke, differentiated service.

Through validated, cost efficient and highly automated processes, our team of experienced DMPK scientists deliver high quality data and works, with you, towards understanding and interpreting data. The estimation of human pharmacokinetic parameters, dose and exposure provides a contemporary framework for multi-parameter optimisation.

Evotec also offers automated, medium and high-throughput assays allowing the profiling of several hundreds of compounds per week against a broad panel of DMPK assays. Tailored packages are designed to address a specific problem associated with a compound, or more frequently, a series of compounds.

DMPK and ADME-Tox services

Cyprotex were acquired by Evotec in December 2016 in order to extend its range of ADME-Tox capabilities. Cyprotex offer a comprehensive range of services to address early stage discovery screening through to later development stage testing.

Quality and efficiency is achieved through the use of state-of-the-art equipment and automated processes

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Capabilities in ADME-Tox and DMPK

Physio-chemical profiling
In vitro metabolism
In vitro permeability and transporters
Protein binding
Bioanalysis and pharmaco-kinetics
In vitro toxicology
Aqueous solubility
CYP and non-CYP reaction phenotyping
Caco-2 permeability
Brain tissue binding
Advanced bioanalytical method development, method transfer and method qualification
Organ specific toxicity models (cardiac, liver, kidney and CNS)
pKa, LogP and LogD
CYP inhibition and non-CYP inhibition
PAMPA
Plasma protein binding and whole blood binding
Pharmacokinetics (PK) services
2D and 3D cell-based models
Cytochrome P450 induction
MDR1-MDCK permeability and MDCK permeability
Blood to plasma ratio
Specialist expertise (HCS, MEA, flow cytometry)
PXR and AhR nuclear receptor activation
P-gp and BCRP inhibition
Mechanistic toxicity (including genotoxicity, phospholipidosis, steatosis, mitochondrial toxicity, phototoxicity)
Time dependent inhibition
P-gp and BCRP substrate identification
Metabolic stability (hepatocytes, microsomes, S9, plasma)
SLC transporter substrate identification (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1A2, OATP2B1, OAT2, OAT4, OCTN2, PEPT1, PEPT2, NTCP)
Metabolite profiling and identification
SLC transporter inhibition (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1A2, OATP2B1, OAT2, OAT4, OCTN2, PEPT1, PEPT2, NTCP)
Hepatic uptake
BSEP inhibition
Microsomal binding
Physio-chemical profiling Aqueous solubility
In vitro metabolism CYP and non-CYP reaction phenotyping
In vitro permeability and transporters Caco-2 permeability
Protein binding Brain tissue binding
Bioanalysis and pharmaco-kinetics Advanced bioanalytical method development, method transfer and method qualification
In vitro toxicology Organ specific toxicity models (cardiac, liver, kidney and CNS)
Physio-chemical profiling pKa, LogP and LogD
In vitro metabolism CYP inhibition and non-CYP inhibition
In vitro permeability and transporters PAMPA
Protein binding Plasma protein binding and whole blood binding
Bioanalysis and pharmaco-kinetics Pharmacokinetics (PK) services
In vitro toxicology 2D and 3D cell-based models
Physio-chemical profiling
In vitro metabolism Cytochrome P450 induction
In vitro permeability and transporters MDR1-MDCK permeability and MDCK permeability
Protein binding Blood to plasma ratio
Bioanalysis and pharmaco-kinetics
In vitro toxicology Specialist expertise (HCS, MEA, flow cytometry)
Physio-chemical profiling
In vitro metabolism PXR and AhR nuclear receptor activation
In vitro permeability and transporters P-gp and BCRP inhibition
Protein binding
Bioanalysis and pharmaco-kinetics
In vitro toxicology Mechanistic toxicity (including genotoxicity, phospholipidosis, steatosis, mitochondrial toxicity, phototoxicity)
Physio-chemical profiling
In vitro metabolism Time dependent inhibition
In vitro permeability and transporters P-gp and BCRP substrate identification
Protein binding
Bioanalysis and pharmaco-kinetics
In vitro toxicology
Physio-chemical profiling
In vitro metabolism Metabolic stability (hepatocytes, microsomes, S9, plasma)
In vitro permeability and transporters SLC transporter substrate identification (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1A2, OATP2B1, OAT2, OAT4, OCTN2, PEPT1, PEPT2, NTCP)
Protein binding
Bioanalysis and pharmaco-kinetics
In vitro toxicology
Physio-chemical profiling
In vitro metabolism Metabolite profiling and identification
In vitro permeability and transporters SLC transporter inhibition (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1A2, OATP2B1, OAT2, OAT4, OCTN2, PEPT1, PEPT2, NTCP)
Protein binding
Bioanalysis and pharmaco-kinetics
In vitro toxicology
Physio-chemical profiling
In vitro metabolism Hepatic uptake
In vitro permeability and transporters BSEP inhibition
Protein binding
Bioanalysis and pharmaco-kinetics
In vitro toxicology
Physio-chemical profiling
In vitro metabolism Microsomal binding
In vitro permeability and transporters
Protein binding
Bioanalysis and pharmaco-kinetics
In vitro toxicology

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Our ADME-Tox services through Cyprotex

In vivo Pharmacokinetics and PK/PD support

Obtaining pharmacokinetic data is a key requirement in the evaluation of new chemical entities providing validation of any in vitro-in vivo extrapolations and an understanding of ADME processes in pre-clinical species which can provide confidence in translation to man and/or highlight key risks. As part of Evotec’s integrated drug discovery platform, in vivo pharmacology studies are also further supported by DMPK and histology.

Capabilities include: 

  • Various administration routes: intravenous (incl. infusion), per os (PO), intra-peritoneal, subcutaneous, intra-cerebrospinal and intramuscular
  • Cassette PK screening of up to 5 compounds simultaneously
  • Different sampling routes: jugular vein cannulation, cardiac puncture, tail vein microsampling, retro-orbital

A range of sensitive techniques are available for sample analysis

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  • Different matrices: blood, plasma, cerebrospinal fluid, tissues, bile, urine and faeces
  • Data analysed with the latest version of Phoenix® WinNonlin® software, using rigorous acceptance criteria
  • Solid state evaluation, salt screening and enhanced formulation for problematic compounds
  • Biomarker development and application within projects
  • Support of pharmacodynamic and efficacy study design

The relationship between concentration-time and response-time profiles varies with different targets and the position of a target in a biological pathway. The team provides analysis and interpretation of pharmacokinetic/pharmacodynamic (PKPD) relationships in support of PD and/or efficacy studies.

We provide simulations from early PK data to assist study design and support translation to man. Early assessments of clinical dose and associated exposure can be explored by thorough evaluation of the relationships between response, concentration and time.

Analysis of biomarkers can also be conducted at Evotec as it can greatly enhance the process; integration of such information in static or ideally dynamic (physiologically-based pharmacokinetic; PBPK) models form the foundation for drug discovery and safety risk assessment.

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In vivo pharmacology

EARLY DRUG FORMULATION TO SUPPORT IN VIVO PK, EFFICACY AND EARLY TOX

Evotec offers a wide variety of formulation and drug delivery strategies to address low drug exposure, the objective being to provide the most appropriate vehicle to conduct in vivo animal studies. Supporting both oral and parenteral routes of administration (IV, SC, IP), our screening platform offers our customers a rapid turnaround and a dedicated formulation approach to maximise exposure potential using optimised quantity of compound.

With more than 250 enabling formulations delivered in the past to support multiple research programmes, our experienced team can recommend the optimal vehicles, selected for their ability to overcome potential solubility and tolerability issues observed in in vivo pre-clinical studies, and in agreement with the dosing volume and the frequency of administrations.

Evotec`s early drug formulation platform includes the following formulation approaches (individually or in combination):

  • Solid form screening such as salt, co-crystal, polymorph, amorphous solid dispersion screenings through a customised robotic 96 well platform
  • Suspension : standard, micronised, nanonised

Evotec provide early drug formulation support for in vivo PK, efficacy and early tox studies

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  • Solutions: aqueous with or without pH adjustment, co-solvent, surfactant, lipid based systems, encapsulation (combined or not)
  • Combination of different approaches (Spring-Parachute, complexing agent etc)
Associated with:
  • In vitro dissolution/re-precipitation animal models implemented to prioritise the formulation options
  • A detailed protocol for formulation preparation and all analytical elements for characterisation with stability data covering at minima the duration of the in vivo study (API dosage by HPLC, chemical and physical stability, particle size distribution and XRPD crystal phase determination of solid in suspension)

Contact us

Evotec

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