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.

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.

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

• 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.

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

• 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)