Postdoc - Postdoctoral Research Fellow - Establishing a Translational Framework for the Preclinical
AbbVie is a global, research-based biopharmaceutical company with a mission to use expertise of dedicated people and unique approach to innovation and to develop advanced therapies that address some of the world's most complex and serious diseases. The Postdoctoral Program is designed for true investigational and experimental research. Participants will be mentored by renowned industry scientists and collaborators at AbbVie and focused on delivering cutting-edge advancements in discovery, development new treatment modalities. The enriching training program offers a balance of structured learning and work experience which fosters a learning environment to advance individual development with accessibility to high-level knowledge building across the drug development continuum.
To be successful, we need outstanding individuals willing to challenge themselves to find the best solutions for our patients. The AbbVie Postdoctoral Program is one way we are doing just that.
Through our Postdoctoral Program, we are hiring postdocs from key academic institutions for preferred areas of science in the U.S., while providing a unique opportunity for participants to build a solid career foundation in the pharmaceutical industry while building the AbbVie brand as an employer of choice for scientific talent. Participants in the Postdoctoral Program play an integral part in our continued success and will help us to further grow as a leader in our industry. The successful candidate will conduct novel and impactful research over a 2-3-year period. High-impact publications and presentations at scientific meetings are expected outcomes along with the opportunity to gain valuable experience working within a top-tier biopharmaceutical company. This assignment is expected to be for two years minimally and no more than three years.
Prodrug Post-doc: Project Overview and Aim
Prodrug development is a common strategy in the pharmaceutical industry for addressing poor physicochemical properties or to achieve product profile for an active moiety. Numerous in vitro approaches and matrices exist for the characterization of prodrug conversion, however, there is currently no guidance on best practice for the translation of in vitro and preclinical data to human, especially with respect to phosphate prodrugs. Significant prodrug conversion during manufacturing and storage prior to administration tend to be a liability for phosphate prodrugs and therefore mechanistic understanding of underlying pathways can be highly beneficial at compound selection stage.
The aim of this project is to assess predictivity of in vitro conversion in various matrices to preclinical and, as an extension, human bioavailability and to establish an in vitro-in vivo correlation. Furthermore, a secondary aim of this work would be to evaluate activity of phosphatases in different segments of the gut and establish relative activity factors (RAFs) across in vitro systems and animal and human intestinal tissue segments, which can be utilized in mechanistic PK models to scale enzyme kinetics of prodrug conversion. Established correlations can then be verified using various in-house prodrugs, as well as, model compounds. These predictive tools can also be leveraged to assess prodrug conversations prior to administration.
Specific aims will include:
1. Evaluation and optimization of in vitro systems for prediction of in vivo performance of a prodrug
+ Assess the translatability of in vitro bioconversion in various systems (including, but not limited to plasma, intestinal microsomes, intestinal mucosa and liver microsomes) to preclinical bioavailability by evaluating in vitro-in vivo correlation (IVIVc) between various enzymes systems and bioavailability in preclinical species
+ Once IVIVc is established in preclinical species, evaluate IVIVc with human bioavailability for the selected system(s) using model compounds (phosphate prodrugs)
2. Collect and incorporate solution and solid-state prodrug stability data under CMC relevant conditions into the prodrug conversion models developed herein. The applicability of the resulting models would then be broadened to provide a resource-sparing read on prodrug conversion liability prior to administration.
+ Evaluate correlation between stability measures and bioconversion to develop guidelines of a risk matrix to inform discovery teams.
3. Translation of in vitro bioconversion kinetics to human.
+ Compare activity of phosphatases in segments of gut tissue of preclinical species and human – determine which species are more representative of human and evaluate inter-species variability.
+ Establish relative activity factors (RAFs) for different GI segments in different species, which can be used to scale in vitro phosphatase bioconversion to in vivo.
+ Verify RAFs using model phosphate prodrugs with available clinical data.
4. Propose a best-practice approach for the characterization (i.e. most in vivo predictive in vitro system(s)) and translation (in silico) of prodrug bioconversion and bioavailability that would replace regular PK studies and enable prioritization of successful prodrugs for tox assessment and clinical development. (potential for publication)
Note: Improved triaging based on the findings of this research would ideally reduce the number of compounds moving to PCS and PRD for characterization.
* Successful completion and defense of a PhD in biochemistry, pharmaceutics, pharmacokinetics or physiology-based pharmacokinetic modeling and simulation (PBPK) with a demonstrated interest in drug development research. Minimum graduate school GPA 3.0; 3.5 preferred. Graduate of accredited and nationally ranked university.
* Record of publication of at least two high-quality papers in a prestigious top-tier review journal(s) preferably with prodrug, gut physiology and physiology-based modeling (PBPK) research focus.
* Excellent problem-solving skills including critical and analytical thinking.
* Excellent communication, leadership, and project management skills.
* Demonstrated scientific writing skills and strong verbal communication skills.
* Demonstrated ability to independently design and execute experiments, interpret data, and identify appropriate follow-up strategies.
* Proven track record of teamwork, adaptability, innovation, initiative, and integrity. Global mindset to thrive in a diverse culture and environment.
* Ability to multitask and work within timelines.
* Work authorization in the United States
* Basic familiarity with drug distribution, pharmacokinetics, metabolism, and translational sciences.
* Provide three letters of recommendation from thesis advisor and thesis committee members
Key Leadership Competencies:
* Builds strong relationships with peers and cross functionally with partners outside of the immediate team to enable higher performance
* Learns fast, grasps the "essence" and can change course quickly where indicated
* Raises the bar and is never satisfied with the status quo
* Creates a learning environment, open to suggestions and experimentation to drive the science in the field of interest
* Embraces the ideas of others, nurtures innovation and manages innovation to reality
* For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook or LinkedIn. At AbbVie,