Pharmacological evaluation of drugs covers complementary aspects, going from experimental pharmacology to optimization of drug usage in clinical practice via a characterization of patient's specificities that could affect pharmacokinetics or pharmacodynamics (clinical pharmacology).
In this context, we conduct bidirectional translational research, from bench to bedside and back again, in the field of experimental, clinical pharmacology and pharmacoepidemiology, with the aim to optimizing drug treatment.
Our common objectives are to use a deep knowledge of the molecular basis of drug action and fate (at both the cellular and the human levels) to achieve personalized pharmacokinetic and pharmacodynamic targets and implement these findings for improving quality of care. Our research focuses on high-risk medications (drugs with a narrow therapeutic window or used for severe pathologies) and/or high-risk populations (frail, immunosuppressed, or polymedicated patients).
The main disciplines that are covered include:
- in the field of experimental research: biophysics and molecular pharmacology, in vitro pharmacokinetics and pharmacodynamis
- in the field of clinical research: population pharmacokinetics and pharmacodynamics;
- in the field of clinical practice research: evaluative and implementation research, an pharmacoepidemiology.
Within TFAR, principal investigators are more specifically experts in one of these three disciplines: FACM (cellular and molecular pharmacology group; Marie-Paule Mingeot-Leclercq and Françoise Van Bambeke) is mainly oriented towards experimental research; PMGK (integrated pharmacometrics, pharmacogenomics and pharmacokinetic group; Laure Elens) towards clinical research; and CLIP (clinical pharmacy research group; Olivia Dalleur, Séverine Henrard and Anne Spinewine), towards clinical practice and implementation research.
Some activities are unavoidably independent, but there is a clear willingness of cross-fertilization amongst us, which is operationalized through the organization of common seminars, co-supervision of translational PhD projects, submission of common grant applications and sharing logistic and technical infrastructure.
Examples of recent and ongoing translational research
The number of translational research projects within TFAR has increased over the last 5 years. In 2019, there were several ongoing projects implying eight PhD students that illustrate the type of integrative approaches existing between the groups:
Pharmacokinetics and clinical toxicity of anti-infective drugs in specific patient populations such as patients in intensive care, HIV infected, hemodialysis patients, patients with off-label use of antibiotics (H Thirot, P Ngougni Pokem, A Bastos, G. Stillemans)
- Evaluating current practices of antibioprophylaxis in Benin to propose and then implement and evaluate strategies for a better use (AD Fiogbe, C Yehouenou, A. Dohou).
- Precision pharmacotherapy of neuroleptics in schizophrenic patients (J. Lagreula).
Biophysics and molecular pharmacology
The objective is to characterize at the molecular level the interaction between drugs and cells or their constituents, in order to unravel the mechanisms responsible for their pharmacological activity or cellular toxicity. Special emphasis is put on drugs:
1. interacting with membrane lipids, considered as novel targets for antibiotics or antitumoral therapies;
2. accumulating within the cells, in order to characterize the molecular cascades leading to cell toxicity.
This fundamental research (mainly performed in FACM) is closely connected to more applied investigations on pharmacokinetics and pharmacodynamics that make use of the evidenced concepts to elaborate and evaluate innovative therapeutic strategies.
In vitro pharmacokinetics and pharmacodynamics
The objective is to identify and to describe the pharmacokinetic and pharmacodynamic aspects that can affect drug activity, considering both the factors modulating drug bioavailability at the site of action and the influence of the environment on drug activity. More specifically,
- Cellular pharmacokinetic studies examine the accumulation, subcellular distribution, metabolism and active efflux of drugs like antibiotics (FACM) or immuno-suppressants and anticoagulants (PMGK), and explore how specific genetic polymorphisms of cytochromes and efflux transporters can modulate the oxidative metabolism or the cellular transport of these drugs (PMGK).
- In vitro pharmacodynamic studies in FACM are focused on models of persistent bacterial infections (intracellular survival, biofilms), trying to define the reasons for antibiotic failure and evaluating novel therapeutic strategies.
This research serves as a rational basis for clinical applications to be tested using pharmacometric approaches and may help rationalizing reasons for therapeutic failure or success in the clinics.
Population pharmacokinetics and pharmacometrics
Pharmacometrics focuses on quantifying variability in pharmacotherapy and considers the complex interaction between genetics, physiology, pharmacology and pharmacokinetics. In our group, this thematic covers multiple fields of complementary expertises essential for the understanding of the fate of xenobiotics administered in humans (in vitro and in vivo pharmacokinetics, pharmacodynamics, population pharmacokinetics, pharmaco-genomics and PK-PD relationships). More specifically, our approaches integrate the study of drug metabolism and active transport as well as modelling and Monte Carlo simulations. Current applications include antibiotics (FACM), immune-suppressants and anticoagulants (PMGK), with the objective of elucidating the determinants of therapeutic responses.Combining these approaches with experimental research help to elucidate mechanisms underlying clinical findings and facilitates the achievement of new discoveries through explorative investigations.
Drug optimisation in clinical practice
‘Implementation’ involves translating results from clinical research into everyday clinical practice and healthcare decision making. It seeks to improve quality of healthcare through the implementation of various interventions. The intent of this research is to understand what, why, and how ‘interventions’ work in real world settings and to test approaches to optimize them. ‘Interventions’, in this case, refer to medications and to various processes related to the use of medications and patient safety. Research in clinical pharmacy (CLIP) therefore aims at evaluating the quality of use of medicines in clinical practice, to better understand the determinants of this quality and to evaluate the impact of specific approaches for optimisation on patient safety. Translational research “from bench to bedside and back again” mainly benefits the research work focusing on specific medications such as antibiotics (FACM) and anticoagulants (PMGK), in both the acute care and ambulatory care settings. We use both quantitative research ([quasi]-experimental studies such as randomised controlled trials, cohort studies, surveys,…) and qualitative studies (interviews, focus groups, observations). The approaches for optimisation tested encompass education and training, multidisciplinary teamwork (including working with clinical pharmacists), patient empowerment, audit and feedback, use of protocols,…
⇒Better defining the positioning of the ß-lactam temocillin in our therapeutic arsenal, by evaluating its activity against clinical isolates, and determining its PK profile in specific patient populations in order to propose PK/PD breakpoints and optimal dosages in the clinics based on Monte-Carlo simulations.
⇒Determining the risk factors for adverse events in patients taking direct oral anticoagulants, including inappropriate use but also individual variations in pharmacokinetics, including those related to genetic polymorphisms.