Université catholique de Louvain
Louvain Drug Research Institute > Cellular and Molecular Pharmacology
Clinical evaluation of new therapeutic approaches
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Clinical trials are the ultimate and most critical final step in the development of new drugs and are also essential to rationally improve their use. In this context, our efforts are directed towards the development of optimized therapeutic schemes for antibiotics, based on the knowledge of the pharmacodynamic and pharmacokinetic parameters governing their efficacy and/or toxicity.

These research programs are closely linked to those exploring the antibiotic efflux and permeability resistance mechanisms, the cellular toxicity of antibiotics and the novel antibiotic targets , and from the activities of the 'center for clinical pharmacy'.

> Aminoglycosides once-a-day and nephrotoxicity
> Optimization of beta-lactams
administration
> Optimisation of glycopeptides administration
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Main research programs

The final and the most important aspect in drugs development is their clinical use. Pharmacology and toxicology have therefore an obvious application which is the definition of the proper use of drugs, and their permanent improvement. In this context, we use the knowledge gained by our studies on the pharmacology of antiinfective drugs to design and perform clinical trials directed to these goals. These studies attempt to apply to the clinical environment the concepts of pharmacodynamics and toxicology which were proven useful in our experimental studies. We also set up the necessary monitoring procedures when these require non-routine investigations or developments. In this context, the following clinical evaluations have been or are being performed:

Administration of aminoglycosides in a "once-a-day" schedule and evaluation of renal alterations

This new model of administration was proposed on the basis of experimental studies demonstrating its potential for being more, or at least as effective than the conventional schedules (3 times a day), while causing less toxic reactions. The lower toxicity stems from the saturable character of aminoglycoside uptake by target tissues (kidney, inner ear). Moreover, the toxicity induced by aminoglycosides proceeds by successive thresholds from recoverable alterations towards irreversible damage. Keeping the level of alterations below a critical threshold results therefore in an effective protection of the patient.
 
Our laboratory was a pioneer in the demonstration of administering aminoglycoside once-a-day. In particular, we developed an assay applicable in the clinic for the early and non invasive detection of aminoglycoside nephrotoxicity. It consists in measuring urinary phospholipidsas an hallmark of early leasions induced in the kidney cortex (phospholipidosis; see further details in the section on cellular toxicity). Results show that phospholipiduria is a useful marker of impending toxicity in correlation with the duration and extent of treatment (Figure 1). It is also a useful monitoring criteria for assessing the safety of new schedules. It can also be used experimentally to assess the effectiveness of nephroprotectants.

This once-a-day schedule of administration was successfully tested in several patient populations and is now introduced in a large number of applications of these drugs.

Figure 1


Phospholipiduria as an early indicator of aminoglycoside-induced nephrotoxicity. The figure compares the level of urinary phospholipids in cancer patients receiving 6 mg/kg netilmicin daily  as a single injection (qd) or divided in 3 injections over each 24 h period (tid) during 7 days. 

Phospholipiduria rises steadily during the treatment period, but returns to normal values within 5 days of treatment discontinuation.

Despite the fact that the interindividual variations are important, it clearly appears that the tid administration causes a more rapid and elevated phospholipidurva than the qd administration. The rise caused by tid treatment shows also a slower reversibility

From Van der Auwera et al, 1991
 

In parallel, experimental and clinical studies have been initiated to develop the use of apoptosis markers for the study of aminoglycoside-induced toxicity.

Selected References (by reverse chronological order; for a full reference list, see our publication list)

Evaluation of beta-lactam antibiotics in special applications in relation with their pharmacodynamic properties

In contrast with aminoglycosides, beta-lactam antibiotics must be administered several times a day, because their serum concentration must ideally remain above the MIC of the offending organisms for the whole period of treatment. While this can be easily achieved in simple applications for these drugs, little is known concerning this aspect in special situations where pharmacokinetic parameters can vary largely from what is observed in 'normal' patients. In this context, we have examined the stability of beta-lactams in their conditions of use over time in order to define in which conditions they can be used for continuous infusion (stability over time and at increasing temperatures [To comply with the European Pharmacopoeia, beta-lactam solutions should always contain at least 90% of intact molecule]; compatibility with other drugs in solutions of perfusion).

beta-lactam concentration time during which the drug remains stable (> 90 % recovery) at 25°C
imipenem
0.8 %
3.5 h
meropenem
1 %
24 h
4 %
12 h
6.4 %
< 6 h
doripenem
1 %
24 h
4 %
> 18 h
6.4 %
< 6 h
piperacillin
13 %
> 24 h
temocillin
8 %
24 h
ceftazidime
12 %
24 h
cefepime
12 %
> 24 h
aztrenam
10 %
> 24 h

We are now evaluating the pharmacokinetics and pharmacodynamics of beta-lactams in specific populations (intensive care, hemodialysis, pediatrics, e.g). in order to propose optimal dosages. In the frame of a FP7 European project, we are also developing a point-of-care approach consisting of an integrated diagnostic tool allowing to measure in real time the free fraction of beta-lactams and proposing dose adjustments based on pharmacodynamic algorithms in order to optimize the chance of therapeutic success while at the same time reducing the risk of selecting resistance

Selected References (by reverse chronological order; for a full reference list, see our publication list)

 Evaluation of vancomycin administration by continuous infusion

For glycopeptides like vancomycin, efficacy is best predicted by the ratio between the Area-Under-the-concentration-Curve (AUC) and the MIC of the offending organism. Optimisation of AUC can be easily achieved using continuous infusion. This mode of administration facilitates therapeutic monitoring and allows for rapid readjustement of dosage to achieve the target concentration. We have evaluated the feasibility of continuous infusion of vancomycin in the clinics by following the serum levels (both total and free drug). We have examined whether the dose selected allowed to reach the pharmacodynamic target (AUC/MIC > 400) taking into account the MIC of the bacteria isolated in these patients. We found a high variability in serum levels and in vancomycin free fractions among patients, suggesting the importance of monitoring serum levels and adapting doses in fonction of the MIC of the isolated pathogen.

Figure 2

Left: mean serum level of vancomycin in 54 patients treated by continuous infusion, with daily readjustement of doses based on therapeutic monitoring. The yellow zone highlights the target concentration. The red arrow points to the fact that 48h are needed to adjust the infusion rate so as to reach the target level.

Right: pharmacodynamic assessment. Patients are categorized according to the AUC/MIC ratio calculated based on pharmacokinetic and microbiological data. The graph shows that reaching the pharmacodynamic target (AUC/MIC > 400) is unlikely in patients infected by bacteria with MIC > 2 mg/L

From Ampe et al., 2013

Selected References (by reverse chronological order; for a full reference list, see our publication list)

Expertises

Additional information:  <tulkens@facm.ucl.ac.be>
Last significant update: May 2016