A critical review of PK / TD in preventing toxicity

Table of Contents

A critical review of PK / TD in preventing toxicity

A critical review of PK / TD in preventing toxicity

What is research all about ?

Antibiotic treatments: What does the clinician want ?

What did the textbooks say about antibiotic dosages and schedules in the 70’s ?

What are we going to discuss ?

Aminoglycosides in the 70’s ...

Aminoglycosides monitoring in the 70’s ...

Aminoglycosides toxicity in the 70’s - 80’s ...

Aminoglycoside toxicity is not linked to peak ...

What is the (likely) mechanism of aminoglycoside nephrotoxicity ?...

Aminoglycoside entry in proximal tubular cells is via brush border binding *...

Aminoglycoside accumulation is kidney is saturable at clinically meaningful concentrations * ...

The once-a-day schedule gives less drug accumulation and less renal alterations in rats * ...

Shall you now go to humans ?

Aminoglycoside once-a-day: the philosophy of one of the first PK / TD clinical trials (1985 ...) 

Phospholipiduria can be a surrogate marker of aminoglycoside-induced renal alterations

Pharmacokinetic results (day 7)...

Phospholipiduria (1)

Phospholipiduria (2)

Phospholipiduria: statistical comment ...

Auditory alterations

General conclusions of the first clinical trials … *

But, will once-a-day be effective ?

Aminoglycosidepeak /MIC ratio is predictive of clinical efficacy

How are you going to show that patients will benefit of receiving aminoglycosides once-a-day ?

The worldwide progress of the once-a-day made by clinicians ...

Aminoglycosides in the last 2 years

Is the once-a-day schedule used ? 

Is the once-a-day schedule good for all indications ? 

Once-a-day schedule in febrile neutropenia ... 

Once-a-day schedule in cystic fibrosis ... 

Once-a-day schedule in endocarditis ... 

Once-a-day schedule in peritoneal dialysis ... 

Do we understand aminoglycoside nephro- and oto-toxicity and its relation to dosage ?

Mimicking human clinical dose in animals

Evidence of apoptosis in proximal tubular cells: TUNEL staining

The severity of AG-induced regeneration (top) and apoptosis (bottom) at “clinical doses” varies among derivatives ...

Aminoglycosides inhibit Mrp2 and P-glycoprotein-mediated fluoresecin-labelled methotrexate transport in killifish proximal tubular cells

Most frequent antibiotic-pumps in eucaryotes (1/2)

Most frequent antibiotic-pumps in eucaryotes (2/2)

Mrp2 is inactivated by nephrotoxins throuh Ca2+-induced endothelin release and PKC activation ...

AG and NMDA receptor ...

The macrolides in 5 slides...

Phospholipidosis induced by macrolides… Implication for drug early evaluation ?

Phospholipidosis induced by macrolides… Implication for drug early evaluation ?

Toxicodynamic models for the discovery of cellular alterations induced by macrolides

Toxicodynamic models for the discovery of cellular alterations induced by macrolides

The fluoroquinolones in 3 slides … or evidencing efflux

Evidencing active efflux ...

Evidencing active efflux ...

Active efflux of ciprofloxacin

Now, the ?-lactams

Continuous infusion of ceftazidime in ICU (3 g/day)

PK / PD in action … continuous infusion of ?-lactams: the case of ceftazidime (4g / day) in Intensive Care Units 

PK / PD in action … continuous infusion of ?-lactams: the case of ceftazidime (4g / day) in Intensive Care Units 

But is it safe ? Ceftazidime stability studies … 25°C

But is it safe ? Ceftazidime stability studies … 37°C ...

Degradation products of ceftazidime

Degradation pathways of ceftazidime (24h in aqueous media)

PPT Slide

Toxicodynamics ...

Thanking people … *

Aminoglycosides...

Aminoglycosides... The once-a-day story...

The ?-lactams, the macrolides, the fluoroquinolones, etc...

But ISAP made it all possible … when we were still youngs and serious...

And also when as young but less serious...

And now, en route to the future ...

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