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ECOLE NATIONALE VETERINAIRE T O U L O U S E. Festschrift in honour of Professor Peter Lees PK/PD modelling of NSAIDs in domestic animals The Royal Veterinary College Camden Campus: 22nd July 2010. PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA, ENVT.
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ECOLE NATIONALE VETERINAIRE T O U L O U S E Festschrift in honour of Professor Peter LeesPK/PD modelling of NSAIDs in domestic animalsThe Royal Veterinary College Camden Campus: 22nd July 2010 PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA, ENVT
1795: Rev Edward Stone described the antipyretic properties of the willow 1897 • 1982 Nobel Prize for Medicine for his research on mechanism of action of NSAID (prostaglandins).
Brander & Pugh (1977)No chapter on NSAIDs Originally these drugs (PBZ…) were synthesized in the days of antiseptic surgery as derivatives of phenol which might be capable of exerting internal antisepsis
Veterinary Pharmacology & Therapeutics No chapter on NSAIDs 1982
Historically, aspirin was not (appropriately) used in veterinary medicine • Historically too expansive for large animals • The doses recommended for small animals are too high. • Such recommendations for salicylates were rather constant in veterinary pharmacology handbooks in e.g. Germany, USA, Russia and Spain from 1900 up to the 70’s. • The fallacy of the allometric rule
The fallacy of allometric scaling for Aspirin • Extrapolation from man to animal using the Surface Law and Metabolic Body Weight was popular.
Simple allometry: the log-log transformation Plasma Half-life Y=aBWb Body weight
The fallacy of allometric scaling for Aspirin • The principal reason for this lack of universal applicability is that allometry deals only with size; specifically, it does not address metabolic differences among species.
Half-life (h) Body Weight (KG) A double log plot of salycilate half-life in different species
The Lloyd E. Davis’ paper (1972) • Introduction: “We believed that information relevant to the biotransformation and rates of disappearance from blood of several drugs in a series of large domestic animals might prove of value”
The Lloyd E. Davis’ paper (1972) • Conclusion: “the present data indicate the futility of extrapolating dose and dosage regimens from one species to another, as has been done in the past, in the treatment of domestic animals”
The main limiting factors to conduct PK studies in the late 1970’s • During the 70's, most chemical separations were carried out using paper chromatography and thin-layer chromatography • Only in the late 1970's, reverse phase liquid chromatography allowed for improved separation between very similar compounds
The main limiting factors to conduct PK studies in the late 1970’s • By the 1980's HPLC was commonly used for the separation of chemical compounds. New techniques improved separation, identification, purification and quantification far above the previous techniques.. Improvements in type of columns and thus reproducibility were made as such terms as micro-column, affinity columns, and Fast HPLC began to immerge
The main limiting factors to conduct PK & PK/PD studies in the late 1970’s 1976 1984 1994 Late 70’: Analog computer
Computer: The main limiting factors to conduct PK & PK/PD studies From Lisboa (2003) to Toulouse (2009)
Why to investigate NSAIDS • All domestic species suffer pain and controlling pain is a priority issue for veterinary pharmacologist • Inflammation is a major source of pain • Acute (e.g. infectious) or chronic (e.g. osteoarthritis) • To determine an adequate dosage regimen • Efficacy • Safety • Selectivity (COX1 vs. COX2)
Peter’s work from 1981 to 2010 2009 1982
Lack of allometric relationship for different NSAIDS in domestic species
Condition of the GI tract and oral PBZ absorption The presence of food in the stomach can have a marked and often unpredictable effect on drug absorption 16 Concentration (µg/ml) 12 8 8 4 4 0 8 0 4 12 24h 12 24h Hay at the time of administration and 5 h after Hay 5 h before and at the time of oral administration
The today most cited Peter’s paperand the second most cited RVC paper
PD PK
What is PK/PD modeling? • PK-PD modeling is a scientific tool to quantify, in vivo, thekey PD parameters (efficacy, potency and sensitivity) of a drug, which allows to predict the time course of drug effects under physiological and pathological conditions (intensity and duration)
What is PK/PD modeling? • PK/PD modeling is a versatile tool which is mainly used in veterinary medicine to select rational dosage regimens (dose, dosing interval) for confirmatory clinical testing.
Dose titration Dose Response Black box PK/PD Response surrogate PK PD Dose Plasma concentration
PD PK The determination of an ED50 or any ED% ED50 = ED50 - is a hybrid parameter (PK and PD) - is not a genuine PD drug parameter Clearancextarget EC50 Bioavailability
Full concentration time curve AUC Cmax , Cmin Biomarkers Surrogate Clinical outcomes Measuring variables in PK/PD trials Measuring exposure Measuring response
Biomarker definition • A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention Markers of drug response Markers of disease or physiological function
EC50 in vivo effect EC50action whole blood assay Inhibition of PGE2 production Suppression of lameness Inhibition of COX NSAID plasma concentration Requires 95% PGE2 inhibition EC50 response Which dependent variable for PK/PD modeling ? EC50 response >> EC50 effect
Biomarkers and surrogates in drug development NSAID Drug development Binding affinity Screening Biomarkers COX inhibition Learning Demonstrate the likely chance of efficacy/safety PGs production Internal decision making Local temperature Pain modulation Surrogate Confirming Demonstrate therapeutic response Lameness Registration dossier Field clinicaloutcome Wellbeing/Demeanor
The tissue cage model • PK investigations • Plasma: shallow compartment • Tissue cage: Deep compartment (size effect) • Influence of inflammation on local concentration of NSAIDs • PD investigations
Flunixin plasma, exudate & transudate concentrations after an IV flunixin administration (1.1mg/kg) Exudate Transudate
The tissue cage model • PK investigations • PD investigations • Biological liquids for in vitro assays (transudat, exudates) • Ex vivo investigations (PK/PD integration) • In vivo investigation ( PK/PD modeling)
The tissue cage model: possible in vivo PK/PD modeling using tissue cage as a surrogate of biophase
PK/PD: in vitro vs. in vivo In vivo Response Body Plasma concentration Extrapolation in vitro in vivo Mechanism-based PK/PD In vitro Medium concentration Response Test system