* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download What is PK/PD modeling? - Physiologie et Thérapeutique Ecole
Survey
Document related concepts
Pharmaceutical industry wikipedia , lookup
Prescription costs wikipedia , lookup
Toxicodynamics wikipedia , lookup
Drug design wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Discovery and development of cyclooxygenase 2 inhibitors wikipedia , lookup
Drug interaction wikipedia , lookup
Pharmacognosy wikipedia , lookup
Theralizumab wikipedia , lookup
Transcript
ECOLE NATIONALE VETERINAIRE TOULOUSE 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 ECOLE NATIONALE VETERINAIRE TOULOUSE ECOLE NATIONALE VETERINAIRE TOULOUSE ECOLE NATIONALE VETERINAIRE TOULOUSE ECOLE NATIONALE VETERINAIRE TOULOUSE ECOLE NATIONALE VETERINAIRE TOULOUSE 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). Modern history of veterinary NSAIDS: 1971 and beyond 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 Veterinary Pharmacology & Therapeutics (Ninth Ed.) 2009 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 y = 10x 0.6 R2 = 1 plasma clearance Plasma Half-life 1000 100 10 1 0.01 Y=aBWb 0.1 1 Body weight Body weight 10 100 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) A double log plot of salycilate half-life in different species Body Weight (KG) 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 on salicylate (1972) Plasma salicylate 37h T1/2h 8.6h 5.9h 1.0h 0.8h Time 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” PK : Concepts and practice 1977 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 in the early eighties 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 The first Peter’s paper on PK of NSAIDs (1981) 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 Concentration (µg/ml) 16 12 8 8 4 4 0 0 4 8 12 24h Hay at the time of administration and 5 h after 12 24h Hay 5 h before and at the time of oral administration The today most cited Peter’s paper and the second most cited RVC paper PK PD PK/PD modelling of NSAIDs in domestic animals Peter’s first PK/PD paper What is PK/PD modeling? • PK-PD modeling is a scientific tool to quantify, in vivo, the key 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 PK Response PD Dose Plasma concentration surrogate The determination of an ED50 or any ED% PD ED50 = Clearance x target EC50 Bioavailability PK ED50 - is a hybrid parameter (PK and PD) - is not a genuine PD drug parameter What kind of data for PK/PD modeling Measuring variables in PK/PD trials Measuring exposure • Full concentration time curve • AUC • Cmax , Cmin Measuring response • Biomarkers • Surrogate • Clinical outcomes 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 Which dependent variable for PK/PD modeling ? EC50 in vivo effect EC50 action whole blood assay NSAID plasma concentration Inhibition of COX Inhibition of PGE2 production Suppression of lameness Requires 95% PGE2 inhibition EC50 response EC50 response >> EC50 effect Biomarkers and surrogates in drug development NSAID Drug development Binding affinity Screening COX inhibition PGs production Local temperature Pain modulation Lameness Wellbeing/Demeanor Biomarkers Demonstrate the likely chance of efficacy/safety Surrogate Demonstrate therapeutic response Field clinical outcome Learning Internal decision making Confirming Registration dossier Ex Vivo biomarker investigation: The tissue cage model Development of equine models of inflammation (1987) 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 Plasma concentration Body Response Extrapolation in vitro in vivo In vitro Medium concentratio n Test system Mechanismbased PK/PD Response Robenacoxib selectivity 100 % inhibition 80 Fitted COX 1 Fitted COX 2 Observed COX-1 Observed COX-2 60 40 20 0 -20 0.001 0.01 0.1 1 10 CGS 34975 concentration (µM) 100 1000 PK/PD applications 1. in vitro to in vivo extrapolation 2. identify key PD parameters (efficacy, potency, selectivity, affinity…) 3. predict dosage regimen 4. sources (PK or PD) variability in drug response (antibiotics) Application of PK/PD to determine a dosage regimen for NSAIDs PBZ Flunixin Meloxicam Ketoprofen Ketoprofen Tolfenamic acid Meloxicam Coxib Meloxicam Nimesulide Tolfenamic acid COXIB Modeling options regarding presence or not of a delay between PK and PD time development No PK modeling E= Emax x Cobserved EC50 + Cobservedl NO PK modeling PK and PD delay E= Emax x C(t)model EC50 + C(t)model PK origin Effect compartment model PD origin Indirect response model YES Concentration or effect Concentration vs time (C(t)) and effect vs time (E(t)) profiles 3 5 4 2 Effect 5 4 5 (Anticlockwise) 6 3 1 6 2 E(t) t1 t2 hysteresis loop 3 1 C(t) 1 4 6 2 Time delay • Effect lags behind concentration for a given concentration (1) there are 2 possible effects this makes data analysis difficult C(t) Decision tree to select a PK/PD model according to the origin of the delay between the plasma concentration and observed effect. PK or PD Delay? No Yes Plasma concentration Directly incorporated in PD model What is the origin of the delay? PK origin PD origin Effect compartment model Indirect effect model As raw data Semi parametric (spline) From an exponential model The “effect compartment model” Dose effect Time Effect Ke0 Concentration Ce(t) Ce Ke0 Effect(t) Effect Cp(t) Time K10 1:PK model Parametric (Exponential) Non parametric (Spline) 2:Link model Ke0 3:PD model Parametric (Emax, Hill) Non parametric (spline) The “effect compartment model” Flunixin & Ketoprofen in horses K21 Central 1 K10 Peripheral 2 K12 K1e Effect E E0 E max N Ce N EC50N Ce N Ke0 Fig 1: PK/PD model applied to the analysis of biological responses Flunixin plasma, exudate & transudate concentrations after an IV flunixin administration (1.1mg/kg) Exudate Transudate Freund adjuvant arthritis in horse Carpitis Stride length (cm) Concentration (µg/ml) PK / PD: flunixine Time (h) PD parameters for different NSAIDs PD parameters Efficacy Potency Sensitivity Drugs Emax (cm) EC50 (µg/mL) Slope PBZ 13.6 3.6 >5 Flunixin 22.8 0.93 >5 Meloxicam 27.4 0.19 >5 PK/PD: Flunixine Stride length (cm) DOSE mg/kg 1 2 16 8 0.5 0 0 4 8 12 16 20 24 h PK/PD: Phenylbutazone DOSE mg/kg Stride length (cm) 14 1.5 2 12 4 8 1.25 4 Time(h) 1.0 0 0 4 8 12 16 20 24 A new class of PK/PD models Mechanism-based PK/PD modeling in drug discovery PK PD Response Dose Plasma concentration Dose Response Plasma concentration Drug receptor interaction Drug specificity affinity intrinsic efficacy Transduction System specificity Pharmacogenomics 1:Dose titration PK Internal dose production 3:Semimechanistic model PD Disease progression Dose + Plasma Biosignal flux Biophase distribution + - Biosensor process Transduction loss Feedback loop Clinical response Dose Plasma concentration as driving force into PD model Biomarker response Complexity of model 2:Empirical PK/PD model Response Black box Dose The building of PK/PD models • PK model – transforming dose into concentration vs. time profile; • Link model – describing transfer of the drug form plasma into the biophase; • System model – that describes the physiological system or the pathological process on which the drug is acting; • PD model – relating biophase concentration to an effect on the system. • Statistical model – that describes the error component of the model and that is typically estimated in population PK/PD investigations. An example of application of PK/PD to determine a dosage regimen for a NSAID in cat As for a conventional dose titration, PK/PD investigations generally require a relevant experimental model (here a kaolin inflammation model) Possibility to perform PK/PD in patient As for a conventional dose titration, PK/PD investigations require to measure some relevant endpoints • To measure the vertical forces, a corridor of walk is used with a force plate placed in its center. • The cat walks on the force plate on leach. Video Measure of vertical forces exerted on force plate Measure of vertical forces exerted on force plate • The measure of vertical force and video control are recorded Vertical forces (Kg) Video Surrogate endpoints: locomotion tests descending, climbing and creeping time Surrogate endpoint for pain withdrawal time: timer stopped when cat withdraws its paw Measure of pain with analgesiometer • Cat is placed in a Plexiglas box. • A light ray is directed to its paw to create a thermal stimulus. • The time for the cat to withdraw its paw of the ray is measured. Video withdrawal time of the paws (second) 150 1600 100 1400 1200 Pain score (%) 50 1000 0 800 -50 600 Observed response -100 400 Fitted response -150 Observed concentration 200 Meloxicam concentration (ng/mL) PK/PD results: analgesic effect Fitted concentration -200 0 0 4 8 12 16 20 24 28 32 36 Time after meloxicam administration (h) Cn Imax + dR = Kin (1) - Kout R dt IC50n + Cn •Emax/Imax •IC50 •Slope=n Simulated dose-response: Robenacoxib: analgesic effect 100 50 Pain score (%) 0 0.1 mg/kg 0.2 mg/kg 0.3 mg/kg 0.4 mg/kg 0.5 mg/kg 1 mg/kg -50 -100 -150 -200 -250 0 4 8 12 Time (h) 16 20 24 Simulations Robenacoxib: once vs. twice a day Simulated time course of pain 100 90 80 Pain (%) 70 60 50 5 mg/kg 2 x 2.5 mg/kg 5 mg/kg split in 12 40 30 20 10 0 0 4 8 12 16 20 24 Time (h) Mean effect 32 % Mean effect 52 % Mean effect 96 % Others reasons to prefer a PK/PD approach to a classical dosetitration? The separation of PK and PD variability PK/PD variability • Consequence for dosage adjustment PK Dose PD BODY Receptor Effect Plasma concentration Kidney function Liver function ... Clinical covariables • disease severity or duration • pathogens susceptibility (MIC) PK/PD population approach Interindividual pharmacokinetic and pharmacodynamic variability of Nimesulide, Tolfenamic Ac. and Prednisolone Coefficient of variation PK PD Clearance Vss EC50 EC50 antipyretic antiinflamatory Nimesulide Tolfenamic Ac. Prednisolone T. Haake, 1997 17 28 12 20 9.5 15 49 47 62 48 49 The future of the PK/PD modeling Clinical drug development Approval Drug discovery Preclinical drug development Learning Confirming Preclinical PK/PD •Integrated information supporting go/no go decision 1. To acquire basic knowledge on drug 2. Extrapolation from in vitro to in vivo Predicting Clinical PK/PD Population PK/PD • To adjust dosage regimen to different subgroups of animals (age, sex, breed, disease) Predictive PK/PD 3. To be an alternative to dose-titration studies to discover an optimal dosage regimen • Simulations • Trial forecasting CONCLUSION • The aim of veterinary pharmacology is to provide a rational basis for the use of drugs in a clinical setting