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ECOLE NATIONALE VETERINAIRE TOULOUSE Predictive value of PK/PD drug modelling: application to analgesic drugs PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA, ENVT Satellite symposium: Validity and Quality of Animal Models for Measurement of Pain Objectives of the presentation 1. Overview on the concept of PK/PD 2. Predictive value of PK/PD modeling for analgesics 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 are the main practical applications of a PK/PD trial Preclinical investigations: It is an alternative to dose-titration studies to discover a dosage regimen Clinical setting: It is a tool to optimize dosage regimen in a clinical setting (pop PK/PD) 1-An overview on the concept of PK/PD Dose titration Dose Response Black box PK/PD PK Response PD Dose Plasma concentration Why is plasma concentration profile a better explicative (independent) variable than dose for determining a dosage regimen ? Dose vs. plasma concentration profile as independent variable Dose Mass (no biological information) Dose X F% Clearance Time Concentration profile (biological information) Why to prefer a PK/PD approach to a classical dose-titration? 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 The 3 structural PD parameters: Dose titration (DT) vs. PK/PD Emax 1 Emax 1 Emax 2 ED50/EC50 Slope Sensitivity 1 1 2 Emax/2 steep shallow 2 Efficacy 2 ED501 ED502 • Range of useful concentrations Potency • Selectivity Dose Titration Emax ED50 No PK/PD Emax EC50 yes Why to prefer a PK/PD approach to a classical dose-titration? 2.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 • Pain severity or duration PK/PD population approach 2-Predictive value of PK/PD for analgesics Predictive value of PK/PD modeling rely on: 1. The question: – Mechanistic question vs. Clinical drug development 2. Selection of a pain model & In life validation of the selected model 3. Appropriate study design & conduct 4. Appropriate PK & PD data 5. Appropriate PK/PD modeling 6. Population PK/PD (clinical setting) The question: a mechanistic question Drug discovery Questions for a veterinary rational drug development: find an optimal dosage regimen for a target species • What is the typical Dosage regimen • Time information and decision – Onset of drug action: fentanyl vs. morphine – Duration of drug action: time of remedication ( Dosage interval) • Extrapolation – Between species • assumption of the same PD parameters – Within the same species: between route of administration • Assumption: different PK profile but same qualitative metabolic profile • Dosage adjustment – Population investigations 2-Selection of a pain model: experimental pain models vs. clinical pain for PK/PD investigations Pain models For PK/PD investigation Clinical Preclinical Inflammatory Dose determination e.g. NSAIDs pain≠nociception Non Inflammatory Dose determination Opioids Gabapentine Surgical models Possibility to standardize Dose confirmation Spontaneous pain neuropathy Dose adjustment Pop PK/PD Pain model selection for PK/PD investigation: value & validity • Validity: – to be discussed by the pain’ specialist – refers to whether a study is able to scientifically answer the questions it is intended to answer – Regarding the ultimate objective: • To investigate neurophysiologic mechanisms of pain or complicate drug mechanism of action • Preclinical determination of a dosage regimen – Simple but reproducible antinociceptive model are often sufficient – Validityof a model =capacity to find a useful dose • Value: – to be demonstrated by the PK/PD trialist Pain model selection for PK/PD investigation: value & validity • Validity • Value – Ethical – Metrological performances • Reliable • Sensitive • Robust & transferable – Convenience – Etc. Models using pressure noxious stimulus or thermal noxious stimulus are considered as valuable in veterinary medicine to approximate a starting dose Inflammatory pressure noxious stimulus. (here a kaolin inflammation model) Measure of vertical forces exerted on force plate • 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 • The measure of vertical force and video control are recorded Vertical forces (Kg) Video Measure of pain with analgesiometer • The time for the cat to withdraw its paw of the ray is measured. withdrawal time of the paws (second) Sensitive and specific model to activate C-fibers Video Validation of the selected model Validation of the model 1. A priori validation makes sure the method is suitable for its intended use – When developing a new method 2. In life validation (routine validation for any new trial) – – – – Animal selection Investigator skill Reproducibility & repeatability of selected animals etc Validation of the model is tedious Predictive value of PK/PD modeling rely on: 1. The question: 2. Selection of a pain model & In life validation of the selected model 3. Appropriate study design & conduct • Crossover design and placebo period 4. Appropriate PK & PD data 5. Appropriate PK/PD modeling 6. Population PK/PD (clinical setting) 4-Appropriate data for PK/PD modeling Measuring variables in PK/PD trials Measuring drug exposure • Full concentration time curve – experimental setting • Cmax , Cmin – Clinical setting Measuring drug response • Biomarkers • Surrogate • Clinical outcomes Measuring exposure • Generally straightforward. • May be more complicate if: – presence of an active metabolite • Tramadol – Racemates • Profens Tramadol plasma concentration (ng/mL) vs. time (min) after an IM administration of tramadol (circa 8 mg/kg); pharmacokinetics of (±)-trans-T and M1 are stereoselective in vivo •Trans-tramadol [(±)-trans-T] hydrochloride is a chiral compound • (+)-, (-)-Trans-T take as the action mainly through inhibiting the reuptake of serotonin and norepinephrine, respectively •The drug is metabolized in the liver to form five phase I metabolites, with the main pathways (in man and rats) being O-demethylation to Odemethyltramadol (M1) •Among the metabolites, M1 is an only active metabolite, and (+)-M1 has a high affinity to the opioid receptor Substances Action RR-T No action SS-T Monoamine re-uptake µ-opioid RR-M1 SS-M1 Monoamine re-uptake Pharmacodynamic parameters of tramadol in the rat Action Action IC50 (ng/mL) RR-T No action NA SS-T Monoamine re-uptake µ-opioid 230 Monoamine re-uptake 869 RR-M1 SS-M1 20.2 Tramadol and tramadol metabolite M1 concentration (ng/mL) vs. time (min) in 8 dogs after an IM administration of tramadol (circa 8 mg/kg) ; Spaghetti plot; semilogarithmic scale No CYP2D6 in dogs but an ortholog i.e CYP2D15 Plasma concentrations of R- and Sketoprofen after intramuscular administration of ketoprofen ( 6 mg/kg) Concentration ( g/ml) 100 R-ketoprofen S-ketoprofen 10 1 0.1 0.01 0 10 20 Time (h) 30 Time development of the plasma concentration of ketoprofen and the mechanical nociceptive thresholds before kaolin injection (negative control), after kaolin injection (positive control) and after ketoprofen administration R-keto S-Keto Nociception Kaolin EC50 R-keto=2.0±05 µg/mL S-ket=38.8±10.8 T. K. FOSSE et al JVPT in press Measuring variables in PK/PD trials Measuring drug exposure Measuring drug response • Full concentration time curve • AUC • Cmax , Cmin • Biomarkers • Surrogate • Clinical outcomes 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 90% PGE2 inhibition EC50 response EC50 response >> EC50 effect 5-PK/PD modelling 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 Thermal threshold Plasma Fentanyl •No hysteresis for fentanyl •Direct incorporation of plasma fentanyl concentration in an Emax model hysteresis loop ΔT(ºC) IV Oral Buprenorphine concentration Modeling strategies when there is a delay of PK origin The “effect compartment model” Dose effect Time Effect Ke0 Concentration Ce(t) Ke0 Effect(t) Effect Cp(t) Time Ce K10 1:PK model Parametric (Exponential) Non parametric (Spline) 2:Link model Ke0 3:PD model Parametric (Emax, Hill) Non parametric (spline) Estimation of EC50 and Ke0 A mechanistic class of PK/PD models An example of dose determination using a PK/PD modeling approach: Tramadol in dogs Thermal stimulus: time course (h) of the paw withdrawal time expressed as a percentage of the control value Tramadol 8mg/kg 150% 100% Placebo 70% 0 1 2 3 4 5 Time (h) 6 7 8 Data modeling using an indirect effect model Kin is the (control) zeroorder rate constant of the response formation Kout is the first-order rate constant of response disappearance Rate of change of the response (withdrawal time, WT) over time Model of placebo effect Observed and fitted response (WT in sec) vs. time (h) to tramadol after IM administration of tramadol to a dogs . 150% Withdrawal time (%) Tramadol 8mg/kg 100 Placebo 70% 0 1 2 3 4 Time (h) 5 6 7 8 Dose effect relationship for tramadol as predicted by the PK/PD model. 14mg/kg 5mg/kg 1mg/kg Placebo time course of effect from 0 to 4h post administration for different IM doses of tramadol ranging from 1 to 14 µmg/kg Dose effect relationship for tramadol. 0 to 4h Emax=362 (%*h) ED50=4.67mg/kg 0 to 6h Emax=581 (%*h) ED50=9.90mg/kg Doses are from 0 to 14 mg/kg and effects are expressed by the Area Under the Effect vs. time curves (%*h) from 0 to 4 or 0 to 6h post tramadol administration Tramadol: dose-effect Relationship: 7mg/kg IM vs PO IM PO Placebo Predictive value of PK/PD modeling rely on: 1. The question: – Mechanistic question vs. Clinical drug development 2. Selection of a pain model & In life validation of the selected model 3. Appropriate study design & conduct 4. Appropriate PK & PD data 5. Appropriate PK/PD modeling 6. Population PK/PD (clinical setting) 6-Experimental vs. observational population approach Two questions regarding experimental approach • What is its validity (clinical relevance) • What about intersubject variability Dog model “accuracy” Experimental Observational Population • Highly selected (as homogeneous as possible) body weight, sex, age... • Representative of the target population different breed, age, pathological conditions… e.g. Beagle dogs Beagle dogs: strain (colony) effect Some strains are very responsive • Some strains are very resilient Some strains are responsive to pain thermal stimulus while some others are totally unresponsive – (strain raised for toxicology and selected and trained to be as quiet as possible) Dog enrolled in a trial based on their individual reproducibility(<25% over 3 days) Cat model “accuracy” Not selected for experimental purposes Are re-homed after trial completion Experimental pain model “accuracy” • Experimental nociception • Clinical pains – Inflammatory pain – Visceral pain – Muscle and joint pain – Peripheral neuropathy – Central neuropathy – Cancer pain Variability is a biological fact not a noise … What is population PK/PD Goal: • to determine the sources of PK and PD variability in the target animal population as well as the magnitude of that variability, in order to design dosage regimens that account for individual animal (or group) characteristics • to adapt dosage regimen to different subjects of the population having a given characteristic (e.g. breed) Pain subjective assessment (composite measurement of behavioral & physiological signs) • Data analysis – Ordinal (Y/N) or interval scale? • Scoring rating scale – Simple descriptive scale (SDS) – Numerical rating scale (NRS) – Visual analogue scale (VAS) • Issues: – reliability • Confounding factors (hospitalization, anesthetics, drugs given perioperatively (including some antibiotics as aminoglycosides…); unresponsiveness of some species; reproducibility between observers – Validity: • No assessment of the subjective part of pain as for self-reporting in man Probability of pain alleviation (POA) • Logistic regression may be used to link measures of drug exposure to the probability of a clinical success POA Dependent variable 1 1 e a bf through_ conc Placebo effect sensitivity Independent variable (analgesic exposure) 2 parameters: a (placebo effect) & b (slope of the exposure-effect curve) Probability of pain relief: 1.2 Probability of pain relief 1 Slope is controlled by the the intersubject variability, For morphine in man, the slope factor is of 3.6 indicating there is approximately fourfold variability between subjects. 0.8 0.6 0.4 0.2 0 0 50 100 150 200 Analgesic plasma AUC 1 1 e 2.190.03509 AUC In analgesic studies in man, the mean effective concentration (MEC), which is the concentration at time remedication is required, is usually obtained in this manner. PK / PD modeling Conclusions 1. A powerful tool for dose determination and adjustment or mechanistic purposes – If a a clear understanding of theoretical background and computer software. – If appropriate design (placebo) and metrological validation of the different endpoints 2. In preclinical setting, the question of the validity of the selected experimental model holds 3. In clinical setting, there is no longer a “model “ but the main difficulty is the validity (reliability) of the pain assessment