Biochemical and Molecular ToxicologyENVR 442/TOXC 442/BIOC 442Principles of Toxicokinetics/ToxicodynanicsKim L.R. Brouwer, PharmD, [email protected]; 919-962-7030Pharmacokinetics/Toxicokinetics:the study of the time course of xenobiotic absorption, distribution, metabolism and excretionADME Absorption– how the xenobiotic enters the body Distribution– where the xenobiotic goes in the body Metabolism– what the body does to the xenobiotic Elimination– how the xenobiotic is removed from the bodyPharmacodynamics/Toxicodynamics:the relationship between xenobiotic concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effectsPharmacokinetics/ Pharmacodynamics/Toxicokinetics ToxicodynamicsDosage Regimen/ExposurePlasmaConcen-trationSiteofActionEffects:PharmacologicToxicToxicokinetic/ADME Studies Pharmacokinetics / Bioavailability Mass Balance Tissue Distribution Metabolite Profile Plasma Protein Binding Inhibition / InductionClinical TestingPre-Clinical TestingIn Vitro PK / PDAnimal PK / PDToxicologyPK-Guided DoseEscalationSafetyAssessmentPhase 1Dose/ResponseEfficacyDose SelectionPatientVariablesPop’n PKIn LargeEfficacy TrialsSpecial PopulationsPhase 2Phase 3Bio-EquivalenceGenericsProduct lineextensionPostMarketingTerms used in Pharmacokinetics/Toxicokinetics: Cmax Tmax t 1/2 AUC AUMC Vdss fu Cl MRT MAT F Cmaxmaximum concentration of compound observed in the matrix of interest Tmaxtime of maximum concentration1001000100000 5 10 15 20 25CmaxTimeConcentrationTmax- time of maximum concentration lambda ()terminal elimination rate constant(slope from a semi-log concentration vs time plot) t 1/2half-life: the time it takes for the concentration of the compound to decrease by 50%1001000100000 5 10 15 20 25- slope = t122lnTimeConcentrationThe Half-life isCompound- and Subject-DependentCompound Name t1/2(h)Rosiglitazone Avandia 3-4Lamotrigine Lamictal 25-33Buproprion Wellbutrin 21Fluticasone Flovent n/aParoxetine Paxil 21Data from LexiCompHalf-life Half-life is used to:– Determine the time to reach steady-state (5 x t1/2)– Determine the time to eliminate all the compound from the body (5 t1/2)– Calculate dosing intervals– Determine how much compound accumulates in the body given a fixed dosing interval or exposure Half-life is a secondary pharmacokinetic parameter that is determined by the volume of distribution (V) and clearance (Cl) of the compoundClxVt693.021 AUCarea under the concentration vs time curve ln ConcentrationAUCTimetauln ConcentrationTime AUC 0 = AUC tauSingle DoseMultiple Dose to Steady-StateTimeSteady-state At Steady-State:Rate of input = Rate of elimination AUMCarea under the first moment curve Time * ConcentrationAUMCTimeMean Residence Time (MRT) The average time one molecule resides in the body MRT = AUMC/AUC Used to express overall persistence of compound in the body Clearance (Cl)– volume of fluid (usually blood) from which compound is removed completely per unit time Mathematically: ClDoseAUC Organs that may be involved in clearance:» GI tract» Liver» Kidney» Lungs» Other sites (e.g., blood, skin)Clearances (Cl) are AdditivePharmacokinetic Parameters of GI158104X in DogDosemg/kg/dayClIV(mL/min/kg)Clr(mL/min/kg)9.510 0.7Clother(mL/min/kg)9.3Linear Pharmacokinetics Linear Kinetics = Dose-Proportional kinetics AUC (or concentration) changes proportionally with doseDoseAUCAvandia Package InsertStationary Pharmacokinetics Pharmacokinetic parameters are independent of timePackage insert for Tegretol (carbamazepine)Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initial half-life values range from 25-65 hrs, decreasing to 12-17 hr s on repeated doses. Tegretol is metabolized in the liver. Volume of Distribution at Steady-State (Vdss) a parameter that relates plasma concentration to total mass of compound in the body Mathematically: VdDose AUMCAUCss*2The Volume of Distribution is Compound- and Subject-DependentCompound Name V (L)Rosiglitazone Avandia 18Lamotrigine Lamictal 70Buproprion Wellbutrin 140Fluticasone Flovent 280Paroxetine Paxil 560 Data from LexiComp Fraction Unbound (fu)– fraction of drug that is not bound to plasma proteins– the unbound concentration is in equilibrium between the tissues and bloodBloodTissueBoundDrugUnboundDrugBoundDrugUnboundDrugProtein-Binding Changes May be Clinically Relevant for the Following Types of Compounds and Routes of AdministrationHigh Extraction RatioLow Extraction RatioIV AdministrationHepatic ClearanceYes NoNonhepatic Clearance Yes NoOral AdministrationHepatic Clearance No NoNonhepatic Clearance Yes†No†No drugs from a list of 456 met these criteriaBenet and Hoener, Clin Pharmacol Ther 71:115, 2002Organ Extraction (E)ClearingOrganCinCoutQQDrug EliminationE =Cin- CoutCinWhen Is Protein Binding Important? In vitro ADME/preclinical toxicology studies Scaling pharmacokinetic/pharmacodynamic parameters from animal models to humans Calculating human doses from in vitromeasures of target concentrations Therapeutic drug monitoring of blood/plasma concentrations for drugs with a narrow therapeutic index Bioavailability (F)fraction of the administered dose that reaches the systemic circulation intact0 < F < 1 Mathematically: FAUCAUCDoseDosePOIVIVPO * Relative Bioavailabilityfraction of the dose of a test product that reaches the systemic circulation relative to a reference product Mathematically: FAUCtestAUCrefDoserefDosetest *Bioavailability is an important determinant of pharmacologic response and therapeutic effectivenessEstimation of Oral Bioavailability (F) After an IV and Oral Dose of Compound XDosemg/kg/dayAUCIV1(g*hr/mL)AUCPO1(g*hr/mL)5.06.25 5.9425.032.41mean, n=48.15F0.250.95Factors Responsible for Pooror Variable Oral Bioavailability Physicochemical Factors Physiologic FactorsInfluence of Formulation Factors on the Concentration-Time Profile Formulations with different release rates (absorption kinetics)Time, h0 4 8 12 16 20 24 28 32 36Rosiglitazone Plasma Concentration, ng/mL050100150200CC
View Full Document
Unlocking...