Pharmacokinetic

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pharmacokinetic parameters pharmacology half life Vd

Text of Pharmacokinetic

  • www.themegallery.comCompany LogoBioavailabilityDoseDestroyed in gutNotabsorbed Destroyed by gut wallDestroyedby livertosystemiccirculation

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  • www.themegallery.comCompany LogoThe true dose is not the drug swallowed;BUT is the drug available to exert its effect. Dissolution Absorption Survive metabolismMay have a drug with very low bioavailability Dosage form or drug may not dissolve readily Drug may not be readily pass across biological membranes (i.e. be absorbed) Drug may be extensively metabolized during absorption process (first-pass, gut wall, liver)Important component of overall variability Variable bioavailability may produce variable exposureWhy do we care about BIOAVAILABILITY?

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  • www.themegallery.comCompany LogoBoundFreeFreeBoundLOCUS OF ACTIONRECEPTORSTISSUE RESERVOIRSSYSTEMIC CIRCULATIONFree DrugBound DrugABSORPTIONEXCRETIONBIOTRANSFORMATION

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  • www.themegallery.comCompany LogoPlasma concentration vs. time profile of a single dose of a drug ingested orallyPlasma Concentration

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  • www.themegallery.comCompany Logo FACTORS INFLUENCING BIOAVAILABILITY: Three distinct factors are involved to influencing bioavailability. These are:1.Pharmaceutical factors:physicochemical properties of the drug. 1. Particle size 2. Crystalline structure3. Salt formFormulation and manufacturing variables.1.Disintegration and dissolution time2.Pharmaceutical ingredients 3.Special coatings4.Nature and type of dosage form

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  • www.themegallery.comCompany Logo2. Patient related factors:

    Physiologic factors. 1.Variations in pH of GI fluids 2.Gastric emptying rate 3. Intestinal motility 4. Presystemic and first-pass metabolism 5. Age, sex 6. Disease statesInteractions with other substances. 1. Food 2. Fluid volume 3. Other drugs3. Route of administration: 1.Parentral administration 2.Oral administration 3.Rectal administration 4.Topical administration

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  • www.themegallery.comCompany LogoConcept of Half Life life = how much time it takes for blood levels of drug to decrease to half of what it was at equilibriumThere are really two kinds of lifedistribution life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in bodys tissue reservoirselimination life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminatedIt is usually the elimination life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug

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  • www.themegallery.comCompany LogoConcept of Half Life

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  • www.themegallery.comCompany LogoEliminationZero order:constant rate of elimination irrespective of plasma concentration.First order:rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time.Rate of elimination AmountRate of elimination = K x Amount

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  • www.themegallery.comCompany LogoMultiple dosingOn continuous steady administration of a drug, plasma concentration will rise fast at first then more slowly and reach a plateau, where: rate of administration = rate of elimination ie. steady state is reached.Therefore, at steady state:Dose (Rate of Administration) = clearance x plasma conc.OrIf you aim at a target plasma level and you know the clearance, you can calculate the dose required.

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  • Four half lives to reach steady state

    Multiple Dosing:

    Constant Dose and Interval:Cav = D/.CL

    [ D = maintenance dose; = dosing interval ]

  • www.themegallery.comCompany LogoTimePlasma ConcentrationRepeated doses Maintenance doseTherapeutic levelSingle dose Loading dose

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  • www.themegallery.comCompany LogoMultiple Dose AdministrationMinimum and maximum conc should be within therapeutic window depends on dose, frequency and t1/2Depending on dosing frequency and t1/2, accumulation occursDegree of accumulation is important for safety assessment purposesTime (hr)Concentration

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  • www.themegallery.comCompany LogoConstant Rate of Administration (i.v.)

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  • www.themegallery.comCompany LogoLoading DoseDose = Cp(Target) x VD

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  • www.themegallery.comCompany LogoMaintenance Dose Calculation

    Maintenance Dose = CL x CpSSav

    CpSSav is the target average steady state drug concentration

    The units of CL are in L/hr or L/hr/kg

    Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24

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  • www.themegallery.comCompany LogoBioequivalenceA comparison of the bioavailability of two or more drug products.

    Two products or formulations containing the same active ingredient are bioequivalent if their rates and extents of absorption are the same

    Bioequivalence may be demonstrated through in vivo or in vitro test methods, comparative clinical trials, or pharmacodynamic studies

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  • www.themegallery.comCompany LogoBioequivalenceDefinition - CFR 320.1It is the absence of significance difference in the rate and extent to which active ingredient or active moiety in pharmaceutical equivalent or pharmaceutical alternative becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

    Note: BE has a specific definition and regulatory requirements. BE is not the same as the BA

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  • www.themegallery.comCompany LogoFDA Methods to Determine BioequivalenceGeneric drug manufacturers must demonstrate that a drug is bioequivalent to a reference drug productIn order of FDA preference, methods used to define bioequivalencePharmacokinetic studiesPharmacodynamic studiesComparative clinical trialsIn vitro studies

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  • www.themegallery.comCompany LogoFDA Determinations of Bioequivalence

    Main TermsPharmaceutical equivalentsPharmaceutical alternativesTherapeutic equivalentsBioavailabilityBioequivalence

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  • www.themegallery.comCompany LogoPharmaceutical EquivalentsDrug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration

    Equivalent products contain the same amount of ingredient in the same dosage form but may differ in characteristics, such as shape, release mechanisms, and packaging

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  • www.themegallery.comCompany LogoPharmaceutical AlternativesDrug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, are different salts, esters, or complexes of the same moiety, are different dosage forms, or are different strengths

    Other pharmaceutical alternativesDifferent dosage forms and strengths within a single product line by a single manufacturerExtended-release formulations when compared with immediate- or standard-release formulations

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  • www.themegallery.comCompany LogoTherapeutic EquivalentsDrug products are considered therapeutic equivalents if they are all of the followingPharmaceutical equivalentsBioequivalentApproved as safe and effectiveAdequately labeledManufactured in compliance with current Good Manufacturing Practice regulations

    Therapeutic equivalents are expected to have the same clinical effect and safety profile

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  • www.themegallery.comCompany LogoTherapeutic IndexTherapeutic index = toxic dose/effective dose

    This is a measure of a drugs safetyA large number = a wide margin of safetyA small number = a small margin of safety

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    *******ACCESS Medical Group, Ltd.S304 Bioequivalence rev0810/6/03*Bioequivalence.The FDA considers drug products bioequivalent if they are pharmaceutical equivalents whose rate and extent of absorption are not statistically different when the products administered to patients or subjects at the same molar dose under similar experimental conditions.1Bioequivalence may be demonstrated through in vivo or in vitro test methods. An in vitro bioequivalence standard may be used, especially when an in vitro test has been correlated with human in vivo bioavailability data.In addition, bioequivalency may also be demonstrated through comparative clinical trials or pharmacodynamic studies.

    Reference1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.*ACCESS Medical Group, Ltd.S304 Bioequivalence rev0810/6/03*FDA Methods to Determine Bioequivalence.Under the Drug Price Competition and Patent Term Restoration Act of 1984, manufacturers seeking approval to market a generic drug product must submit data demonstrating that the drug product is bioequivalent to the reference (innovator) drug product.1Methods used to define bioequivalence include PK studies, pharmacodynamic (PD) studies, comparative clinical trials, and in vitro studies. The choice of study used is based on the site of action of the drug and the ability of the study design to adequately compare the generic and reference drug products.

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