Pharmaco Elimination

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    PHARMACOKINETI

    CS &PHARMACODYNAM

    ICS

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    PHARMACOKINETICS &PHARMACODYNAMICS

    Pharmacokinetics - all processes thatcontribute to the time course of drugconcentrations in various body fluids,generally blood or plasma, that is, allprocesses affecting drug absorption,

    distribution, metabolism, and excretion.Pharmacodynamics characterizes theeffect intensity and/or toxicity resulting fromcertain drug concentrations at the assumedeffect site.Simplified, pharmacokinetics characterizeswhat the body does to the drug , whereaspharmacodynamics assesses what thedrug does to the body

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    PK/PD MODELING AS COMBINATIONOF THE CLASSICPHARMACOLOGICAL DISCIPLINES

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    PHARMOCOKINETICS OF PEPTIDES & PROTEINS

    Traditional pharmocokinetic principles-applicable for peptides & proteinsPeptides- having hormone activity usuallyhave short elimination half-lives, which is

    desireable for close regulation of theirendogenous levels & thus function.But transport proteins likealbumin/antibodies having several dayselimination half-lives ensures continuousmaintenance of necessary conc. in theblood stream.

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    ABSORPTIONClinically usable absorption of exogenously

    applied peptides & proteins after oral applicationwith conventional dosage forms is not present.Lack of systemic availability- caused by 2factors:High gastrointestinal enzyme activity &

    function of gastrointestinal mucosa as absorptionbarrier.Lack of activity after oral admin for mostpeptides & proteins resulted in the past

    The utilization of non-oral admin pathways-nasal, buccal, rectal, vaginal, pulmonary drugdelivery.Absorption rate constant- combination of absorption into systemic circulation &

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    DISTRIBUTION Whole body distribution studies- for classical

    small- molecule drugs in order to excludetissue accumulation of potentially toxicmetabolites.

    Biodistribution studies for peptides &proteins are primarily performed to accesstargeting to specific tissues as well as toidentify the major elimination organs.

    Volume of distribution of proteins is usuallysmall & limited to the volume of extracellularspace because of their high molecular weight&the related limited mobility .

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    After intravenous application, peptides andproteins usually follow a biexponential

    plasma concentrationtime profile that canbest be described by a two-compartmentpharmacokinetic model.For eg: leuprorelin, a synthetic agonist analog

    of luteinizing hormone-releasing hormone(LHRH) or clenoliximab, a macaquehumanchimeric monoclonal antibody specific to theCD4molecule on the surface of T-lymphocytes, and for AJW200, a humanizedmonoclonal antibody to von Willebrand factor.

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    PROTEIN BINDINGOnly free, unbound fraction of a drug

    substance is accessible to distribution &elimination processes as well as interactionswith its target structure at the site of action.

    They frequently interacting with specificbinding proteins that are involved in theirtransport & regulation & binding proteinsmay enable or facilitate cellular uptakeprocesses, thus affect pharmacodynamics.Eg: IGF-1 (insulin-like growth factor), t-PA,interleukin-2, somatotropin.

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    IGF-1, with one binding at least 95%of IGF-1 in plasmaBinding affinity higher than IGFreceptor- reservoir function thatprotects the body from insulin-like

    hypoglycemia.Elimination half-life

    bound IGF-1 is significantly longer

    than for free IGF-1, since only theunbound IGF-1 is accessible toelimination via glomerular filtration

    or peritubular extraction

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    Somatotropin- at least two binding

    proteins in plasma.Protein binding substantially reduceselimination - smaller clearance of total compared to free somatotropin,& also decreases its activity viareduction of receptor interactions.Peptides & proteins -nonspecificallybound to plasma proteins.

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    ELIMINATION Non metabolic pathway- renal or biliary

    excretion are negligible for most peptides &proteins. If biliary excretion occurs- subsequent

    metabolism of these compounds in thegastrointestinal tract.

    Elimination- unspecifically everywhere in thebody or can be limited to a specific organ or

    tissue. Locations of intensive peptide & protein

    metabolism are liver, kidneys,gastrointestinal tissue & other body tissues.

    Molecular weight determines the major

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    PROTEOLYSIS

    Proteolytic enzymes- proteases & peptidasesare available throughout the body (in blood, invascular endothelium, cell membrane).While peptidases & proteases in the

    gastrointestinal tract & in lysosomes arerelatively unspecific, soluble peptidases in theinterstitial space & exopeptidases on the cellsurface have higher selectivity & determine

    the specific metabolism pattern of an organ The proteolytic activity of subcutaneoustissue, Eg, results in-partial loss of activity of subcutaneously compared to i.v administratedinterferon- .

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    GASTROINTESTINAL ELIMINATION For oral administered- this is the major site

    of metabolism. Presystemic metabolism- for lack of oral

    bioavailability.

    Parenterally administered- may bemetabolized in the intestinal mucosafollowing intestinal secretion.

    Atleast 20% of the degradation of endogenous albumin takes place in thegastrointestinal tract.

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    RENAL ELIMINATION

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    HEPATIC ELIMINATION

    The rate of hepatic metabolism is largely dependent

    on specific amino acid sequences in the protein.An important first step -proteins and peptides is theuptake into hepatocytes.Small peptides may cross the hepatocyte membrane

    via passive diffusion if they have sufficienthydrophobicity.Uptake of larger peptides and proteins is facilitatedvia various carrier-mediated, energy dependent

    transport processesReceptor mediated endocytosis is an additionalmechanism for uptake into hepatocytes

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    RECEPTOR-MEDIATED ELIMINATIONUsually negligible compared to total amount of

    drug in the body for conventional small-molecule drugs & affects pharmocokineticprofile.

    This binding lead to elimination through

    receptor-mediated uptake & intracellularmetabolism.The endocytosis process notlimited to heptocytes,& occurs in other cells.No. of receptors is limited, their binding &related drug uptake can usually be saturatedwithin therapeutic conc.It is major source for nonlinear

    pharmocokinetic behaviour of drugs.

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    SPECIES SPECIFICITY & ALLOMETRYDrug exhibit distinct sp. Specificity withregard to structure & activity. with identicalphysiological function may have differentamino acid sequence in different sp & haveno activity or even immunogenic.Extent of glycosylation of speciesdifferences- Eg: for interferon- /erythropoietin- alter drugs clearence.

    Extrapolation of animal data to predictpharmacokinetic parameters scaling toolfor drug development.

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    Pharmacokinetic parameters betweendifferent species are related via body weightusing a power function:

    P= a. W bP- pharmacokinetic parameter scaled,W body weight in kilograms

    a- allometric exponenta & b- specific constant for each parameterof each compound.General tendencies for allometric exponentare 0.75 for rate constants, 0.25 for half lives.

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    IMMUNOGENICITYBecause of antigenic potential of proteins,

    formation of antibodies is a frequentlyobserved.Genetically engineered mouse- humanchimeric antibodies try to minimize this

    immunogenicity in man by joining variabledomains of the mouse to the constant regionsof the human immunoglobulins. Eg: anti-EGFRIgG.Extravascular injection- stimulate antibodyformation, due to increased immunogenicity of protein aggregates & precipitates formed at

    the injection site.

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    Protein- antibody complexation- modifythe distribution, metabolism, excretion-

    pharmacokinetic of the protein drug.

    Elimination- may be increased ordecreased.

    It is slowed down if the antibody- drugcomplex forms a depot for the protein

    drug.

    This effect would prolong the drugs

    therapeutic activity.

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    PHARMACOKINETICS OF OLIGONUCLEOTIDESAntisense oligonucleotide- specifically &

    selectively inhibit the production of disease-related pdts, with formivirsen- 1 st drug.Phosphothioate oligonucleotide- alone havehuman pharmacokinetic data.

    After intravenous administration- PONs follow2 compartment characteristics and rapidlycleared from plasma.

    Plasma pharmacokinetics- non linear, with amore than proportional increase in AUC withdose due to saturation of tissue uptake.

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    PONs are detected in nearly in alltissues & organs except brain. The

    extent of tissue uptake is dependenton the dose rate.Major accumulation of PON- liver &

    kidney, less in spleen, bone marrow,lymph nodes.Chemical modification in its backbone, however may alter proteinbinding & organ distribution.Mechanism for uptake into target cellshave not been fully elucidated

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    PHARMACOKINETICS OF DNAIn vivo disposition of plasmid DNA and its

    complexes depends largely on itsphysicochemical characteristics, a strongnegative charge and high molecular weightAfter intravenous administration in rats,pDNA is detected in all major organsincluding lungs, liver, kidney, and spleen.Low-level detection in the brain is most

    likely an artifact from residual blood, giventhat pDNA is unlikely to cross the blood-brain barrier

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    EXPOSURE/ RESPONSE FOR BIOTECH DRUGSSince biotech drugs are usually highly potent

    compounds with steep dose-effect curve, acareful characterization of the dose-concentration-effect relationship

    The application of PK/PD modeling isbeneficial in all phases of preclinical andclinical drug development, with a focus on

    dosage optimization and identification of covariates that are causal for intra- andinterindividual differences in drug responseand/or toxicity

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    mechanism-based PK/PD modelingapproach that appropriatelycharacterizes the real physiologicalprocess leading to the drugstherapeutic effect.

    Application of the three mostcommon PK/PD modeling classes,

    direct link models, indirect linkmodels, and indirect responsemodels,

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    SUMMARYBiotech drugs, including peptides, proteinsand antibodies, oligonucleotides, and DNA,are projected to cover a substantial marketshare in the health care systems of thefuture.A more widespread application of pharmacokinetic and pharmacodynamicconcepts including exposure-response

    correlations has repeatedly been promotedby industry, academia, and regulatoryauthorities for all preclinical and clinicalphases of drug development