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