PHARMACOKINETI CS & PHARMACODYNAM ICS

PHARMACOKINETICS & PHARMACODYNAMICS

Pharmacokinetics

- all processes that contribute to the time course of drug concentrations in various body fluids, generally blood or plasma, that is, all processes affecting drug absorption, distribution, metabolism, and excretion. Pharmacodynamics characterizes the effect intensity and/or toxicity resulting from certain drug concentrations at the assumed effect site. Simplified, pharmacokinetics characterizes what the body does to the drug, whereas pharmacodynamics assesses what the drug does to the body

PK/PD MODELING AS COMBINATION OF THE CLASSIC PHARMACOLOGICAL DISCIPLINES

PHARMOCOKINETICS OF PEPTIDES & PROTEINS

Traditional

pharmocokinetic principlesapplicable for peptides & proteins Peptides- having hormone activity usually have short elimination half-lives, which is desireable for close regulation of their endogenous levels & thus function. But transport proteins like albumin/antibodies having several days elimination half-lives ensures continuous maintenance of necessary conc. in the blood stream.

ABSORPTION
Clinically

usable absorption of exogenously applied peptides & proteins after oral application with conventional dosage forms is not present. Lack of systemic availability- caused by 2 factors:High gastrointestinal enzyme activity & function of gastrointestinal mucosa as absorption barrier. Lack of activity after oral admin for most peptides & proteins resulted in the past The utilization of non-oral admin pathwaysnasal, buccal, rectal, vaginal, pulmonary drug delivery. Absorption rate constant- combination of absorption into systemic circulation &

DISTRIBUTION

Whole body distribution studies- for classical small- molecule drugs in order to exclude tissue accumulation of potentially toxic metabolites. Biodistribution studies for peptides & proteins are primarily performed to access targeting to specific tissues as well as to identify the major elimination organs. Volume of distribution of proteins is usually small & limited to the volume of extracellular space because of their high molecular weight &the related limited mobility .

 After

intravenous application, peptides and proteins usually follow a biexponential plasma concentrationtime profile that can best be described by a two-compartment pharmacokinetic model. For eg: leuprorelin, a synthetic agonist analog of luteinizing hormone-releasing hormone (LHRH) or clenoliximab, a macaquehuman chimeric monoclonal antibody specific to the CD4molecule on the surface of Tlymphocytes, and for AJW200, a humanized monoclonal antibody to von Willebrand factor.

PROTEIN BINDING
Only

free, unbound fraction of a drug substance is accessible to distribution & elimination processes as well as interactions with its target structure at the site of action. They frequently interacting with specific binding proteins that are involved in their transport & regulation & binding proteins may enable or facilitate cellular uptake processes, thus affect pharmacodynamics. Eg: IGF-1 (insulin-like growth factor), t-PA, interleukin-2, somatotropin.

 IGF-1,

with one binding at least 95% of IGF-1 in plasma Binding affinity higher than IGF receptor- reservoir function that protects the body from insulin-like hypoglycemia. Elimination half-life bound IGF-1 is significantly longer than for free IGF-1, since only the unbound IGF-1 is accessible to elimination via glomerular filtration or peritubular extraction

 Somatotropin-

at least two binding proteins in plasma. Protein binding substantially reduces elimination - smaller clearance of total compared to free somatotropin, & also decreases its activity via reduction of receptor interactions. Peptides & proteins -nonspecifically bound to plasma proteins.

ELIMINATION

Non metabolic pathway- renal or biliary excretion are negligible for most peptides & proteins. If biliary excretion occurs- subsequent metabolism of these compounds in the gastrointestinal tract. Elimination- unspecifically everywhere in the body 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

PROTEOLYSIS
Proteolytic

enzymes- proteases & peptidases are available throughout the body (in blood, in vascular endothelium, cell membrane). While peptidases & proteases in the gastrointestinal tract & in lysosomes are relatively unspecific, soluble peptidases in the interstitial space & exopeptidases on the cell surface have higher selectivity & determine the specific metabolism pattern of an organ The proteolytic activity of subcutaneous tissue, Eg, results in-partial loss of activity of subcutaneously compared to i.v administrated interferon- .

GASTROINTESTINAL ELIMINATION

For oral administered- this is the major site of metabolism. Presystemic metabolism- for lack of oral bioavailability. Parenterally administered- may be metabolized in the intestinal mucosa following intestinal secretion. Atleast 20% of the degradation of endogenous albumin takes place in the gastrointestinal tract.

RENAL ELIMINATION

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 the uptake into hepatocytes. Small peptides may cross the hepatocyte membrane via passive diffusion if they have sufficient hydrophobicity. Uptake of larger peptides and proteins is facilitated via various carrier-mediated, energy dependent transport processes Receptor mediated endocytosis is an additional mechanism for uptake into hepatocytes

RECEPTOR-MEDIATED ELIMINATION
Usually

negligible compared to total amount of drug in the body for conventional smallmolecule drugs & affects pharmocokinetic profile. This binding lead to elimination through receptor-mediated uptake & intracellular metabolism.The endocytosis process not limited to heptocytes,& occurs in other cells. No. of receptors is limited, their binding & related drug uptake can usually be saturated within therapeutic conc. It is major source for nonlinear pharmocokinetic behaviour of drugs.

SPECIES SPECIFICITY & ALLOMETRY

Drug

exhibit distinct sp. Specificity with regard to structure & activity. with identical physiological function may have different amino acid sequence in different sp & have no activity or even immunogenic. Extent of glycosylation of species differences- Eg: for interferon-/ erythropoietin- alter drugs clearence. Extrapolation of animal data to predict pharmacokinetic parameters scaling tool for drug development.

 Pharmacokinetic

parameters between different species are related via body weight using a power function: P= a. W b P- pharmacokinetic parameter scaled, W body weight in kilograms a- allometric exponent a & b- specific constant for each parameter of each compound. General tendencies for allometric exponent are 0.75 for rate constants, 0.25 for half lives.

IMMUNOGENICITY
Because

of antigenic potential of proteins, formation of antibodies is a frequently observed. Genetically engineered mouse- human chimeric antibodies try to minimize this immunogenicity in man by joining variable domains of the mouse to the constant regions of the human immunoglobulins. Eg: anti-EGFR IgG. Extravascular injection- stimulate antibody formation, due to increased immunogenicity of protein aggregates & precipitates formed at the injection site.

 Protein-

antibody complexation- modify the distribution, metabolism, excretionpharmacokinetic of the protein drug. decreased. may be increased or

Elimination-

It

is slowed down if the antibody- drug complex forms a depot for the protein drug. effect would prolong the drugs therapeutic activity.

This

PHARMACOKINETICS OF OLIGONUCLEOTIDES
Antisense

oligonucleotide- specifically & selectively inhibit the production of diseaserelated pdts, with formivirsen- 1st drug. Phosphothioate oligonucleotide- alone have human pharmacokinetic data. After intravenous administration- PONs follow 2 compartment characteristics and rapidly cleared from plasma. Plasma pharmacokinetics- non linear, with a more than proportional increase in AUC with dose due to saturation of tissue uptake.

 PONs

are detected in nearly in all tissues & organs except brain. The extent of tissue uptake is dependent on the dose rate. Major accumulation of PON- liver & kidney, less in spleen, bone marrow, lymph nodes. Chemical modification in its back bone, however may alter protein binding & organ distribution. Mechanism for uptake into target cells have not been fully elucidated

PHARMACOKINETICS OF DNA
In

vivo disposition of plasmid DNA and its complexes depends largely on its physicochemical characteristics, a strong negative charge and high molecular weight After intravenous administration in rats, pDNA is detected in all major organs including lungs, liver, kidney, and spleen. Low-level detection in the brain is most likely an artifact from residual blood, given that pDNA is unlikely to cross the bloodbrain barrier

EXPOSURE/ RESPONSE FOR BIOTECH DRUGS

Since

biotech drugs are usually highly potent compounds with steep dose-effect curve, a careful characterization of the doseconcentration-effect relationship application of PK/PD modeling is beneficial in all phases of preclinical and clinical drug development, with a focus on dosage optimization and identification of covariates that are causal for intra- and interindividual differences in drug response and/or toxicity

The

 mechanism-based

PK/PD modeling approach that appropriately characterizes the real physiological process leading to the drugs therapeutic effect. of the three most common PK/PD modeling classes, direct link models, indirect link models, and indirect response models,

Application

SUMMARY
Biotech

drugs, including peptides, proteins and antibodies, oligonucleotides, and DNA, are projected to cover a substantial market share in the health care systems of the future. A more widespread application of pharmacokinetic and pharmacodynamic concepts including exposure-response correlations has repeatedly been promoted by industry, academia, and regulatory authorities for all preclinical and clinical phases of drug development