TABLE 54 General pharmacokinetic and pharmacodynamic features of protein versus chemical drugs

Features

Protein Drugs

Chemical

Molecular weight (MW)

>1500Da

<1000Da

Route of administration

Parenteral

All routes

(Injection: IV, SC, IM)

(PO, IV, IM, SC, TD, TOP)

Volume of distribution

Mainly limited to blood volume

Dictated by hydrophobicity and plasma and tissue protein binding

Plasma protein binding

Does not play a significant role (esp. for proteins > 50 kDa)

Important

Extracellular fluid

Molecular weight and intrinsic

Mostly depends on MW and

distribution

properties of the proteins are important

hydrophobicity

Cell-surface receptor

May play a significant role

May be important in some cases

(ligand) interactions

Phagocytosis

Aggregated proteins and macromolecules with MW > 300 kDa

Does not play a role

Elimination

Protein denaturation;

Biotransformation (e.g.,

proteolysis

oxidation and conjugation), hydrophobicity, and protein binding

Renal

Filtration (MW < 40-50kDa)

Filtration; transport; metabolism

(cleared without reabsorption);

tubular reabsorption

metabolism

Hepatic

Phagocytosis; receptor-mediated

Hydrophobicity and molecular

endocytosis (hepatocytes);

weight

biotransformation

Immunogenicity

May play a significant role for macromolecules that require repetitive administration

Usually not important

Abbreviations: MW, molecular weight;IV, intravenous, SC, subcutaneous, IM, intramuscular, PO, per oral,TD, transdermal,TOP, topical, kDa, kilo Daltons.

Abbreviations: MW, molecular weight;IV, intravenous, SC, subcutaneous, IM, intramuscular, PO, per oral,TD, transdermal,TOP, topical, kDa, kilo Daltons.

morphism. State of health can also determine clearance. Patients with renal or hepatic disease have decreased drug clearances compared with those having normal renal or hepatic function. Determination of the clearance of the endogenous marker creatinine is routinely used to assess renal function.

In the clinic, total body clearance of a drug is estimated by taking the ratio of the administered dose, corrected for bioavail-ability, to the total area under a plot of drug concentration in plasma versus time produced by that dose.

Most protein pharmaceuticals exhibit a short half-life—measured in minutes—and high clearance because they are smaller than 30kDa and are readily cleared by glomerular filtration in the kidneys. Some pharmacokinetic features of protein phar-

■TABLE 5.5. Comparison of various parenteral routes on bioavailability and ease of use

Parenteral Routes Bioavailability, Biologic Response, and Ease of Use

IV—intravenous 100% systemic availability, most rapid biologic effect, potential for significant adverse effects, most invasive of parenteral routes, half-life governed by clearance

SC—subcutaneous Less than complete systemic availability, half-life may be limited by absorption

IM—intramuscular Systemic availability may be less than 100%, reduced peak concentrations compared to IV administration, potentially delayed and reduced biologic effects, less invasive than IV route, half-life may depend on absorption maceuticals compared with small-molecule drugs are listed in Table 5.4.

0 0

Post a comment