Pharmacokinetics

• 1. Defining The Pharmacokinetic Scope

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  Pharmacokinetics describes how the body affects a specific substance after administration. This branch of pharmacology focuses on chemical xenobiotics such as pharmaceutical drugs, pesticides, food additives, and cosmetics. Researchers analyze chemical metabolism to discover the fate of a chemical from the moment it is administered until complete elimination. The field relies heavily on mathematical modeling to place emphasis on drug plasma concentration over time elapsed since administration. A 2006 entry in Mosby's Dictionary of Medicine defines this scope clearly for health professionals. Pharmacodynamics studies how the drug affects the organism while pharmacokinetics studies how the organism affects the drug. Both concepts together influence dosing decisions, therapeutic benefits, and adverse effects seen in PK/PD models.

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• 2. The Four Phases Of Drug Movement

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  A number of phases occur once the drug enters into contact with the organism. These processes are described using the acronym ADME or LADME if liberation is included as a separate step. Liberation involves active pharmaceutical ingredients separating from their pharmaceutical formulation. Absorption represents the process of a drug entering systemic circulation from the site of administration. Distribution refers to the dispersion of substances throughout fluids and tissues of the body. Metabolism includes irreversible breakdown into metabolites by enzymes like cytochrome P450 or glucuronosyltransferase. Excretion marks the removal of the substance or metabolites from the body. Some textbooks combine the first two phases because drugs often enter in an active form without a liberation phase. Other authors group distribution, metabolism, and excretion into a single disposition phase. Toxicological aspects sometimes appear under the title ADME-Tox or ADMET. The study of these distinct phases requires knowledge of excipient properties and biological membrane characteristics.

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• 3. Key Metrics And Parameters

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  The units of dose in standard tables are expressed in moles or molar concentrations. A typical graph depicts plasma concentration over 96 hours with oral administrations every 24 hours. Steady state is reached after about 5 times 12 equals 60 hours according to this data. Cmax represents the peak plasma concentration of a drug after administration. Tmax indicates the minimum time taken to reach that peak concentration. The lowest trough concentration before the next dose reaches 27.7 mmol/L in some examples. Average plasma concentration over the dosing interval in steady state measures 55.0 h×mmol/L. Volume of distribution relates drug concentration in plasma to drug amount in the body at 6.0 L. Elimination half-life shows the time required for concentration to reach half its original value at 12 hours. Area under the curve calculates total drug exposure as 1,320 h×mmol/L. Clearance defines the volume of plasma cleared of the drug per unit time at 0.38 L/h. Bioavailability remains a unitless factor representing the systemically available fraction of a drug at 0.8.

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• 4. Mathematical Modeling Approaches

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  Models have been developed to simplify conceptualization of many processes taking place between an organism and a chemical substance. Pharmacokinetic modeling may be performed by noncompartmental or compartmental methods. Multi-compartment models provide best approximations to reality despite high complexity. Monocompartmental models and two compartmental models remain most frequently used due to simplicity. Model outputs allow industry calculation of bioequivalence when designing generic drugs. Noncompartmental methods estimate PK parameters directly from a table of concentration-time measurements. These methods do not assume any specific model and generally produce accurate results acceptable for bioequivalence studies. Total drug exposure is often estimated by area under the curve methods using the trapezoidal rule. Compartment models estimate the concentration-time graph by modeling it as a system of differential equations. Single compartment models presuppose blood plasma concentrations determine drug concentration in other fluids. Two-compartment models consider organs with well-developed blood supply versus those with lower blood flow. The choice of model comes down to deciding which one offers the lowest margin of error for the drug involved.

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• 5. Bioavailability And Formulation

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  A drug's bioavailability can be defined as the proportion of the drug that reaches systemic circulation. Intravenous administration provides the greatest possible bioavailability considered to yield 100 percent availability. Bioavailability of other delivery methods compares with intravenous injection or standard values related to other methods. If a drug has a bioavailability of 0.8 and administered dose equals 100 mg, effective dose becomes 80 mg. This concept depends on pharmaceutical form, chemical form, route of administration, stability, and metabolism factors. When two drugs have same bioavailability they are said to be biological equivalents or bioequivalents. Bioequivalence serves as yardstick in authorization of generic drugs in many countries. Different forms of tablets will have different pharmacokinetic behaviors after their administration. The Henderson-Hasselbalch equation calculates non-ionized concentration subject to absorption based on pH equilibrium. Mathematical quantification integrates these concepts into overall equations involving purity and rate of administration.

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• 6. Clinical Monitoring Applications

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  Population pharmacokinetics studies sources and correlates of variability in drug concentrations among individuals receiving clinically relevant doses. Steady-state concentrations of drugs eliminated mostly by kidney are usually greater in patients with kidney failure than normal function. Clinical pharmacokinetics applies knowledge regarding drug pharmacokinetics to therapeutic situations for specific patient populations. Ciclosporin relaunch demonstrates how individualizing patient dose by analyzing plasmatic concentrations facilitates organ transplants. Determination of plasma concentrations remains easiest data to obtain and most reliable for monitoring purposes. Narrow therapeutic range between toxic and therapeutic concentrations drives the need for such monitoring. High toxicity and high risk to life also necessitate careful clinical pharmacokinetic oversight. Antibiotics like gentamicin and vancomycin require monitoring due to narrow safety margins. Immunosuppressors including tacrolimus and sirolimus benefit from population-based dosing strategies. Mass spectrometry provides necessary sensitivity to observe concentrations after low dose and long time period. Secondary electrospray ionization presents advantage of avoiding animal sacrifice in microdosing studies.

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