Pharmacokinetics Overview

Pharmacokinetics Overview

• Pharmacokinetics is the study of how the body affects drugs—measuring and interpreting drug/metabolite changes in plasma, urine, and other body regions over time.
• It provides insight into drug distribution, movement, and effects within the body.
• Pharmacokinetics relies on ADME (Absorption, Distribution, Metabolism, and Excretion).
• Pharmacodynamics describes the drug's effects on the body and drug interactions with receptors or target molecules.

Why PK is Important in Pharmacology

• PK development became feasible in the 20th century due to advanced analytical techniques like high-performance chromatography and mass spectrometry.
• In silico (computer) modeling of PK is increasingly important.
• Practical focus is on measuring drug concentrations in blood plasma, linking to the biological effect rather than just dose.
• Individual variability (differences in plasma concentration among individuals) is a primary factor in absorption, distribution, and elimination.
• Therapeutic Drug Monitoring (TDM) is used for drugs with a narrow therapeutic range to personalize dosages and minimize side effects. TDM involves frequent blood samples and dose adjustments, which can be costly.
• Drugs with a wide margin of safety are preferred to reduce the need for intensive monitoring.

Continuation of PK

• Clinical practice is changing with the use of direct oral anticoagulants instead of warfarin, due to ease of use and reduced monitoring needs.
• Future improvements aim to reduce monitoring needs for more drugs.
• Formal interpretation of PK data uses concentration-time data models.
• Dose adjustments are critical in achieving desired plasma concentrations.
• PK data, obtained from preclinical experiments on cells, tissues, or laboratory animals and early-phase human trials using single ascending doses (SADs), are used to estimate active concentration ranges.
• Descriptive PK parameters, such as maximum plasma concentration (C_max) and time to achieve maximum concentration (T_max), are important.
• Mathematical parameters like volume of distribution (Vd) and clearance (CL) are crucial.

Application to Different Drugs and Considerations

• PK parameters vary significantly between low-molecular-weight (LMW) drugs and macromolecular biopharmaceuticals.
• Therapeutic antibodies typically have low clearance rates and long elimination half-lives.
• Dose-related adverse effects often occur near the maximum concentration (C_max).
• Qualitative aspects of absorption, distribution, and elimination vary among drug types.

Uses of PK

• PK is crucial for interpreting toxicological and pharmacological data in drug development.
• Determining appropriate doses and dosing regimens for clinical trials is essential.
• Allometric scaling, using animal data to estimate human doses considering body surface area instead of body weight, is increasingly used in preclinical studies, particularly with methadone.
• Early-phase human trials determine suitable doses and ensure safety by monitoring real-time drug exposure data.
• Key parameters such as maximum concentration (C_max) and area under the curve (AUC) are crucial in early-phase trials.
• Regulatory concepts, like bioavailability and bioequivalence, are vital for licensing generic drugs and biosimilars. Biosimilars are biotherapeutic products with similar efficacy to authorized bio-originator products.
• PK principles are important in clinical practice for understanding dosing regimens, timing blood sampling, and interpreting drug concentrations for Therapeutic Drug Monitoring (TDM).
• Adjustment of doses and identifying drug interactions is crucial.
• PK is crucial in intensive care, anesthesiology, and other specialized care when managing severely ill patients. Personalized dosing regimens are crucial based on urgency of need and anticipated changes in PK due to illnesses such as renal or liver impairment.

Drug Elimination Clearance

• Total drug clearance (CL_tot) is a fundamental PK parameter representing the volume of plasma cleared of a drug per unit of time.
• CL_tot comprises renal, metabolic clearance, and other elimination routes (e.g., faeces, breath).
• The clearance rate is proportional to plasma drug concentration (Cp) and clearance value (CL_tot) in a linear relationship.
• At a steady state, input rate equals elimination rate and is determined through a constant infusion rate until a steady-state plasma concentration is achieved.
• Calculation of CL_tot from a constant infusion rate and the steady-state concentration (C_ss) can be done.
• Single intravenous bolus doses allow for estimation of CL_tot by monitoring plasma concentrations over time. Area under the curve (AUC) is useful to measure clearance and drug exposure, estimated graphically.
• CL_tot from AUC can be calculated.

Single Compartment Model

• The body is represented as a single, well-mixed compartment.
• Drug quantity is rapidly delivered to and removed by metabolism or excretion.
• Initial concentration (C₀) is determined by the volume of distribution (Vd) and the amount delivered (Q).
• Drug elimination follows linear kinetics and exponentially decreases over time (Cp).
• The elimination rate constant (K) represents the fraction of drug eliminated per unit of time.
• Elimination half-life (t_1/2) is the time for plasma concentration to decrease by half.
• Predicting drug elimination and time course after drug infusion or discontinuation.
• Loading dose determination by Vd is essential to rapidly achieve desired therapeutic plasma concentrations, given its significance in situations needing quicker therapeutic response.

Repeated Dosing

• Therapeutic drug dosing involves repeated doses instead of single injections or continuous infusion.
• Repeated dosing creates oscillations in plasma concentration.
• Higher frequency and smaller doses help stabilize and mimic continuous infusion.
• Steady-state concentration is typically achieved after 3-5 half-lives for faster drug action.
• Loading doses can be employed with drugs having long half-lives in critical situations to rapidly achieve therapeutic levels.

Effect Variation in Rate of Absorption

• Slow absorption is comparable to variable-rate infusion into the bloodstream.
• Transfer is delayed and maximum drug concentration in the plasma is lower with a reduced peak concentration (less sharp).
• Rate of absorption does not influence area under the plasma concentration-time curve (AUC) if absorption is complete, and incomplete absorption due to pre-systemic metabolism reduces the overall AUC.
• Plasma concentration, steady-state values, are unaffected by the rate of absorption.

More Complicated Kinetic Models

• Single compartment models oversimplify.
• More complex models (e.g., two-compartment models) are necessary for understanding the body's more complex physiology.
• Different parts of the body have unique distribution characteristics because of variable blood supply, tissue partitioning, and capillary permeability.
• These differences affect drug distribution.
• Two-compartment models are useful for representing more complex physiological situations.
• Non-compartmental analysis is usually used more often in drug development to simplify complexity.

Two-Compartment Models

• Drug molecules can distribute between a central (plasma) and peripheral compartment.
• Plasma concentration will decrease exponentially as drug moves from the central to peripheral compartments, presenting a two-phase pattern.
• Fast (alpha) and slow (beta) phases exist due to differences in drug distribution through tissues. The alpha phase reflects redistribution throughout plasma and tissues, while the beta phase represents elimination.
• The end of the alpha phase provides a measure of combined distribution volumes for both compartments.
• Half-life values for elimination (beta phase ) are critical for drug action.

Saturation Kinetics

• Some drugs exhibit saturation kinetics, where a carrier or enzyme reaches saturation, leading to constant elimination rates.
• Duration of action is more related to dose than rate.
• Dosage adjustments are crucial as exceeding the maximum metabolic rate leads to unpredictable increases in drug levels.
• Dose-dependent saturation kinetics makes drug responses less predictable compared to linear kinetics.

Population Pharmacokinetics

• PK data in patient populations is sometimes necessary, especially for chronically ill children.
• Data gathering is challenging and can be limited in scope and quality.
• Non-linear mixed-effects modeling (NONMEM) is a method used for population PK analysis, accommodating inter-individual and within-individual variability in PK over time.
• Population PK analysis is vital for understanding how population studies relate to individual patients.
• Mathematical modeling is necessary to interpret population studies correctly.

Limitations of PK Approach

• Simple PK models can be complex to interpret.
• Monitoring plasma concentrations may not be sufficient in ensuring a reliable and uniform drug response in all cases.
• Assumptions relating plasma concentration and target concentration may not always hold; drugs acting on non-blood stream targets or those with active metabolites are less likely to demonstrate a direct relation.
• Variable drug actions affecting metabolism and delayed responses may not be reflected in plasma concentration monitoring alone. Different concentration-effect relationships are required for drugs with various mechanisms of action.