Biopharma and Pharmacokinetics Overview

Introduction: Biopharma/Kinetics

• The presentation introduces the study of biopharmaceutics and pharmacokinetics.
• It discusses ADME (Absorption, Distribution, Metabolism, and Excretion) processes.
• Learning objectives are provided as a study guide.

Learning Objectives

• Application of drugs in disease states is discussed.
• Understanding & application of Pharmacokinetics.
• Understanding & application of Biopharmaceutics.
• Defining and assessing bioavailability with parameters.
• Factors influencing bioavailability are explored (Formulation, dosage forms, route of admin.).
• Important drug admin. routes (intravascular and extravascular) are reviewed.
• Typical plasma concentration-time profiles are outlined.
• Importance of absorption & elimination in bioavailability.
• Parameters used to assess absorption rate and extent (tmax, Cp(max), AUC) are reviewed.
• Factors affecting absorption and elimination rate constants are listed.
• The role of pharmacokinetics in disease management is explored (diagnosis, drug selection, dosage, patient assessment, drug concentration, and clinical judgement).
• Formulation strategies for drug delivery (tablets, capsules, suspensions, etc.) and their importance are outlined.
• Exception cases for drug use are discussed.
• The aim of drug development is creating optimum dosage forms for successful therapeutic outcomes is emphasized.
• Pharmacokinetics is defined as a field studying drug absorption, distribution, metabolism, and excretion (ADME), and corresponding effects in humans and animals.

Bioavailability

• The relative amount of an administered dose reaching general circulation and rate of absorption are defined.
• Bioavailability is defined as the rate and extent of active drug absorption.

Biopharmaceutics

• Study of factors influencing bioavailability.
• Chemical nature (weak acid/base, large/small molecule) of a drug is a key factor.
• Characteristics of inert excipients (binding agents, surfactants, diluents, lubricants, etc.) in formulations.
• The design of dosage forms from a physical perspective (particle size, surface area, solubility, among others) is a critical factor in bioavailability.

Method of Manufacture and Physical-Chemical Properties

• Methods of manufacture (dry granulation, wet granulation, direct compression).
• Physical-chemical properties of drugs (particle size, particle size distribution, surface area, hydrophobicity, polymorphism (amorphous/crystalline)).
• The goal is to produce a dosage form that provides consistent bioavailability at a desired rate.
• The importance of consistent bioavailability is emphasized particularly for medications with a narrow therapeutic index.

Sites of Drug Administration

• Two main categories: Intravascular and Extravascular.
  • Intravascular:
    • Intravenous (bolus and infusion).
    • Intra-arterial.
  • Extravascular:
    • Oral (tablets, capsules, solutions, suspensions).
    • Intramuscular.
    • Subcutaneous.
    • Sublingual.
    • Rectal (suppositories and enemas).

Important Features of Intravascular Administration

• Absence of an absorption phase.
• Immediate onset of action.
• Entire dose is available to produce effects.
• Important for life threatening situations.
• Adverse reactions are harder to control.
• Dosage calculations and administration are critical.

Important Features of Extravascular Administration

• Presence of an absorption phase.
• Onset of action dependent on factors like formulation, route, physical-chemical properties of drug, and physiological variables.
• Not all administered dose always reaches the general circulation (incomplete absorption / first-pass effect).

Absorption

• Absorption rate constant (Ká), rate of absorption (mg/hr), and factors influencing absorption rate constant are discussed.
• Absorption rate related to dose is directly proportional, but it declines with time due to Fick's first law of diffusion.
• Absorption rate constant (Ká) is constant under defined conditions but different for different drugs and formulations.
• Factors impacting absorption rate constant include drug dissolution and pH at the site of administration.
• Peak time (tmax) and peak plasma concentration [(Cp)max ] collectively assess absorption rate.

Distribution

• Distribution is the reversible transfer of drug to and from the site of measurement (typically blood or plasma).
• Reversible transfer of drug to and from the site of measurement is always present, regardless of adminstration route.
• Drugs leaving the measurement site without returning have undergone elimination.
• Rate and extent of drug distribution depend on factors such as tissue perfusion, drug binding to proteins, and tissue membrane permeability.

Apparent Volume of Distribution

• The apparent volume of distribution (V) describes the extent of drug distribution in the body.
• The more lipophilic a drug, the higher its apparent volume of distribution and greater tissue penetration.
• The apparent volume of distribution is constant for each drug, but it's affected by conditions like disease states and changes in blood or tissue composition/membrane permeability.
• There are drugs with low and high apparent volumes of distribution.

Compartmental Models

• Pharmacokinetics is often described using compartmental models (one compartment, two compartment, etc.).
• Single compartment model is suitable if drug distribution equilibrium is fast; multiple compartment models (e.g., two or three compartments) are needed if distribution is slow.

Metabolism

• Metabolism is the chemical conversion of one species to another.
• Active metabolites are important as they are frequently responsible for therapeutic effects.
• Inactive metabolites are also produced, yet they don't effect the body.
• The liver is the primary organ for drug metabolism.

Excretion

• Elimination (loss of drug from site of measurement) is irreversible.
• Excretion: The loss of a drug in a chemically unchanged form (or as a metabolite).
• The kidneys are the primary organ excreting drugs and their metabolites.
• The lungs can also excrete drugs (in gaseous form, e.g., anaesthetics).

Elimination Parameters

• Elimination half-life (t1/2) and elimination rate constant (K) are parameters used in elimination studies.
• They are correlated, with t1/2 = 0.693/K.
• The elimination half-life is a constant for a drug under defined conditions and is independent of dose and route.
• Factors affecting elimination include renal impairment (which often increases elimination half-life).
• Another elimination route is via a mother's breast milk, though typically not significant.

Disposition

• Disposition is comprehensive process encompassing the events following the absorption of a drug, and includes distribution and elimination.
• Absorption, distribution, metabolism, and excretion (ADME) are involved.

Peak Time and Peak Plasma Concentration

• Peak time (tmax) is the time at which the highest plasma concentration occurs after extravascular administration.
• Peak time is influenced by absorption rate, route of administration, dosage form, and formulation, and factors such as renal impairment can impact peak time.
• Peak plasma concentration ((Cp)max ) is the highest plasma concentration achieved.
• Peak plasma concentration will be influenced by the route of drug adminstration, dosage form, and formulation.

Area Under the Curve (AUC)

• Area under the curve (AUC) is a measure of the total drug exposure over time from a plasma concentration versus time curve.
• It represents the total amount of drug that reaches the general circulation and is the primary measure of total drug exposure reflecting fraction absorbed and fraction surviving metabolism.
• AUC is directly proportional to administered dose and is influenced by absorption, distribution, metabolism, and excretion (ADME).