Biopharmaceutics and Pharmacokinetics Module 8 & 9 PDF

BIOPHARMACEUTICS AND PHARMACOKINETICS MODULE 8: DOSAGE REGIMEN DESIGN I. INTRODUCTION A rational dosage regimen is based on the assumption that there is a target concentration that will produce the desired therapeutic effect. By considering the pharmacokinetic factors tha...

BIOPHARMACEUTICS AND PHARMACOKINETICS MODULE 8: DOSAGE REGIMEN DESIGN I. INTRODUCTION A rational dosage regimen is based on the assumption that there is a target concentration that will produce the desired therapeutic effect. By considering the pharmacokinetic factors that determine the dose-concentration relationship, it is possible to individualize the dose regimen to achieve the target concentration. II. MAINTENANCE DOSE In most clinical situations, drugs are administered in such a way as to maintain a steady state of drug in the body, ie, just enough drug is given in each dose to replace the drug eliminated since the preceding dose. Thus, calculation of the appropriate maintenance dose is a primary goal. Clearance is the most important pharmacokinetic term to be considered in defining a rational steady-state drug dosage regimen. For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination is directly proportional to concentration. At steady state, the dosing rate (“rate in”) must equal the rate of elimination (“rate out”). Thus, if the desired target concentration is known, the clearance in that patient will determine the dosing rate. If the drug is given by a route that has a bioavailability less than 100%, then the dosing rate predicted by the above equation must be modified. For oral dosing: If intermittent doses are given, the maintenance dose is calculated from: Note that the steady-state concentration achieved by continuous infusion or the average concentration following intermittent dosing depends only on clearance. The volume of distribution and the half-life need not be known in order to determine the average plasma concentration expected from a given dosing rate or to predict the dosing rate for a desired target concentration. NDCorcinoRPh2024 Page 1 of 4  III.LOADING DOSE When the time to reach steady state is appreciable, as it is for drugs with long half-lives, it may be desirable to administer a loading dose that promptly raises the concentration of drug in plasma to the target concentration. In theory, only the amount of the loading dose need be computed—not the rate of its administration—and, to a first approximation, this is so. The volume of distribution is the proportionality factor that relates the total amount of drug in the body to the concentration; if a loading dose is to achieve the target concentration: EXAMPLE A target plasma theophylline concentration of 10 mg/L is desired to relieve acute bronchial asthma in a patient. Calculate the maintenance dose for the drug if its clearance is 2.8 L/h/70 kg and it is administered every 12 hours. NDCorcinoRPh2024 Page 2 of 4  MODULE 9: BIOAVAILABILITY AND BIOEQUIVALENCE I. BIOEQUIVALENCE Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (eg, in certain extended-release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug. II. DEFINITION OF TERMS Pharmaceutical alternatives mean drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates. Pharmaceutical equivalents mean drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient, that is, the same salt or ester of the same therapeutic moiety, or, in the case of modified-release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. Therapeutic alternatives are drug products containing different active ingredients that are indicated for the same therapeutic or clinical objectives. Active ingredients in therapeutic alternatives are from the same pharmacologic class and are expected to have the same therapeutic effect when administered to patients for such condition of use. For example, ibuprofen is given instead of aspirin; cimetidine may be given instead of ranitidine. Therapeutic equivalents are drug products that are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling. The FDA believes that products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product. NDCorcinoRPh2024 Page 3 of 4  III.THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms. These factors are dissolution, solubility, and intestinal permeability. According to the BCS, drug substances are classified as follows: Class 1: high solubility–high permeability Class 2: low solubility–high permeability Class 3: high solubility–low permeability Class 4: low solubility–low permeability NDCorcinoRPh2024 Page 4 of 4