Methods for Measurement of bioavailability
- 2. Measurement of Bioavailability Pharmacokinetic method Plasma level time studies Urinary excretion studies Pharmacodynamic method Acute pharmacologic response Therapeutic response
- 3. Pharmacokinetic method 1. Plasma Level Time Studies : Principle: • The method is based on the assumption that two dosage forms that exhibit super imposable plasma level time profiles in a group of subjects should result in identical therapeutic activity (and they would be termed as bioequivalent). • These studies cab be single dose or multiple dose studies.
- 4. Pharmacokinetic method 1. Plasma Level Time Studies : Single Dose Study Following steps are involved in a single dose study. Collection of serial blood samples for period of 2-3 biological half lives after drug administration. Analysis for drug concentration. Obtain plasma level time profile by this plot. Making a plot of plasma concentration versus time of sample collection.
- 5. Pharmacokinetic method 1. Plasma Level Time Studies : FDA Guidelines on Collection of Blood Samples: 1. When comparison of the test product and the reference material is to be based on blood concentration time curves. 2. In a study comparing oral dosage forms, the sampling times should be identical. 3. In a study comparing an intravenous dosage form and an oral dosage form, 4. In a study comparing drug delivery systems other than oral or intravenous dosage forms with an appropriate reference standard.
- 6. Pharmacokinetic method Type of Study Advantages Disadvantages Single Dose Study • Easy to conduct. • Offer less exposure to drug. • Less tedious. • Dose does not give any idea of drug/metabolites. • Difficult to predict the steady state characteristics of the drugs. MultipleDose Study • Easy to predict the peak and valley characteristics of drug • Fewer blood samples requirements • Less sensitive analytical method • Difficult to control • Highly tedious • Time consuming 1. Plasma Level Time Studies : Single dose verses multiple dose study
- 7. Pharmacokinetic method 1. Plasma Level Time Studies : Basic Pharmacokinetic Parameters of Plasma level time Studies • Pharmacokinetics provides a mathematical basis to assess the time course of drugs and their effects in the body. • It enables the following processes to be quantified: Absorption, Distribution, Metabolism, and Excretion. • The effectiveness of a dosage regimen is determined by the concentration of the drug in the body. A plasma level time profile curve of a orally administereddrug.
- 8. 1. Plasma Level Time Studies : FDA Guidelines on the design of a multiple- dose in vivo bioavailability study (a) Basic Principles : 1. In selected circumstances it may be necessary for the test product and the reference material to be compared after repeated administration. 2. The test product and the reference material should be administered to subjects in the fasting or non fasting state. 3. The drug product is an extended release dosage form. Pharmacokinetic method
- 9. Pharmacokinetic method 1. Plasma Level Time Studies : (b) Study Design : 1. A multiple-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons. 2. The,drug elimination period should be either: At least five times the half-life of the active drug ingredient or therapeutic moiety, or its active metabolite(s), measured in the blood or urine; or At least five times the half-life of decay of the acute pharmacological effect.
- 10. Pharmacokinetic method 1. Plasma Level Time Studies : (c) Achievement of steady-state conditions : • Whenever a multiple-dose study is conducted, unless some other approach is more appropriate for valid scientific reasons. • Sufficient doses of the test product and reference material should be administered in accordance with the labeling to achieve steady state conditions.
- 11. Pharmacokinetic method 1. Plasma Level Time Studies : (d) Collection of blood or urine samples • Whenever comparison of the test product and the reference material is to be based on blood concentration time curves at steady state. • Whenever comparison of the test product and the reference material is to be based on cumulative urinary excretion-time curves at steady state.
- 12. Pharmacokinetic method 1. Plasma Level Time Studies : (e) Steady-state parameters : • In certain instances, e.g., in a study involving a new drug entity, blood clearances at steady- state obtained in a multiple dose study should be compared to blood clearances. • In a linear system, the area under the blood concentration- time curve during a dosing interval in a multiple dose steady- state study is directly proportional to the fraction of the dose absorbed.
- 13. Pharmacokinetic method 2. Urinary Excretion Studies : Principle: • The urinary excretion of unchanged drug is directly proportional to the plasma concentration of drug. • The study is particularly useful for drugs extensively excreted unchanged in the urine. • Example: thiazides, sulphonamides, urinary antiseptics, hexamine etc.
- 14. Pharmacokinetic method 2. Urinary Excretion Studies : Method : • Collection of urine at regular interval for a time span equal to 7 biological half lives. • Analysis of unchanged drug in the collected sample. • Determination of the amount of drug excreted in each interval. Note: At each sample collection total emptying of bladder is necessary to avoid errors resulting from addition of residual amount to the next urine.
- 15. Pharmacodynamic method 1. Acute Pharmacologic Response It may include measurement of one or more of the following pharmacological reponses: • Change in ECG or EEG reading. • Pupil diameter etc are related to time course of a given drug. Disadvantages • Variable pharmacologic response. • Accurate correlation between measured response and drug available is difficult.
- 16. Pharmacodynamic method 2. Therapeutic Response Principle: • Observing the clinical response to a drug formulation given to patient suffering from disease for which it is intended to be used. • But the method is associated with the fact that the response observed is often too improper. • Pharmacodynamic studies are not recommended for orally administered drug products