![The extent of bioavailability can be determined by
following equations:
F = [AUC]oral Div
[AUC]iv D oral
F = [AUC]test Dstd
[AUC]std Dtest
Where, D= Dose administered
With multiple dose study, the method involves drug
administration for at least 5 biological half-lives with a
dosing interval equal to or greater than the biological
half-life to reach steady-state.19](https://image.slidesharecdn.com/bioavailability-180419180357/85/Bioavailability-absolute-bioavalability-relative-bioavailability-Purpose-of-bioavailability-Methods-of-assesing-bioavailability-19-320.jpg)
Bioavailability , absolute bioavalability, relative bioavailability, Purpose of bioavailability, Methods of assesing bioavailability
- 1. Bioavailability Presented to: Prof.H.S. Keerthy Department of Pharmaceutics MALLIGE COLLEGE OF PHARMACY Presented by: Manikant Prasad Shah Mpharm II Sem.1
- 2. CONTENTS Purpose of Bioavailability Studies Relative and Absolute Availability Methods for assessing Bioavailability 2
- 3. Introduction Definition: Bioavailability is defined as the rate and extent (amount) of absorption of unchanged drug from its dosage form. It is an absolute consideration when a rapid onset of action is desired as in the treatment of acute conditions such as asthma attack, pain, etc. 3
- 4. … If the size of the dose to be administered is same, then bioavailability of a drug from its dosage form depends upon 3 major factors: i. Pharmaceutical factors related to physicochemical properties of the drug and characteristics of the dosage form. ii. Patient-related factors. iii. Route of administration 4
- 5. The influence of route of administration on drug’s bioavailability is generally in the following order : Parenteral > Oral > Rectal > Topical The dose available to the patient is called as Bioavailable Dose. It is often less than the administered dose. The amount of drug that reaches the systemic circulation is called as systemic availability. The term bioavailability fraction F, refers to the fraction of administered dose that enter the systemic circulation. F = Bioavailability dose Administered dose 5
- 6. Objectives Primary stages of development of a suitable dosage form for a new drug entity to obtain evidence of its therapeutic utility. Determination of influence of excipients, patient related factors and possible interaction with other drugs on the efficiency of absorption. 6
- 7. Development of new formulations of the existing drug. Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage and stability of drug absorption. Comparison of availability of a drug substance from different dosage forms or from the same dosage form produced by different manufacturers. 7
- 8. Purpose of Bioavailability Studies Bioavailability studies are performed for both approved active drug ingredients and therapeutic moieties not yet approved for marketing by the FDA. New formulations of active drug ingredients must be approved by the FDA before marketing. In approving a drug product for marketing, the FDA ensures that the drug product is safe and effective for its labeled indications for use. Moreover, the drug product must meet all applicable standards of identity, strength, quality, and purity. To ensure that these standards are met, the FDA requires bioavailability/pharmacokinetic studies and, where necessary, bioequivalence studies for all drug products.8
- 9. Bioavailability may be considered as one aspect of drug product quality that links in-vivo performance of the drug product used in clinical trials to studies demonstrating evidence of safety and efficacy. Bioavailability studies are used to define the effect of changes in the physicochemical properties of the drug substance and the effect of the drug product (dosage form) on the pharmacokinetics of the drug. Data from these in-vivo bioavailability studies are important to establish recommended dosage regimens and to support drug labeling. 9
- 10. In-vivo bioavailability studies are also performed for new formulations of active drug ingredients or therapeutic moieties that have full NDA approval and are approved for marketing. The purpose of these studies is to determine the bioavailability and to characterize the pharmacokinetics of the new formulation, new dosage form, or new salt or ester relative to a reference formulation. 10
- 11. In-vivo bioavailability study Bioavailability- Absolute versus Relative o When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration, it is called as Absolute Bioavailability (F). o When the systemic availability of a drug after oral administration is compared with that of an oral standard of the same drug (such as an aqueous or non-aqueous solution or a suspension), it is referred to as Relative or Comparative Bioavailability (Fr). 11
- 12. Absolute Bioavailability Compares the bioavailability of the active drug in systemic circulation following non-intravenous administration with the same drug following intravenous administration For drugs administered intravenously, bioavailability is 100% Determination of the best administration route Fab = (AUC)drug /(AUC)IV Absolute Bioavailability of Nimodipine for different routes: Oral : 1.17 % Nasal : 67.4 % Intravenous: 100%12
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- 14. Relative Bioavailability Relative Bioavailability Compares the bioavailability of a formulation (A) of a certain drug when compared with another formulation (B) of the same drug, usually an established standard. F rel = ( AUC) drug/ (AUC) standard 14
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- 16. Methods for assessing bioavailability The methods useful in quantitative evaluation of bioavailability can be broadly divided into two categories: A. Pharmacokinetic methods B. Pharmacodynamic method A. Pharmacokinetic Methods: • These are very widely used and based on the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. 16
- 17. • Thus these are indirect methods. • The two major pharmacokinetic methods are: i. Plasma level-time studies ii. Urinary excretion studies Plasma Level-Time Studies The method is based on the assumption that two dosage forms that exhibit superimposable plasma level-time profiles in a group of subjects should result in identical therapeutic activity. 17
- 18. The 3 parameters of plasma level-time studies which are considered important for determining bioavailability are: 1. Cmax : The peak plasma concentration that gives an indication whether the drug is sufficiently absorbed systemically to provide a therapeutic response. It is a function of both rate and extent of absorption. Cmax will increase with an increase in the dose as well as with an increase in the absorption rate. 2. Tmax : The peak time that gives an indication of the rate of absorption. It decreases as the rate of absorption. 3. AUC : The area under the plasma level-time curve that gives a measure of the extent of absorption or the amount of drug that reaches the systemic circulation. 18
- 19. The extent of bioavailability can be determined by following equations: F = [AUC]oral Div [AUC]iv D oral F = [AUC]test Dstd [AUC]std Dtest Where, D= Dose administered With multiple dose study, the method involves drug administration for at least 5 biological half-lives with a dosing interval equal to or greater than the biological half-life to reach steady-state.19
- 20. Bioavailability can also be determined from the peak plasma concentration at steady-state Css,max according to following equation: Fr = (Css,max)test Dstd τtest (Css,max)std Dtest τstd Where τ = dosing interval 20
- 21. Determination of AUC and Css,max on multiple dosing upto steady-state 21
- 22. Urinary Excretion Studies This method of assessing bioavailability is based on the principle that the urinary excretion of unchanged drug is directly proportional to the plasma concentration of drug. The method involves: o Collection of urine at regular interval. o Analysis of unchanged drug in the collected sample o Determination of amount of drug excreted in each interval and cumulative amount excreted.22
- 23. The three major parameters examined in urinary excretion data obtained with a single dose study are: 1. (dXu/dt)max : The maximum urinary excretion rate, it is obtained from the peak of plot between rate of excretion versus midpoint time of urine collection period. Its value increases as the rate and extend of absorption increases. 2. (tu)max : The time for maximum excretion rate, it is analogous to the tmax of plasma level data. Its value decreases as the absorption rate increases. 3. Xu ∞ : The cumulative amount of drug excreted in the urine, it is related to the AUC of plasma level data and increases as the extend of absorption increases. 23
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- 25. The extent of bioavailability is calculated from equations given below: F = (Xu ∞)oral Div (Xu ∞)iv Doral Fr = (Xu ∞)test Dstd (Xu ∞)std Dtest With multiple dose study to steady-state, the equation for computing bioavailability is : Fr = (Xu,ss)test Dstd τtest (Xu,ss)std Dtest τstd Where Xu,ss = the amount of drug excreted unchanged during a single dosing interval at steady state 25
- 26. B. Pharmacodynamic Methods : These methods are complementary to pharmacokinetic approaches and involve direct measurement of drug effect on a pathophysiological process as a function of time The two pharmacodynamic methods involve determination of bioavailability from: i. Acute pharmacological response ii. Therapeutic response 26
- 27. Acute Pharmacological Response • When bioavailability measurement by pharmacokinetic methods is difficult, inaccurate or non-reproducible, an acute pharmacological effect such as a change in ECG or EEG readings, pupil diameter, etc. is related to the time course of a given drug. • The method requires measurement of responses for at least 3 biological half-lives of the drug in order to obtain a good estimate of AUC. Disadvantages of this method include – 1) More variable pharmacological response 2) Accurate correlation between measured response and drug available from the formulation is difficult. 27
- 28. Therapeutic Response Method : • This method is based on observing the clinical response to a drug formulation given to patients suffering from disease for which it is intended to be used. Drawbacks : 1) Quantitation of observed response is too improper. 2) Unless multiple-dose protocols are employed, a patient who require the drug for a disease would be able to receive only a single dose of the drug every few days or perhaps each week. 3) Many patients receive more than one drug, and the results obtained from a bioavailability study could be compromised because of a drug-drug interaction. 28