bioavailability

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determinants of bioavailability:

determinants of bioavailability BY SHILPA.KANETI M.PHARM II-SEM PHARMACY PRACTICE VCOP,MGM HOSPITAL

contents:

contents INTRODUCTION TO BIOAVAILABILTY DEFINITION OBJECTIVES SIGNIFICANCE ABSOLUTE V S RELATIVE BIOAVAILABILITY DETERMINANTS FACTORS INFLUENCING BIOAVAILABILTY REFERENCES

introduction:

introduction The therapeutic effectiveness of a drug depends upon the ability of the dosage form to deliver the medicament to its site of action at a rate & amount sufficient to elicit the desired Pharmacological response. This attribute of the dosage form is referred to as physiologic availability or Bioavailability.

Definition :

Definition Bioavailability(%F) is the amount of drug that reaches the systemic circulation after absorption and first pass clearance. OR It is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route. This defines how much drug needs to be administered to achieve therapeutic effect.

contd…:

contd … Functional definition of %F % F oral= F abs × FG × FH Where F abs is the fraction absorbed FG is the fraction escaping the intestine FH is the fraction escaping the liver

Objectives of bioavailability studies:

Objectives of bioavailability studies Development of new formulation of existing drugs Determination of influence of excipients, patient related factors and possible interaction with other drugs on the efficiency of absorption Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption

Contd..:

Contd.. Primary stages of the development of a suitable dosage form for a new drug entity to obtain evidence of its therapeutic utility Comparison of availability of drug substance from different or same dosage forms produced by different manufacturers.

SIGNIFICANCE of bioavailability studies :

SIGNIFICANCE of bioavailability studies 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 Essential pharmacokinetic parameters, including the rate and extent of systemic absorption, elimination half-life, and rates of excretion and metabolism, should be established after single- and multiple-dose administration.

Contd…:

Contd… Data from these in-vivo bioavailability studies are important to establish recommended dosage regimens and to support drug labeling 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.

Bioavailability — absolute Vs relative:

Bioavailability — absolute Vs relative ABSOLUTE BIOAVAILABILITY : is the systemic availability of the drug after extravascular administration (oral,rectal,transdermal,subcutaneous) compared to IV dosing The absolute availability of a drug is generally measured by comparing the respective AUCs after extravascular and IV administration.

Contd…:

Contd… Absolute availability after oral drug administration using plasma data can be determined as follows F ab = (AUC) drug . (Dose) IV (AUC) IV . (Dose) drug

Contd..:

Contd.. RELATIVE (APPARENT) AVAILABILITY : is the availability of the drug from a drug product as compared to a recognized standard. The availability of drug in the formulation is compared to the availability of drug in a standard dosage formulation, usually a solution of the pure drug evaluated in a crossover study.

Contd..:

Contd. . The relative availability of two drug products given at the same dosage level and by the same route of administration can be obtained using the following equation: F rel = ( AUC) drug . (Dose ) standard (AUC) standard .(Dose) drug

GRAPH SHOWING DETERMINANTS OF BIOAVAILABILITY:

GRAPH SHOWING DETERMINANTS OF BIOAVAILABILITY

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I)PHARMACOKINETIC PARAMETERS A)PLASMA DRUG CONCENTRATION STUDIES i )Time for peak plasma conc.(t) max ii)Peak plasma drug concentration C max iii)Area under plasma drug conc -time curve(AUC) DETERMINANTS FOR ASSESSING BIOAVAILABILTY

PLASMA CONCENTRATION --- TIME PROFILE:

PLASMA CONCENTRATION --- TIME PROFILE C max T max AUC 16

Contd…:

Contd… i )t max . The time of peak plasma concentration corresponds to the time required to reach maximum drug concentration after drug administration At t max , peak drug absorption occurs and the rate of drug absorption exactly equals the rate of drug elimination Drug absorption still continues after t max is reached, but at a slower rate. When comparing drug products, t max can be used as an approximate indication of drug absorption rate

Contd…:

Contd … The value for t max will become smaller (indicating less time required to reach peak plasma concentration) as the absorption rate for the drug becomes more rapid. Units for t max are units of time (eg; hrs, min).

Contd…:

Contd… ii)C max . The peak plasma drug concentration ,represents the maximum plasma drug concentration obtained after oral administration of drug . provides indications that the drug is sufficiently systemically absorbed to provide a therapeutic response. provides warning of possibly toxic levels of drug.

Contd…:

Contd… The units of C max are concentration units (eg, mg/ mL , ng/ mL ). Although not a unit for rate, C max is often used in bioequivalence studies as a surrogate measure for the rate of drug bioavailability.

Contd….:

Contd…. iii)Area Under Curve :- AUC is the measurement of the extent of the drug bioavailability. It is the area under the drug plasma level-time curve from t =0 & t = ∞, and is equal to the amount of unchanged drug reaching the general circulation divided by the clearance [ AUC] 0 ∞ = ∫ 0 ∞ Cpdt [ AUC] 0 ∞ = FD 0 = FD O / kV D Clearance

Contd….:

Contd…. Where F = fraction of dose absorbed Do = dose, k = elimination rate constant, V D = volume of distribution AUC is independent of route of administration and process of drug elimination as long as the elimination process don’t change

Contd…:

Contd… The AUC can be determined by numerical integration procedure such as trapezoidal rule method The units for AUC are concentration time ( μ g hr/ml) For many drugs, AUC is directly proportional to the dose For eg. If a single dose of drug is increased from 250- 1000mg the AUC will also show a four fold increase

Contd…:

Contd… Plasma level–time curve following administration of single doses of (A) 250 mg, (B) 500 mg, and (C) 1000 mg of drug Linear relationship between AUC & dose

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B)URINARY EXCRETION STUDY PARAMETERS i )cumulative amount of drug excreted in the urine( D)∞u i i)maximum rate of drug excretion, ( dD u / dt ) max iii)total time for the drug to be excreted( t) ∞ Contd. .

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i ) D u ∞ The cumulative amount of drug excreted in the urine, D u ∞ is directly related to total amount of drug absorbed. Experimentally, urine samples are collected periodically after administration of the drug product. 26

Contd…:

Contd… Each urine specimen is analyzed for free drug with a specific assay. When the drug is almost completely eliminated (point c), the plasma concentration approaches zero and maximum amount of the drug excreted in the urine, D u ∞ is obtained

Slide 28:

The relationship between cumulative amount of drug excreted in urine and plasma level time curve is shown in fig., ( 1) 28

Contd..:

Contd.. ii) (dD u / dt ) max Because most drugs are eliminated by first order rate process , the rate of drug excretion is dependent on first order elimination rate constant k and the concentration of drug in the plasma Cp. In fig , the maximum rate of drug excretion would be at point B, the minimum rate of drug excretion would be at point A and C Graph comparing rate of drug excretion w.r . to time should be similar in shape as the plasma level- time curve for that drug

Contd…:

Contd… iii) t ∞ :- It is the total time for the drug to be excreted . In fig 1 & 2 , slope of curve segment A-B is related to the rate of drug absorption, whereas point C is related to the total time required after drug administration for the drug to be absorbed and completely excreted ( t = ∞).

Slide 31:

II ) PHARMACODYNAMIC PARAMETERS Maximum pharmaco dynamic effect ( E max ) Time for maximum pharmacodynamic effect Area under the pharmacodynamic effect–time curve Onset time for pharmacodynamic effect Contd…

contd..:

contd.. An Acute Pharmacodynamic effect such as an effect on pupil diameter , heart rate , or B.P can be used as an index of drug bioavailability In this case, an acute pharmacodynamic effect- time curve is constructed. Measurement of pharmacodynamic effect should be made with sufficient frequency to permit a reasonable estimate of the total AUC for a time period at least three times a half life of the drug.

Contd..:

Contd.. In this to determine bioavailability requires demonstration of a dose related response. Bioavailability is determined by characterization of dose-response curve. PD parameters that are obtained include total area under the acute PD effect- time curve, peak PD effect, & time for peak PD effect. onset time & duration of PK effect may also be included in the analysis of data.

Clinical trials in determining bioavailability:

Clinical trials in determining bioavailability Well-controlled clinical trials in humans establish the safety and effectiveness of drug products and may be used to determine bioavailability However, the clinical trials approach is the least accurate, least sensitive, and least reproducible of the general approaches for determining in-vivo bioavailability The FDA considers this approach only when analytical methods and pharmacodynamic methods are not available to permit use of one of the approaches described above.

INVITRO BIOAVAILABILITY STUDIES:

INVITRO BIOAVAILABILITY STUDIES Drug dissolution studies may under certain conditions give an indication of drug bioavailability. Ideally, the in-vitro drug dissolution rate should correlate with in-vivo drug bioavailability . Dissolution studies are often performed on several test formulations of the same drug. The test formulation that demonstrates the most rapid rate of drug dissolution in vitro will generally have the most rapid rate of drug bioavailability in vivo .

Factors influencing bioavailability:

Factors influencing bioavailability

Contd….…:

Contd…. …

Contd…:

Contd…

Contd…:

Contd… A drug faces its biggest hurdles during absorption. Medicines taken by mouth are shuttled via a special blood vessel leading from the digestive tract to the liver, where a large amount may be destroyed by metabolic enzymes in the so-called first -pass effect.

Contd..:

Contd.. The first-pass effect is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation. The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally Bioavailable fraction(F) is the fraction of administered dose that enters the systemic circulation F = Bioavailable dose Administered dose 40

Slide 41:

Processes that reduce the availability of orally taken drugs Dose Destroyed in gut Destroyed by gut wall Destroyed by liver to systemic circulation Not absorbed 03/03/2010 41 BIOBIO-2010, Hyderabad

WAYS OF BYPASSING FIRST PASS METABOLISM:

Two ways to bypass first pass metabolism involve giving the drug by sublingual and buccal routes The drugs are absorbed by the oral mucosa in both methods In sublingual administration the drug is put under the tongue where it dissolves in salivary secretions In buccal administration the drug is placed between the teeth and the mucous membrane of the cheek.eg..nitroglycerine Sublingual and buccal methods both avoid destruction by the GI fluids and first pass effect of the liver WAYS OF BYPASSING FIRST PASS METABOLISM

Contd…:

Contd…

Contd….:

Contd… . The influence of route of administration on drug’s bioavailability is generally in the following order; Parenteral > Oral > Rectal > Topical Within the parenteral route, IV injection of a drug results in 100% bioavailability as the absorption process is bypassed

Bioavailability of drug from common routes of administration :

Bioavailability of drug from common routes of administration PARENTERAL BIOVAILABILITY ADVANTAGES DISADVANTAGES Intravenous Complete systemic absorption .For immediate or controlled effect .Can inject large fluid volumes Suitable for irritating drugs .More chance of ADR .Tissue damage at site of injection .Requires skill in insertion of infusion set Intramuscular .Rapid absorption from aqueous solutions & slow from non-aqueous solutions .Easier to inject than iv .volumes may be used compared to sub cutaneous Variable routes of absorption depending on blood flow & muscle group injected. subcutaneous Rapid absorption from aqueous solution Used for vaccines & drugs not absorbed orally. Rate of drug absorption depends on blood flow.

Contd…:

Contd… ENTERAL ROUTES BIOAVAILABILITY ADVANTAGES DISADVANTAGES B uccal or sublingual .Rapid absorption of lipid soluble drugs . No pre -systemic metabolism Some drugs may be swallowed Oral Slower absorption rate compared to IV bolus or IM injection Safest & easiest .suitable for both immediate & modified release drug products Some drugs are unstable in GIT or undergo pre systemic metabolism Rectal .more reliable absorption from enema(solution) .useful when patient can’t swallow Absorption may be erratic.

Contd…:

Contd… OTHER ROUTES BIOAVAILABILITY ADVANTAGES DISADVANTAGES Transdermal . Slow absorption .increased absorption with occlusive dressings. .Transdermal patch is easy to use & withdraw. .low pre systemic metabolism .continuous release for a specified period .some irritation by patch or drug .permeability of skin varies with age,gender,anatomic site Inhalation .Rapid absorption .may be used for local or systemic effects .may stimulate cough reflex .some drug may be swallowed

Slide 48:

Plasma concentration Time (hours) Bioavailability ( AUC)o (AUC)iv = i.v . route oral route 48 .

references:

references Biopharmaceutics & Pharmacokinetics --- D.M.Brahmankar Applied Biopharmaceutics & Pharmacokinetics ---Leon Shargel www.google .com

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Thank you

Thought for the day:

Thought for the day

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