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Factors affecting Bioavailability. Measurement of Bioavailability. Methods for enhancing Bioavailability. Introduction to Bioequivalence. Limitations of BA/BE studies. HISTORY: : HISTORY: Phenytoin toxicity in epileptic patients which occurred in the year 1968 in Australia The differences in the bioavailability observed with different digoxin formulations in the year 1971. DEF : BIOAVAILABILITY : DEF : BIOAVAILABILITY “The term Bioavailability is defined as a rate & extent (amount) of absorption of unchanged drug from its dosage form.” - Brahmankar & Jaiswal Slide 5: “Bioavailability is a term used to indicate the fractional extent to which a dose of drug reaches its site of action or a biological fluid from which the drug has access to its site of action.” - Goodman & Gillman Objectives of Bioavailability studies : : Objectives of Bioavailability studies : During primary stages of development of suitable dosage forms of new drug entity . Determination of influence of excipients , patient related factors & possible interaction with other drugs on the efficiency of absorption . Development of new formulations of existing drugs . Significance of Bioavailability : Significance of Bioavailability Drugs having low therapeutic index, e.g. cardiac glycosides, quinidine, phenytoin etc.and narrow margin of safety ( e.g. antiarrythmics, antidiabetics, adrenal steroids, theophylline ) Drugs whose peak levels are required for the effect of drugs, e.g. phenytoin, phenobarbitone, primidone, sodium valporate, anti-hypertensives,antidiabetics and antibiotics. Drugs that are absorbed by an active transport,e.g. amino acid analogues. Purine analogues etc. Slide 8: Drugs which are disintegrated in the alimentary canal and liver,e.g.chiorpromazine etc. or those which under go first pass metabolism. Formulations that give sustained release of drug. Any new formulation has to be tested for its bioavailability profile. Drugs with steep dose response relationship i.e. drugs obeying zero order kinetics / mixed order elimination kinetics ( e.g. warfarin , phenytoin, digoxin, aspirin at high doses, phenylbutazone) Components : Components Rate of absorption – the rapidity with which the drug is absorbed. - Rapid onset : conditions like acute attack of asthma, intense acute pain - Slower onset : To prolong duration of action To avoid adverse effects. Extent of absorption -chronic conditions like HTN, Epilepsy Bioavailable fraction (F) : Bioavailable fraction (F) It refers to the fraction of administered dose that enters the systemic circulation. Bioavailable dose F = ------------------------------ Administered dose Factors affecting Bioavailability : : Factors affecting Bioavailability : A ) Pharmaceutic factors :1) Physicochemical properties of drug : : A ) Pharmaceutic factors :1) Physicochemical properties of drug : Drug solubility & dissolution rate. Particle size & effective surface area. Polymorphism & Amorphism. Amorphous > metastable > stable Pseudopolymorphism (Hydrates / Solvates ) Anhydrates > hydrates e.g. Theophylline, Ampicillin Organic solvates > non solvates e.g. fludrocortisone Salt form of the drug. Weakly acidic drugs – strong basic salt e.g.barbiturates , sulfonamides. Weakly basic drugs – strong acid salt Lipophilicity of the drug . pKa of the drug & pH . Drug stability. 2) Dosage form characteristics & Pharmaceutic Ingredients : : 2) Dosage form characteristics & Pharmaceutic Ingredients : Disintegration time (tab/cap) Dissolution time. Manufacturing variables. Pharmaceutic ingredients ( excipients / adjuvants ) Nature & type of dosage form. Solutions> Emulsions> Suspensions> Cap> Tab> Enteric Coated Tab > Sustained Release Product age & storage conditions. B ) Patient related factors : : B ) Patient related factors : Age Gastric emptying time . Intestinal transit time . Gastrointestinal pH .(HCL > Acetic > citric ) Disease States . Blood flow through the gastrointestinal tract . Gastrointestinal contents : Other drugs . Food . Fluids Other normal g.i. contents Presystemic metabolism (First – Pass effect ) by : Luminal enzymes . Gut wall enzymes . Bacterial enzymes . Hepatic enzymes . C ) Routes of administration : : C ) Routes of administration : Parenteral > Rectal > Oral > Topical Slide 16: Route Bioavailability (%) Characteristics Intravenous 100 (by definition) Most rapid onset (IV) Intramuscular 75 to ≤ 100 Large volumes often feasible; may be (IM) painful Subcutaneous 75 to ≤ 100 Smaller volumes than IM; may be painful (SC) Oral (PO) 5 to < 100 Most convenient; first pass effects may be significant Rectal (PR) 30 to < 100 Less first-pass effects than oral Inhalation 5 to < 100 Often very rapid onset Transdermal 80 to ≤ 100 Usually very slow absorption; used for lack of first-pass effects; prolonged duration of action Absolute Bioavailability ( F ) : Absolute Bioavailability ( F ) Def : “When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration ,is called as Absolute Bioavailability” Dose (iv) x AUC (oral) % Absorption = ------------------------------- X 100 Dose (oral) x AUC (iv) Relative Bioavailability ( Fr ) : Relative Bioavailability ( Fr ) Def : “ When the systemic availability of the drug after oral administration is compared with that of oral standard of same drug ( such as aqueous or non aqueous solution or a suspension ) is referred as Relative Bioavailability” e.g. comparison between cap. Amox and susp. Amox Single dose vs Multiple dose studies : : Single dose vs Multiple dose studies : Single dose study : Advantages: More common Easy, less tedious Less exposure to drug Disadvantages: Difficult to predict steady state characteristics : Multiple dose study : Advantages : Accurate Easy to predict the peak & valley characteristics of drug Few blood samples required Ethical Small intersubject variability Better evaluation of controlled release formulations. Can detect non linearity in pharmacokinetics. Higher blood levels ( d/t cumulative effect ) Disadvantages : Poor subject compliance . Tedious , time consuming More drug exposure. Human volunteers :Healthy subjects vs. patients ? : Human volunteers :Healthy subjects vs. patients ? Patients : used in multiple dose studies. Advantages : Patient gets benefited from the study. Reflects better therapeutic efficacy. Drug absorption pattern in disease states evaluated. Avoids ethical quandary. Disadvantages : Disease states , other drugs affects study Difficult to follow stringent study conditions. Slide 22: Healthy human volunteers : Young Healthy Male ( females : e.g. OC pills study ) Body wt. within narrow range. Restricted dietary & fixed activity conditions. Measurement of Bioavailability : Measurement of Bioavailability 1 ) Plasma level-time studies: : 1 ) Plasma level-time studies: Two dosage forms that exhibit super imposable plasma level-time profiles should result in identical therapeutic response. [AUC]oral x [D] iv F = ------------------------------ [AUC]iv x [ D ]oral Slide 26: Important parameters Cmax - peak plasma concentration t max - time taken to reach peak concentration - it indicates rate of absorption AUC - Area Under the plasma level time Curve give the measure of extent of absorption In multiple dose study: : In multiple dose study: Urinary excretion studies : : Urinary excretion studies : Urinary excretion α plasma concentration of drug Mainly used in drugs extensively excreted unchanged in urine. E.g. Thiazide diuretics Sulfonamides Urinary antiseptics : nitrofurantoin , Hexamine. [Xu∞]oral x D iv F = ------------------------------- [ Xu∞]iv x D oral Slide 29: (dXu / dt)max : Maximum urinary excretion rate (tu ) max : Time for maximum urinary excretion rate Xu : Cumulative amount of drug excreted in the urine. Biological fluids used for determination of Bioavailability : Biological fluids used for determination of Bioavailability Plasma Urine Saliva CSF Bile B. Pharmacodynamic methods : B. Pharmacodynamic methods 1) Acute Pharmacological Response : - Used when pharmacokinetic methods are difficult , inaccurate & non reproducible. - E.g. Change in ECG/EEG readings. Pupil diameter Disadvantages : More variable Active metabolite interferes with the result. Slide 32: 2 ) Therapeutic Response : - measurement of clinical response to a drug formulation given to patients suffering from disease for which it is intended to be used. Disadvantages : Improper quantification of observed response. Drug dissolution rate & Bioavailability : : Drug dissolution rate & Bioavailability : Correlation between Dissolution testing and bioavailability In vivo determination test : Tool in the development of new dosage form. In vitro dissolution test : To ensure batch to batch consistency Best available tool which can quantitatively assure about bioavailability. Drug Dissolution Apparatus : Drug Dissolution Apparatus Rotating Basket Apparatus Example of Closed Compartment Apparatus : Rotating Basket Apparatus Example of Closed Compartment Apparatus Rotating Paddle ApparatusExample of Closed Compartment Apparatus : Rotating Paddle ApparatusExample of Closed Compartment Apparatus BIOEQUIVALENCE : BIOEQUIVALENCE Definition : “ It is a relative term which denotes that the drug substance in two or more identical dosage forms , reaches the circulation at the same relative rate & to same relative extent i.e. their plasma concentration-time profiles will be identical without significant statistical differences.” Slide 38: Pharmaceutical equivalence : “Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration.” Therapeutic equivalence : “ It indicates that two or more drug products that contain the same therapeutically active ingredient, elicit identical pharmacological effects & can control the disease to the same extent” Clinical equivalence: “ when the same drug from two or more dosage forms gives identical in vivo effects as measured by a pharmacological response or by control of a symptom or a disease.” Methods for enhancement of Bioavailability : Methods for enhancement of Bioavailability Pharmaceutical Approach: : Pharmaceutical Approach: It involves modification of --formulations, manufacturing process or the physicochemical properties of drug without changing the chemical structure. Mainly aimed at enhancement of dissolution rate ( rate limiting step ). Pharmacokinetic approach : : Pharmacokinetic approach : Modification of chemical structure . Biologic approach : Changes in the routes of administration. : Micronization . Methods: - spray drying - air attrition methods. E.g. : Aspirin Griseofulvin Steroidal compounds Sulfa drugs Methods to increase effective surface area : Slide 43: Use of surfactants : ‘Surfactants promote wetting & penetration of fluids into solid drug particles.’ Better membrane contact. Enhanced membrane permeability. - Surfactants are used below CMC(critical micelle concentration) E.g. Spironolactone Use of salt forms: E.g. Alkali metal salts of acidic drugs like penicillins Strong Acid salt of basic drugs like atropine. Slide 44: Alteration of pH of drug microenvironment: In situ salt formation Buffered formulation e.g. Aspirin Use of Metastable Polymorphs : - more stable than stable polymorph e.g. Chloramphenicol palmitate . Slide 45: Solute-solvent complexation: - Solvates of drugs with organic solvents ( pseudo polymorphs) have higher aqueous solubility than their respective hydrates or original drug . E.g. 1:2 Griseofulvin – Benzene solvate. Selective adsorption on insoluble carriers : - A highly active adsorbent like inorganic clay e.g. Bentonite, enhance dissolution rate by maintaining concentration gradient at its maximum. E.g. Griseofulvin Indomethacin Prednisone. Slide 46: Solid solution( Molecular dispersion/mixed crystals ) : - It is a binary system comprising of solid solute molecularly dispersed in a solid solvent. - Systems prepared by Fusion method : Melts - e.g. Griseofulvin-succinic acid Solid dispersions (Co evaporators/co precipitates) : - Both the solute and solid carrier solvent dissolved in common volatile liquid e.g. Alcohol - The drug is precipitated out in an amorphous form as compared to crystalline forms in solid solutions/eutectics. E.g. Amorphous sulfathiazole in crystalline urea. Slide 47: Eutectic mixture : -It is intimately blended physical mixture of two crystalline components. - Paracetamol -urea - Griseofulvin – urea - Griseofulvin-succinic acid Disadvantage : Not useful in : Drugs which fail to crystallize from mixed melt. Thermo labile drugs Carrier like succinic acid decompose at their melting point. Slide 48: Molecular encapsulation with Cyclodextrins : -β and γ Cyclodextrins have ability to form inclusion complexes with hydrophobic drug having poor aqueous solubility. - These molecules have inside hydrophobic cavity to accommodate lipophilic drug , outside is hydrophilic. E.g. Thiazide diuretics Barbiturates Benzodiazepines NSAIDS. Limitations of BA/BE studies : : Limitations of BA/BE studies : Difficult for drugs with a long elimination half life. Highly variable drugs may require a far greater number of subjects Drugs that are administered by routes other than the oral route drugs/dosage forms that are intended for local effects have minimal systemic bioavailability. E.g. ophthalmic, dermal, intranasal and inhalation drug products. Biotransformation of drugs make it difficult to evaluate the bioequivalence of such drugs:e.g. stereoisomerism Slide 50: Thank You ! You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.