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Bioavailibility 112070804016

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Bioavailibility 112070804016

  1. 1. PREPARED BY:- PARTH PATEL M.Pharm-IQuality Assurance GUIDED BY:Mr. Ashok mahajan
  2. 2.  BIOAVAILABILITY: means rate & extent of absorption of unchanged drug from its dosage form or site of administration to the systemic circulation. Order: Parentral(i,.v)>oral>rectal>topical Absolute Bioavailability: It is the systemic availability of drug after extravascular administration compared to i.v dosing of the same drug. F= [AUC]oral / [AUC]i.v*doseiv/doseoral
  3. 3.  Relative Bioavailability: It is the systemic availability of the drug after oral administration is compared with that of an oral standard of the same drug. Fr=[AUC]test/ [AUC]std*dosetest/dosestd, where,Fr=Relative Bioavailability
  4. 4.  Primary stages of development of a suitable dosage form for a new drug entity. Development of new formulation of existing drugs. Determination of influence of Excipient, patient related factors, drug-interaction on efficiency of absorption. Control of quality of drug prior to marketing.
  5. 5.  A number of factors such as health, age, weight, enzyme status and number are concern. It is better to have the subjects of similar kinetics to avoid major variations. Health : Subjects should be of great health that is ascertained by various biochemical and medical examination.
  6. 6. Age : Elderly and children have different kinetics to adults. Subjects between 18 – 35 years are preferred.Number : Number of participants should be kept minimum required for carrying out a reliable, well designed study.
  7. 7. However, in overweight and underweight Vd maybe different. Hence, to better match the subject ,normal weights are preferred. Usually 140-200lbEnzyme Status : Enzyme activity can be altered by alteredkinetics of the drug in case of smokers or subjectstaking other drugs leading to drug-druginteraction.
  8. 8. Methods Of Bioavailability Indirect Direct Or Or Pharmacokinetic Pharmacodynamic Method method Urinary AcutePlasma-level Therapeutic Excretion Pharmacological Studies Response Studies Response
  9. 9.  Based on assumption that 2 dosage forms that exhibit super-imposable plasma level-time profiles in a group of subjects should result in identical therapeutic activity. For a single dose studies,3 sampling points & multiple dose studies 5-6 sampling points should be taken. Requires collection of blood for a period of 2-3 biological half-lives.
  10. 10.  Cmax : Represents maximum plasma drug concentration after oral administration of a drug. Indicates whether drug is sufficiently absorbed systemically to give a therapeutic response. Warns about toxic level of a drug.
  11. 11.  tmax: Represents to time required to reach maximum plasma concentration after drug administration. Indicates rate of absorption. At tmax, rate of absorption equals to rate of elimination. AUC: It is a measure of extent of drug bioavailability. Independent of route of administration. Measured by trapezoidal rule method.
  12. 12.  Based on assumption that the urinary excretion of unchanged drug is directly proportional to the plasma drug concentration. Concentration of metabolite excreted is never taken into account. Involves collection of urine for 7 biological half-lives.
  13. 13. (1) (dXu/dt)max: Maximum urinary excretion rate. Analogous to Cmax. It increases as rate & extent of absorption increases.(2) (tu)max: Time for maximum excretion rate. It increases as the rate of absorption decreases.(3) Xu: Cumulative amount of the drug excreted in the urine. It increases as the rate of absorption increases.
  14. 14. (1) Acute Phamacological Response: requires demonstration of dose-response curve. Includes determination of change in EEG or ECG readings,pupil diameter. Requires measurement of responses for at least 3 biological half-lives. Used when indirect method produce inaccurate results.
  15. 15. (2) Therapeutic response: Based on observing the clinical response to a drug formulation given to patient suffering from disease for which intended to be used. Disadvantages: Quantitation of response is too imprecise. Physiological status of the patient may be changed during study. Patient may not get sufficient drug for adequate treatment.
  16. 16. (1) Patient-related factors: Age Meal Body posture Emotional state Disease state G.I.T contents: - food-drug interaction - drug-drug interaction
  17. 17. (2) Dosage form related: Disintegration time Manufacturing variables - Manufacturing process - Excipients Nature & type of dosage form: Solutions>emulsion>suspension>coarse powder>capsules>tablets
  18. 18. (3) Physico-chemical properties of drug: Particle size & effective surface area It can be lowered by micronization,but it is true for non-hydrophobic drug. e.g. :Griseofulvin,Chloramphenicol,etc. It is vice-versa for hydrophobic drug e.g.: Aspirin,Phenacetin,Phenobarbital.Polymorphism & Amorphous Chloramphenicol palmitate A,B,C,out of these three polymorphic forms,B shows best availability.
  19. 19. Pseudo polymorphism (hydrates & solvates) Anhydrous form of theophylline & ampicillin have higher aqueous solubility than monohydrate & trihydrate form. Chloroform solvate of Griseofulvin are more water- soluble than their non-solvated form.Salt form of the drug Bioavailability of novobiocin from its sodium or calcium salt, & free acid was found to be in ratio of 50:25:1. Lipophilicity of the drug
  20. 20.  Bioavailability problems in oral controlled delivery system:(a) G.I.T transit time & regional absorption(b) Incomplete absorption(c) Increased first pass metabolism(d) Dose dumping(e) Effect of food(f) Effect of diurnal variation(g) Increased variability
  21. 21.  Satisfactory steady-state plasma level should be obtained with test & reference product in patients. Determination of Css should be determined by comparison of Cmin on 3 or more consecutive days. Failure to achieve satisfactory steady state may indicate lack of patient compliance, failure of dosage form performance.
  22. 22.  Comparison of pharmacokinetic parameters should be limited to subject who achieve steady-state condition. Comparison of AUC during a dosing interval is only proper if both test & reference drug are at steady state. Fluctuation greater than 15% should be closely examined or food effect, diurnal variation, achievement of steady state. Fluctuation=Cmax- Cmin/(Cmax+Cmin/2)
  23. 23. 1.Title a. Principal investigator b. Project or protocol number & date2.Study objective
  24. 24. 3.Study design a. Design b. Drug products -Test product -Reference product c. Dosage regimen d. Sample collection schedule e. Housing/Confinement f. Fasting meals g. Analytical method
  25. 25. 4.Study population a. Subjects b. Subject selection -Medical history -Physical examination - Laboratory tests c. Inclusion/Exclusion criteria d Restrictions/Prohibitions
  26. 26. 5. Clinical procedures a. Basic principles b. Biological sampling schedule & handling procedures c. Activity of subjects6. Ethical considerations: a. Basic principles b. Instituitional review board c. Informed consent d. Indications for subject withdrawal e. Adverse reactions & emergency procedures
  27. 27. 7. Facilities8. Data analysis a. Analytical validation procedure b. Statistical treatment of data9. Drug accountability10. Appendix
  28. 28.  Shargel.L,Applied Biopharmaceutics & pharmacokinetics, Fourth edition, Page no.247-252. Robinson.J,Controlled drug delivery,Second edition, Marcel Dekker Vol-29,Page no.294-321..
  29. 29.  Brahmankar.D.M,Biopharmaceutics & Pharmacokinetics-A Treatise, Page no.292-392.

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