Bioavailability

M PHARMA SECOND SEM SEMINAR

1. BIOAVAILABILITY PAD.DR.D.Y.PATIL COLLEGE OF PHARMACY AKURDI PUNE. PRESENTED BY MR.VILAS KAMBLE M.PHARM.II SEM. GUIDED BY MRS . DR.USHA SHINDE

2. CONTENT

3. INTRODUCTION The therapeutic effectiveness of a drug depends upon the ability of dosage form to deliver the medicament to its site of action at a rate and attribute of a dosage form.

4. INTRODUCTION Definition:- The rate and extent (amount) of absorption of unchanged drug from its dosage form.

5. INTRODUCTION Bioavailability depends upon three major factor.

6. INTRODUCTION

7. INTRODUCTION However, for reasons of stability and convenience, most drug are administered orally. In such case the dose available to the patient, called as bioavailable dose. Bioavailable fraction:- Bioavailable dose = Administered dose

8. OBJECTIVE In R&D of suitable dosage form. Determination of influence of excipient, patient related factors and drug interaction on the efficiency of absorption. Development of new formulation of existing drug. QC of dosage form. Comparison of BA of a drug substance from different dosage forms or from the same dosage form produce by different manufacture.

9. CONSIDERATION IN BIOAILABILITY STUDY DESIGN Absolute vs. relative Absolute bioavailability (F):- W hen the systemic BA of a drug administer orally is determine to its i.v administration, it is called as absolute BA. Importance:- To characterize drug’s inherent absorption properties from the i.v site.

10. CONSIDERATION IN BIOAILABILITY STUDY DESIGN Relative bioavailability (F r ):- When the systemic availability of a drug after oral administration is compare with that of an oral standard of the same drug it is refer to as comparative or relative bioavailability. Importance:- Used to characterize absorption of drug from its formulation.

11. CONSIDERATION IN BIOAILABILITY STUDY DESIGN Single dose vs. Multiple Dose studies. The dose to be administered for a bioavailability study is determine by preliminary clinical experiment.

12. CONSIDERATION IN BIOAILABILITY STUDY DESIGN Single dose study

13. CONSIDERATION IN BIOAILABILITY STUDY DESIGN Multiple dose study

14. CONSIDERATION IN BIOAILABILITY STUDY DESIGN

15. CONSIDERATION IN BIOAILABILITY STUDY Design Human volunteers-Healthy Subject vs. Patient Ideally, the bioavailability study should be carried out in patients for whom the drug is intended to be used.

16. CONSIDERATION IN BIOAILABILITY STUDY Design

17. MEASUREMENT OF BOAVAILABILITY

18. MEASUREMENT OF BOAVAILABILITY Pharmacokinetic method:- These method are based on the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus, these are indirect methods

19. MEASUREMENT OF BOAVAILABILITY Plsma level time studies:- Most common type of human bioavailability studies . Based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action . Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content

20. MEASUREMENT OF BOAVAILABILITY Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content. A profile is constructed showing the concentration of drug in blood at the specific times the samples were taken . Bioavailability is generally assessed by the determination of following three parameters.

21. MEASUREMENT OF BOAVAILABILITY Two dosage form having same plasma level time profile should result in identical therapeutic activity. Plot of concentration vs. time of sample collection to obtained a plasma level time profile

22. MEASUREMENT OF BOAVAILABILITY TIME IN MIN. CONCE OF DRUG IN MICROGRAM PER ML

23. MEASUREMENT OF BOAVAILABILITY Bioavailability is generally assessed by the determination of following three parameters .

24. MEASUREMENT OF BOAVAILABILITY

25. MEASUREMENT OF BOAVAILABILITY Cmax: (Peak plasma drug concentration)  Maximum concentration of the drug obtained after the administration of single dose of the drug. Expressed in terms of μg/ml or mg/ml. Tmax : (Time of peak plasma conc.) Time required to achieve peak concentration of the drug after administration. Gives indication of the rate of absorption. Expressed in terms of hours or minutes.

26. MEASUREMENT OF BOAVAILABILITY 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.

27. MEASUREMENT OF BOAVAILABILITY The extent of bioavailability can be determined by the following equations: For single dose study For multiple dose study:

28. MEASUREMENT OF BOAVAILABILITY Urinary Excretion Studies: Urinary excretion of unchanged drug is directly proportional to plasma concentration of drug. Thus , even if a drug is excreted to some extent (at least 10 to 20%) in the urine, bioavailability can be determined. e.g.: Thiazide diuretics, Sulphonamides . Method is useful when there is lack of sufficiently sensitive analytical technique to measure drug concentration . Noninvasive method, so better patient compliance.

29. MEASUREMENT OF BOAVAILABILITY Three Important Parameters in urine excretion data for single dose study:

30. MEASUREMENT OF BOAVAILABILITY Plot of urinary excretion rate V s time

31. MEASUREMENT OF BOAVAILABILITY (dx u / dt )max :(Maximum urinary excretion rate) Its value increases as rate and/or extent of absorption increases. Obtained from peak of plot between rate of excretion versus midpoint time of urine collection period.   ( t u ) max: Time for maximum excretion rate

32. MEASUREMENT OF BOAVAILABILITY Its value decreases as absorption rate increases. Analogues of t max of plasma level data . X u ∞ : Cumulative amount of drug excreted in urine Related to AUC of plasma level data. It increases as the extent of absorption increases .  

33. MEASUREMENT OF BOAVAILABILITY The extent of bioavailability is calculated from equation : For single dose study: For multiple dose study:

34. MEASUREMENT OF BOAVAILABILITY Acute Pharmacologic Response Method : When bioavailability measurement by pharmacokinetic method is difficult, an acute pharmacologic effect such as effect on pupil diameter, EEG & ECG readings related to time course of drug. Bioavailability can then be determined by construction of pharmacological effect- time curve as well as dose response graphs.

35. MEASUREMENT OF BOAVAILABILITY Disadvantage: It tends to be more variable. Observed response may be due to an active metabolite whose concentration is not proportional to concentration of parent drug.

36. MEASUREMENT OF BOAVAILABILITY Therapeutic Response Method: This method based on observing the clinical response to a drug formulation given to patient suffering from disease.

37. MEASUREMENT OF BOAVAILABILITY Drawbacks: The major drawbacks of this method is that quantitation of observed response is too improper to allow for reasonable assessment of relative bioavailability between two dosage forms of the same drug. E.g.: Anti-inflammatory drugs. Many patients receive more than one drug

38. MEASUREMENT OF BOAVAILABILITY Drug dissolution studies may under certain conditions give an indication of drug bioavailability. Dissolution studies are often performed in several test formulations of the same drug.

39. MEASUREMENT OF BOAVAILABILITY The test formulation that demonstrates the most rapid rate of drug bioavailability in-vitro will generally have the most rapid rate of drug bioavailability in-vivo . The FDA may also use the other in-vitro approaches for establishing bioequivalence. Ex: Cholestyramine resin.

40. REFRENCES Brahmankar .D.M , Sunil Jaiswal, “Biopharmaceutics and Pharmacokinetics-A Treatise”, Second edition, page no. 236-337 . V Venkateshwarlu , “ Biopharmaceutics & pharmacokinetics’’ page no. 403-416.