Bioavailability

i hope it will b useful for pharmacy students
especially useful for those who got biopharmaceutics as a subject

1. BIOAVAILABILITY PRESENTED BY SUBODH S SATHEESH MPHARM PHARMACEUTICS 1 ECPS

2. Introduction Essential to ensure uniformity in standards of quality, efficacy & safety of Pharmaceutical products Reasonable assurance is to be provided that various products containing same active ingredient, marketed by different licensees are clinically equivalent & interchangeable Release of an active substance should be known & reproducible Both Bioavailability & Bioequivalence focus on release of substance from its dosage form & subsequent absorption in circulation Similar approaches to measure Bioavailability should be followed in demonstrating Bioequivalence 2 ECPS

3. Bioavailability Measurement of the relative amount & rate at which, the drug from administered dosage form,reaches the systemic circulation & becomes available at the site of action Bioavailable fraction (F), refers to the fraction of administered dose that enters the systemic circulation F = Bioavailable dose Administered dose 3 ECPS

4. 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 F ab = (AUC) drug (AUC) IV 4 ECPS

5. Absolute Bioavailability of Nimodipine for different routes: Oral : 1.17 % Nasal : 67.4 % Intravenous : 100% 5 ECPS

6. 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 6 ECPS

7. Therapeutic range MTC MEC Plasma concentration versus time curve Formulation A Formulation B 7 ECPS

8. Factors affecting bioavailability Liquids > Solids Important for sparingly soluble drugs ↓ the size, ↑ the absorption Ionization : Unionized form penetrates the GI mucosal lining quickly pH of the fluid : Weakly acidic drugs : Aspirin, Barbiturates→ Stomach, duodenum Weakly basic drugs : Pethidine , Ephedrine→ Small intestine Strongly acidic / basic drugs : highly ionized & poorly absorbed Prolonged gastric emptying : Delays absorption due to stasis Disease states : Malabsorption , Achlorhydria , Cirrhosis, Biliary obstruction can hamper absorption Interactions with other drugs foods etc Whether the formulation is administered in fasted or fed state Presence of other agents 8 ECPS

9. Single dose and multiple dose studies Easier method but many disadvantages Tedious method Cannot effectively describe the steady state character of drugs Most of the disadvantages can be overcome by multiple dose methods 9 ECPS

10. Multiple dose studies Clinical uses of drugs are accurately reflected Requires collection of few blood sample Better evaluation of performance of C-R formulations Nonlinearity of p.kinetics can be easily detected Easy to predict peak and valley characters of drug 10 ECPS

11. Limitations More difficult and costly to conduct Requires more time to complete Poor complaince by patients 11 ECPS

12. Measurement of bioavailability Pharmacokinetic methods Plasma level time studies Urinary excretion data Pharmacodynamic methods Acute pharmacologic response Therapeutic response 12 ECPS

13. Plasma level time studies Collection of blood samples Construction of plot Sample points to be assessed Cmax Tmax AUC 13 ECPS

14. Extent of bioavailability F= (AUC) oral D iv /(AUC) iv D oral Fr = (AUC) test D std / (AUC) std D test F r = (AUC) test Dstd τ test / (AUC) std D test τ test F r = ( Cssmax ) D std τ test /( Cssmax ) std D test τ std 14 ECPS

15. Urinary excretion data Method Direct measurement of bioavailability, both absolute and relative. When coupled with plasma level-time data, it can also be used to estimate renal clearance of unchanged drug If Vd is known, total systemic clearance and nonrenal clearance can also be calculated. 15 ECPS

16. D isadvantages One cannot however compute Vd and Clt from urine data alone . One must also remember that urinary excretion data is not an accurate substitute for the plasma level data the data can be employed as a rough estimate of the pharmacokinetic parameters. if the drug has very long biological half-life, the resulting low urinary drug concentration may be too dilute to be assessed with accuracy 16 ECPS

17. Criteria for obtaining valid UE data A significant amount of drug must be excreted unchanged in the urine (at least 10 %). Before administration of drug, the bladder must be emptied completely. Volunteers must be instructed to completely empty their bladder while collecting urine samples. Frequent sampling should be done in order in order to obtain a good curve. During sampling, the exact time and volume of urine excreted should be noted. Urine samples must be collected for at least 7 biological half-lives in order to ensure collection of more than 99% of excreted drug . Changes in urine pH and urine volume may alter the urinary excretion rate 17 ECPS

18. Parameters obtained ( dXu / dt )max ( tu )max Xu ∞ 18 ECPS

19. Extent of bioavailability Absolute bioavailability  F = [ Xu ]∞ oral x [Dose] iv / [ Xu ]∞ i.v x [Dose] oral Relative bioavailability: Fr = [ Xu ]∞ test x [Dose] std [ Xu ]∞ std x [Dose] test With multiple dose study to steady state, the eq for computing bioavailability is : Fr = [ Xu,ss ]∞ test x [Dose] std [ Xu,ss ]∞ std x [Dose] test 19 ECPS

20. Pharmacodynamic methods Acute pharmacologic response Therapeutic response 20 ECPS

21. BIOAVAILABILITY STUDY PROTOCOL 21 ECPS

22. Steps involved Study objective Experimental design Washout period Drug product Route of administration Dosage regimen Frequency and duration of sampling Analysis of biological fluids 22 ECPS

23. Experimental designs Parallel group design Latin square design Cross over design Balance incomplete block design 23 ECPS

24. Parallel-Group Design Even number of subjects in two groups Each receive a different formulation No washout necessary For drugs with long half life Treatment A Treatment B 1 2 3 4 5 6 7 8 9 10 11 12

25. 2 formulations, even number of subjects, randomly divided into 2 equal groups First period , each member of one group receive a single dose of the test formulation; each member of the other group receive the standard formulation After a wash period (5 half lives), in second period , each member of the respective groups will receive an alternative formulation & experiment will be repeated. Subjects Period 1 Period 2 1-8 T S 9-16 S T Parallel group design 25 ECPS

26. Latin Square Design More than two formulations A group of volunteers will receive formulations in the sequence shown 26 ECPS

27. Balance Incomplete Block Design (BIBD) More than 3 formulations, Latin square design will not be ethically advisable Because each volunteer may require drawing of too many blood samples If each volunteer expected to receive at least two formulation, then such a study can be carried out using BIBD 27 ECPS

28. Washout period Time interval between treatments Removal of administered dose Ensures more than 99% of washout Depends on the experimental design 28 ECPS

29. Other steps Drug product Reference standard Route of administration Administration of drug products 29 ECPS

30. sampling For at least three elimination half-lives (cover >80% of AUC) Absorption phase : 3-4 points Around T max : 3-4 points During elimination : 4 points Intervals not longer than the half-life of the drug If urine tested, collect it for at least 7 half-lives 30 ECPS

31. Selection of subjects Healthy adult volunteers Age : 18-45 yrs Age/Sex representation corresponding to therapeutic & safety profile Weight within normal limits→ BMI Women : Pregnancy test prior to 1 st & last dose of study; OC pills C/I Drug use intended in Elders (Age >60yrs) Teratogenic Drugs→ Male volunteers Highly toxic drugs : Patients with concerned disease (stable) eg . Cancer 31 ECPS

32. Study conditions Maintenance of uniform diet Washout Bioavailability trails has to be done 32 ECPS

33. Analysis of biological samples Collection by Sampling procedure Selective methods It should be specific and highly sensitive Non specific analytical methods should be avoided 33 ECPS

34. REFERENCES Bioavailability and bioequivalence by S Kunal page 1-43 Biopharmaceutics and pharmacokinetics a treatise by DM Brahmankar 315-333 Biopharmaceutics and pharmacokinetics my Leon Shargel Bioavailability and bioequivalence by Dr Mothilal 34 ECPS

35. 35 ECPS