1. Bioavailability Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics Faculty of Pharmacy Omer Al-Mukhtar University Tobruk, Libya. E-mail: nanjwadebk@gmail.com 2014/03/151 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

2. CONTENTS 1.Concept and terminology. 2.Methods of assessing bioavailability. 3.Evaluation and design of a single dose bioequivalency study. 4.Determination of bioavailability and bioequivalency in multiple dose regimen. 5.References. 2014/03/152 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

3. What is Bioavailability Bioavailability, Indicates measurement of the rate and extent (amount) of therapeutically active drug that reaches the systemic circulation and is available at the site of action. 2014/03/153 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

4. Concept of Bioavailability Rate and extent at which therapeutically active drug reaches systemic circulation. The fraction of administered dose that reaches the systemic circulation in contrast to that stated on label. Rate & extent of absorption of unchanged drug from its dosage form. A measure relative to some standard of rate & amount of drug, which reaches the systemic circulation unchanged following the administration of dosage form. 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 4

5. Why bioavailability studies FDA requires that the drug product is safe and effective. Measure of bioavailability: AUC/dose. Absolute availability: Absolute availability for drugs with approved NDA, bioavailability studies are required for new drug formulations-bioequivalence to the reference formulation. Relative availability: Relative availability for drugs without full NDA, bioequivalence to the reference drug in the standard formulation. For determining safety and efficacy of drug product. 2014/03/155 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

6. Types of Bioavailability  Absolute Bioavailability :- If the systemic availability of a drug administered orally is determined by doing its comparison with I.V. administration, it is known as absolute bioavailability. 2014/03/156 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

7. Types of Bioavailability  Relative Bioavailability :- If the systemic availability of a drug administered orally is determined by doing its comparison with that of an oral standard of the same drug, it is known as a relative bioavailability. 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 7

8. Types of Bioavailability  Range of Bioavailability – 0 to 1.  It is usually expressed as percentages (%).  An absolute bioavailability of 1 (or 100%) indicates complete absorption.  Relative bioavailability of 1 (or 100%) implies that the bioavailability of drug from both the dosage forms is the same but does not indicate the completeness of the systemic drug absorption. 2014/03/158 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

9.  Bioavailability of drug from dosage form depends upon following.  Route of administration  Patient related factors  Physicochemical properties of the drug  Characteristics of the dosage form 2014/03/159 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. Types of Bioavailability

10. Bioavailability The influence of route of administration on drug’s bioavailability is generally in the following order Parenteral > Oral > Rectal > Topical Most drugs are administered orally, for reason of stability and convenience. The dose available to patient – Bioavailable dose. 2014/03/1510 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

11. Plasma concentration Time (hours) i.v. route oral route 11 2014/03/1511 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. Bioavailability

12. Methods of assessing bioavailability Pharmacokinetic methods ( indirect ) 1. Blood analysis 2. Urinary excretion data Pharmacodynamic methods ( direct ) 1. Acute pharmacological response 2. Therapeutic response 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 12

13. Pharmacokinetic methods ( indirect ) 1. Blood analysis Plasma level time studies or The plasma concentration – time curve or blood level curve. A direct relationship exists concentration of drug at the site of action & concentration of drug in the plasma. Serial blood samples are taken after drug administration & analyzed for drug concentration. A typical blood level curve obtained after oral administration of drug. 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 13

14. Pharmacokinetic methods ( indirect ) 2. Urinary excretion data The method of determination bioavailability provided that the active ingredient is excreted unchanged in the significant quantity of urine. The cumulative amount of active drug excreted in urine is directly proportional to extent of systemic drug absorption. The rate of drug excretion is directly proportional to rate of systemic drug absorption. 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 14

15. Pharmacodynamic methods ( direct ) 1. Acute pharmacological response Bioavailability can be determined from the acute pharmacologic effect – time curve as well as from dose response graph. 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 15

16. Pharmacodynamic methods ( direct ) 2. Therapeutic response This method is based on the observing the clinical response to a drug formulation given to a patients suffering from disease for which it is intended to be used. Eg. Anti inflammatory drugs, the reduction in the inflammation is determined. 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 16

17. Pharmacokinetic and Pharmacodynamic Parameters 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 17

18. Parameters determined Pharmacokinetic parameters Peak Plasma Concentration (C max ) Time of Peak concentration (t max ). Area Under Curve (AUC) Pharmacodynamics parameters Minimum Effective Concentration (MEC) / Minimum Inhibitory Concentration (MIC). Maximum Safe Concentration (MSC) / Maximum Safe Dose (MSD). Duration of action Onset of action. Intensity of action. 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 18

19. AUC or Extent of absorption can be measured by 3 methods 1.Planimeter Instrument for mechanically measuring the area 2. Cut & weigh method AUC is cut & weighed on analytical balance. The weight obtained is converted to proper unit by dividing it by the wt of a unit area of same paper. 3. Trapezoidal method 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 19

20. AUC or Extent of absorption can be measured by 3 methods 3. Trapezoidal method AUC = ½ ( C 1 + C 2 ) (t 2 – t 1 ) + ½ (C 2 + C 3 ) (t 3 – t 2 ) +……. ½ (C n-1 + C n ) (t n – t n-1 ) C = Concentration t = time subscript= sample number AUC = Area Under Curve 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 20

21. AUC-Area under curve C max - Maximum concentration T max -Time to maximum concentration 2014/03/1521 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. Methods of assessing bioavailability

22. Bioequivalence -Bioequivalence means pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions. -Bioequivalence studies are usually performed to compare the rate and/or extent of absorption of a new drug product or a generic equivalent with that of a recognized standard. 2014/03/1522 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

23. Dosage forms that are to be evaluated only for bioequivalence purpose. Dosage forms meant for a single dose administration for a therapeutic benefit such as analgesic for relief of headache. Evaluation and design of a single dose bioequivalency study 2014/03/1523 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

24. Evaluation and design of a single dose bioequivalency study 2014/03/1524 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

25. Determination of bioavailability and bioequivalency in multiple dose regimen Dosage forms designed to achieve special release profiles. e.g. time-release products, enteric-coated preparations. Drugs undergoing first pass metabolism. Special dosage regimens such as loading dose. 2014/03/1525 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

26. Dosage forms designed to achieve special release profiles. e.g. time-release products, enteric-coated preparations. Drugs undergoing first pass metabolism. Special dosage regimens such as loading dose. Determination of bioavailability and bioequivalency in multiple dose regimen 2014/03/1526 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

27. Bioavailability and Bioequivalence Two dosage forms are bioequivalent: not bioequivalent: 2014/03/1527 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

28. References “Biopharmaceutics & Pharmacokinetics”, D. M. Brahmankar & Sunil B. Jaiswal, Vallabh Prakashan. “Text book of Biopharmaceutics & pharmacokinetics”, Dr. Shobharani R. Hiramath. “Applied Biopharmaceutics & pharmacokinetics”, Leon Shargel & Andrew B.C. www.google.com 2014/03/1528 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

29. THANK YOU E-mail: nanjwadbk@gmail.com 2014/03/15 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 29