This document discusses bioavailability and factors affecting it. It defines bioavailability as the rate and extent of absorption of a drug into systemic circulation from its dosage form. Absolute bioavailability is the systemic availability of a drug after extravascular administration compared to intravenous dosing. Relative bioavailability compares the systemic availability of a drug after oral administration to that of an oral standard. The document then discusses primary stages of drug development, factors affecting subject selection in bioavailability studies, and methods of assessing bioavailability including pharmacokinetic, urinary excretion, and pharmacological response methods.

1. PREPARED BY:-
PARTH PATEL
M.Pharm-I
Quality Assurance
GUIDED BY:
Mr. Ashok mahajan

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.  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.  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.  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. 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. However, in overweight and underweight Vd may
be different. Hence, to better match the subject ,
normal weights are preferred. Usually 140-200lb
Enzyme Status :
 Enzyme activity can be altered by altered
kinetics of the drug in case of smokers or subjects
taking other drugs leading to drug-drug
interaction.

8. Methods
Of
Bioavailability
Indirect Direct
Or Or
Pharmacokinetic Pharmacodynamic
Method method
Urinary Acute
Plasma-level Therapeutic
Excretion Pharmacological
Studies Response
Studies Response

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.  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.  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.  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. (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. (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. (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. (1) Patient-related factors:
 Age
 Meal
 Body posture
 Emotional state
 Disease state
 G.I.T contents:
- food-drug interaction
- drug-drug interaction

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. (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. 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.  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.  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.  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. 1.Title
a. Principal investigator
b. Project or protocol number & date
2.Study objective

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. 4.Study population
a. Subjects
b. Subject selection
-Medical history
-Physical examination
- Laboratory tests
c. Inclusion/Exclusion criteria
d Restrictions/Prohibitions

26. 5. Clinical procedures
a. Basic principles
b. Biological sampling schedule & handling
procedures
c. Activity of subjects
6. Ethical considerations:
a. Basic principles
b. Instituitional review board
c. Informed consent
d. Indications for subject withdrawal
e. Adverse reactions & emergency procedures

27. 7. Facilities
8. Data analysis
a. Analytical validation procedure
b. Statistical treatment of data
9. Drug accountability
10. Appendix

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.  Brahmankar.D.M,Biopharmaceutics &
Pharmacokinetics-A Treatise, Page no.292-392.