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.