Date post: | 07-Aug-2015 |
Category: |
Documents |
Upload: | subodh-satish-s |
View: | 22 times |
Download: | 4 times |
ECPS 1
BIOAVAILABILITY
PRESENTED BYSUBODH S SATHEESH
MPHARM PHARMACEUTICS
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
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
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
Fab = (AUC)drug
(AUC)IV
ECPS 5
Absolute Bioavailability of Nimodipine for different routes:Oral : 1.17 % Nasal : 67.4 %Intravenous: 100%
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
ECPS 7
Plasma concentration versus time curve
Formulation A
Formulation B
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
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
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
ECPS 11
Limitations
More difficult and costly to conduct Requires more time to complete Poor complaince by patients
ECPS 12
Measurement of bioavailability
Pharmacokinetic methods Plasma level time studies Urinary excretion data Pharmacodynamic methods Acute pharmacologic response Therapeutic response
ECPS 13
Plasma level time studies
Collection of blood samples Construction of plot Sample points to be assessed Cmax Tmax AUC
ECPS 14
Extent of bioavailability
F= (AUC)oral Div/(AUC)iv Doral
Fr = (AUC)test Dstd / (AUC)std Dtest
Fr = (AUC)test Dstd τtest/ (AUC)std Dtestτtest
Fr = (Cssmax) Dstd τtest/(Cssmax)std Dtest τstd
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.
ECPS 16
Disadvantages
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
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
ECPS 18
Parameters obtained
(dXu/dt)max (tu)max Xu∞
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
ECPS 20
Pharmacodynamic methods
Acute pharmacologic response Therapeutic response
ECPS 21
BIOAVAILABILITY STUDY
PROTOCOL
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
ECPS 23
Experimental designs
Parallel group design Latin square design Cross over design Balance incomplete block design
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 B1 2
3 4
5 6
7 8
9 10
11 12
ECPS 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
ECPS 26
Latin Square Design
More than two formulations
A group of volunteers will receive formulations in the sequence shown
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
ECPS 28
Washout period
Time interval between treatments Removal of administered dose Ensures more than 99% of washout Depends on the experimental design
ECPS 29
Other steps
Drug product Reference standard Route of administration Administration of drug products
ECPS 30
sampling
For at least three elimination half-lives (cover >80% of AUC)
• Absorption phase : 3-4 points
• Around Tmax : 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
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 1st & 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
ECPS 32
Study conditions
Maintenance of uniform diet Washout Bioavailability trails has to be done
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
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
ECPS 35