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Pharmacokinetics Pharmacodynamics
“what the body does to the drug” “what the drug does to the body”
Absorption wanted effects - efficacy
Distribution unwanted effects - toxicity
Metabolism
Elimination
disposition
Pharmacokinetics Pharmacodynamics
General Outline
Basic Pharmacokinetic Concepts
Bioavailability
Definition
How absorption affects bioavailability?
Food Effect
How drug metabolism affects bioavailability?
How transporters affect bioavailability?
Bioequivalence
Definition
Bio-IND
Waivers of In Vivo Study Requirements
Biopharmaceutics Classification System (BCS)
Basic Concepts
Easy to understand using intravenous route
Drug Product
No absorption phase
Simple to follow
Concepts clear with less assumptions
Drug in Distribution to
Blood Tissue and Receptor sites
IV administration, contd.,
its PK characteristics.
This is achieved by analyzing the changes
of the drug and/or its metabolite(s) in
blood, plasma, urine etc.
A simple approach is to generate Drug
Concentration-Time profile
Sampling at
Dosing Bio-analytics Conc. vs time
Pre-determined
profiles
Time intervals
Two-Compartment Model
Dose
Central compartment (drug entry and elimination) 1 2
Tissue compartment (drug distributes)
Volume of Distribution
The concentration in plasma is achieved after distribution is complete is a function of dose
and extent of distribution of drug into tissues
This extent of distribution can be determined by relating the concentration obtained with a
known amount of drug in the body
Volume of Distribution
Case -1
At Time zero, the drug amount in the body is the dose (500 mg)
Calculated drug concentration at Time zero is 50 mg/L
Then, the V = 10 L
Case -2
Dose = 500 mg
Calculated Concentration at time Zero is 5 mg/L
Then, V = 100 L
Drug metabolism/biotransformation
½ life = how much time it takes for blood levels of drug to decrease to half
of what it was at equilibrium
There are really two kinds of ½ life…
“distribution” ½ life = when plasma levels fall to half what they were
at equilibrium due to distribution to/storage in body’s tissue reservoirs
“elimination” ½ life = when plasma levels fall to half what they were
at equilibrium due to drug being metabolized and eliminated
It is usually the elimination ½ life that is used to determine dosing
schedules, to decide when it is safe to put patients on a new drug
4
C o n c . [m g /L ]
0 4 8 12 16 20 24
Time [hours]
Elimination
ke
lny ln y
2
T1/2
ln2
ke
T1/2
0.693
ke
T1/2
“Rule of Five”
Clearance
Clearance
Quantifies Elimination
Is Usually Constant
Clearance
Proportionality factor relating rate of drug elimination to plasma
drug concentration
Rate of eliminatio n CL C
Rate of eliminatio n
CL
C
(dx/dt)
CL
C
Integrate
DoseIV
CL
AUC
Bioavailability & Bioequivalence, June 2, 2004
Bioavailability & Bioequivalence
Clearance
Rate of elimination is proportional to the amount (A) of drug present
Rate of eliminatio n k * A
Rate of eliminatio n k * V * C
Rate of eliminatio n
k*V
C
Clearance k * V
0.693 * V
Clearance
Half - life
Dependence of Half-life on
Clearance and Volume
Time (hr)
Minimum and maximum conc should be within therapeutic window – depends on dose,
frequency and t1/2
Depending on dosing frequency and t 1/2, accumulation occurs
Degree of accumulation is important for safety assessment purposes
Absolute Bioavailability
Relative Bioavailability
no I.V. reference
comparison AUC values (ratio) of different dosage forms / formulations
Frel = (AUC a / AUC b) * (Dose b /Dose a)
5 5
4 4
Solution
Capsule
Conc. [mg/L]
Conc. [mg/L]
3 3
2 2
1
1
0
0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time [hours] Time [hours]
F=0.6
F=0.4*
16
14
F=0.2*
12
10
AUC
8
6
4
2
0
I.v. (20 mg) P.O. (80 mg) P.O. (80 mg)
Capsule Solution
*dose - adjusted
Anatomical Considerations
Gut Lumen
Portal Vein
Liver
Gut Wall
Systemic
Circulation
Metabolism Metabolism
Release + Dissolution
Permeation Elimination
Absorption
Bioavailability
Absorption Phase:
dDABS/dt > dDELIM/dt
Post-absorption Phase:
dDABS/dt < dDELIM/dt
Bioavailability & Bioequivalence, June 2, 2004
Bioavailability & Bioequivalence
Physiological Considerations
Surface area
small intestine = 200 m2
stomach = 1 m2
Permeability
intestinal membrane>stomach
Blood flow (for perfusion rate-limited absorption)
small intestine = 1000 mL/min through intestinal
capillaries
stomach = 150 mL/min
Gastric emptying and pH
GI transit
Rate of gastric emptying is a controlling step for
rapid absorption
Physico-Chemical Factors
Partition Theory
Polymorphism
Particle Size
Complexation
Passive diffusion
Active transport
Rate of diffusion = P *(C1-C2)
where P is permeability coefficient
Lipophilicity (partition between oil
and water)
Hydrophilicity (paracellular
movement depends on size, shape
and charge)
Transcellular
Paracellular
Bioavailability & Bioequivalence, June 2, 2004
Bioavailability & Bioequivalence
Passive diffusion
1 2
A = Passive diffusion
B = Active transport/
carrier mediated
system
Terbutaline
Furosemide
Atenolol
Enalaprilate
blood blood
membrane
tissue tissue
pH – pKa Ionization
Weak acid
pka - pH = log [(un-ionized)/(ionized)]
Weak base
pka - pH = log [(ionized)/(un-ionized)]
Examples:
Aspirin, pka : 3.5, at pH = 1, mostly unionized
Phenytoin, pka : 8.3, unionized in stomach
Diazepam, pka : 3.3, mostly ionized in stomach
Procainamide, pka : 9.5, mostly ionized in stomach
Du o d e n u m 4.9-6.4 3-4 h o u rs
Je ju n u m 4.4-6.4 3-4 h o u rs
C o lo n 7.4 Up to 18 h o u rs
0.5/hr
0.2/hr
Rate of Absorption:
peak plasma drug concentrations (Cmax)
time to Cmax (tmax)
Extent of Absorption:
area under the concentration-time curve (AUC)
Effect of Food
A required study – helps for dosage
administration in Clinical Trials Test Meal
Measure PK parameters (rate and extent) under
2 eggs fried in butter
Fasted and Fed conditions.
2 strips of bacon
Single dose cross over study is recommended.
2 slices of toast with butter
FDA Guidance gives type of food
4 oz of hash-brown potatoes
High Fat Meal (breakfast) – total of 800 –
1000 calories 8 oz of whole milk
of which 150 cal from Proteins, 250 cal from
carbohydrates and 500 – 600 cal from fat.
M E A N R IV A S T IG M IN E P L A S M A L E V E L S (n g /m L )
7
3 3 mg (fasted) N=20
3 mg (fed) N=19
-1
0 2 4 6 8 10 12 14
TIME (hrs)
60
30
0
0 6 12 18 24
Time (h)
Food Effect
Statistical analysis is done for significant difference
Attention should be paid for the absorption rate and total exposure with
and without food. Cases when time to peak concentration is important
(analgesic)
Summary
Absorption is influenced by physico-chemical properties of the drug,
formulation factors, and the anatomy and physiologic functions at the site
of drug absorption.
Drug metabolism/Biotransformation
Extrahepatic:
Gut wall
Intestinal Flora
Lung
Kidney
Drug-Drug interaction
Inhibition (↑AUC and ↑Cmax)
Induction (↓AUC and ↓Cmax)
Age
Disease (hepatic impairment)
P-glycoproteins expressed in
Intestine limit absorption low BA
liver increase bile secretion low BA
kidney increase secretion in urine shorten t1/2
Brain protect CNS from penetration of toxic drugs
or decrease efficacy of CNS drugs
Some lymphocytes drug resistance for HIV drugs
Bioequivalence: Background
Using bioequivalence as the basis for approving generic copies of drug
products was established by the “Drug Price Competition and Patent Term
Restoration Act of 1984,” also known as the Waxman-Hatch Act.
This Act expedites the availability of less costly generic drugs by permitting
FDA to approve applications to market generic versions of brand-name drugs
without conducting costly and duplicative clinical trials.
At the same time, the brand-name companies can apply for up to five
additional years longer patent protection for the new medicines they
developed to make up for time lost while their products were going through
FDA's approval process. Brand-name drugs are subject to the same
bioequivalence tests as generics upon reformulation.
Bioequivalence
Definition - CFR 320.1
It is the absence of significance difference in the rate and
extent to which active ingredient or active moiety in
pharmaceutical equivalent or pharmaceutical alternative
becomes available at the site of drug action when
administered at the same molar dose under similar conditions
in an appropriately designed study
When do we do BE studies ?
Generic Formulations
Bioequivalence
Bio-IND
Contents of a Bio-IND
Contents of a Bio-IND
Tests and specifications for identity, strength, quality, and purity for
active ingredient(s) and Certificates of Analysis of excipients;
Method and place of manufacturing including the type of equipment,
batch size and batch records
Tests and specifications for the finished dosage form (Certificates of
Analysis);
Stability testing data on the drug product stored for three months at
400C and 75% relative humidity including information on the
container/closure system(s) used in the stability tests unless other
conditions are appropriate for that product.
If the CSO determines that the safety reviews will not be completed
within thirty days, he or she will inform the firm and may request
that the start of the study be deferred until the reviews are completed.
Upon completion of the safety reviews, OGD will notify the firm that the
study may begin or that the study has been placed under a clinical hold
pursuant to 21 CFR § 312.42.
BCS Classifications
CLASS BOUNDARIES
SOLUBILITY DETERMINATION
PERMEABILITY DETERMINATION
Two dissolution profiles are considered similar when the f2 value is 50.
Note: When both test and reference products dissolve 85% or more of the label amount of the drug
in 15 minutes using all three dissolution media recommended above, the profile comparison with
an f2 test is unnecessary.
References
http://www.fda.gov/cder/guidance/index.htm
http://www.access.gpo.gov/nara/cfr/waisidx_03/21cfr320_03.ht
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