Your SlideShare is downloading. ×
0
Bioavailability
By : Aditya Arya
• Bioavailability is the fraction of administered drug
that reaches the systemic circulation.
• Bioavailability is express...
Determination of bioavailability:
Bioavailability is determined by comparing
plasma levels of a drug after a particular ro...
By plotting plasma concentrations of the drug
versus time, we can measure the area under the
curve (AUC).
This curve refle...
Pharmacokinetic Studies
Key Measurements
• AUC
– Area under the concentration-
time curve
• Cmax
– Maximum concentration
–...
FDA Requirements for
Bioequivalence
125%
100%
80%
Product A
Bioequivalent
Reference
Drug
Product B
Not Bioequivalent
• Pro...
Factors that influence bioavailability:
First-pass hepatic metabolism:
When a drug is absorbed across the GI tract, it
ent...
Solubility of the drug:
Very hydrophilic drugs are poorly absorbed
because of their inability to cross the lipid-rich
cell...
Chemical instability:
Some drugs, such as penicillin G, are unstable in the
pH of the gastric contents. Others, such as in...
Bioequivalence:
Two related drugs are bioequivalent if they show
comparable bioavailability and similar times to
achieve p...
Therapeutic equivalence :
Two similar drugs are therapeutically equivalent if
they have comparable efficacy and safety.
Cl...
Volume of Distribution :
The volume of distribution (VD) , also known 
as apparent volume of distribution, is 
a pharmacol...
Volume of distribution may be increased by renal 
failure (due to fluid retention) and liver 
failure (due to altered body...
Distribution of drug in the absence of elimination:
The apparent volume into which a drug distributes, VD, is 
determined ...
Apparent volume of distribution :
total amount of drug in the body
VD = ----------------------------------------------
dru...
For example :
If 25 mg of a drug (D = 25 mg) are 
administered and the plasma 
concentration is 1 mg/L, then 
       VD = ...
Distribution of drug when elimination is present:
In reality, drugs are eliminated from the body, and a plot of 
concentra...
Calculation of drug concentration if
distribution is instantaneous:
Assume that the elimination process began at the time ...
Uneven drug distribution between compartments:
The apparent volume of distribution assumes that the drug distributes 
unif...
Concept of “Half Life”
 ½ life = how much time it takes for blood levels of 
drug to decrease to half of what it was at 
...
Concept of “Half Life”
Time [hours]
0 4 8 12 16 20 24
Conc.[mg/L]
0
1
2
3
4
5
Dependence of Half-life on
Clearance and Volume
For a given dose rate, the blood drug
concentration is inversely proportional to
clearance
Bioavailability: The rate and extent to which the parent
compound reaches the general
circulation.
Absolute Bioavailabilit...
The VD may also be used to determine how
readily a drug will displace into the body
tissue compartments relative to the bl...
 Pharmacokinetics
 “what the body does to the
drug”
• Absorption
• Distribution
• Metabolism
• Elimination
 Pharmacodyn...
Dose regimen ResponseExposure
Site of action
Pharmacokinetics Pharmacodynamics
 Basic Pharmacokinetic Concepts
 Bioavailability
Definition
How absorption affects bioavailability?
Food Effect
How ...
Basic Concepts
 Easy to understand using intravenous
route
 No absorption phase
 Simple to follow
 Concepts clear with...
IV administration, contd.,
 Following dose administration,
we need to follow its drug’s
disposition to understand its PK
...
Concentration versus Time Profiles
One-
Compartment
Model
Assumes body as one
compartment
1
Two-Compartment Model
Central ...
Concept of “Half Life”
 ½ life = how much time it takes for blood levels of
drug to decrease to half of what it was at
eq...
Concept of “Half Life”
Time [hours]
0 4 8 12 16 20 24
Conc.[mg/L]
0
1
2
3
4
5
Dependence of Half-life on
Clearance and Volume
For a given dose rate, the blood drug
concentration is inversely proportional to
clearance
Bioavailability: The rate and extent to which the parent
compound reaches the general
circulation.
Absolute Bioavailabilit...
Time [hours]
0 4 8 12 16 20 24
Conc.[mg/L]
0
1
2
3
4
5
Time [hours]
0 4 8 12 16 20 24
Conc.[mg/L]
0
1
2
3
4
5
Solution
Cap...
Thank you
Pharmacology   bioavailability
Pharmacology   bioavailability
Pharmacology   bioavailability
Pharmacology   bioavailability
Pharmacology   bioavailability
Pharmacology   bioavailability
Pharmacology   bioavailability
Pharmacology   bioavailability
Upcoming SlideShare
Loading in...5
×

Pharmacology bioavailability

2,845

Published on

Published in: Education
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
2,845
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
128
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide
  • Pharmacokinetic Studies. Key Measurements.
    To investigate the bioequivalence of 2 drug products or compounds, the FDA considers PK studies that determine the area under the concentration-time curve (AUC), maximum concentration (Cmax), and time to Cmax (Tmax) for the study compound (generic) and a reference compound (innovator).1 Each of these values for the study compound are compared with those of the reference compound.
    For the study and reference compounds to be considered bioequivalent, their rates and extents of absorption must not show a significant difference when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions.
    The red area in the diagram represents the AUC, or the extent of absorption, of the reference compound. The yellow area represents the AUC of the study compound. Cmax is an indicator of the absorption rate and Tmax is influenced by the route of compound administration.
    A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds.
    Reference
    1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.
  • FDA Requirements for Bioequivalence.
    The rate and extent of absorption between a drug being tested and the reference drug is compared statistically using characteristics of concentration-time curves, such as AUC and Cmax.
    For a drug to be approved as bioequivalent to the reference drug, its AUC and Cmax values must fall within a 90% confidence interval (CI), or between 80% and 125%, of the reference drug values.
    In the example shown on this slide, Product A is bioequivalent to the reference drug. Its AUC value falls within 80% to 125% of the reference drug. Product B is not bioequivalent to the reference drug. Its AUC value falls outside of 80% to 125% of the reference drug.1
    Reference
    1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.
  • Transcript of "Pharmacology bioavailability"

    1. 1. Bioavailability By : Aditya Arya
    2. 2. • Bioavailability is the fraction of administered drug that reaches the systemic circulation. • Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. • For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent. Bioavailability:
    3. 3. Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection in which all of the agent rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma.
    4. 4. By plotting plasma concentrations of the drug versus time, we can measure the area under the curve (AUC). This curve reflects the extent of absorption of the drug. [Note: By definition, this is 100 percent for drugs delivered IV.] Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection
    5. 5. Pharmacokinetic Studies Key Measurements • AUC – Area under the concentration- time curve • Cmax – Maximum concentration – A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds • Tmax – Time to maximum concentration Study Compound Reference Compound Time Concentration Cmax Tmax AUC
    6. 6. FDA Requirements for Bioequivalence 125% 100% 80% Product A Bioequivalent Reference Drug Product B Not Bioequivalent • Product A is bioequivalent to the reference drug; its 90% confidence interval of the AUC falls within 80% to 125% of the reference drug • Product B is not bioequivalent to the reference drug; its 90% confidence interval of the AUC falls outside of 80% to 125% of the reference drug Pharmacokinetic ReferenceRange
    7. 7. Factors that influence bioavailability: First-pass hepatic metabolism: When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs, such as propranolol or lidocaine, undergo significant biotransformation during a single passage through the liver.
    8. 8. Solubility of the drug: Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases. There are some drugs that are highly lipid-soluble, and they are transported in the aqueous solutions of the body on carrier proteins such as albumin.
    9. 9. Chemical instability: Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes. Nature of the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption.
    10. 10. Bioequivalence: Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two related drugs with a significant difference in bioavailability are said to be bioinequivalent.
    11. 11. Therapeutic equivalence : Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety. Clinical effectiveness often depends on both the maximum serum drug concentrations and on the time required (after administration) to reach peak concentration. Therefore, two drugs that are bioequivalent may not be therapeutically equivalent.
    12. 12. Volume of Distribution : The volume of distribution (VD) , also known  as apparent volume of distribution, is  a pharmacological term used to quantify the  distribution of a medication between plasma and the rest  of the body after oral or parenteral dosing. It is defined as  the theoretical volume in which the total amount of drug  would need to be uniformly distributed to produce the  desired blood concentration of a drug. Volume of distribution may be increased by renal  failure (due to fluid retention) and liver failure (due to  altered body fluid and plasma protein binding ).  Conversely it may be decreased in dehydration.
    13. 13. Volume of distribution may be increased by renal  failure (due to fluid retention) and liver  failure (due to altered body fluid and plasma  protein binding. Conversely it may be decreased in dehydration.
    14. 14. Distribution of drug in the absence of elimination: The apparent volume into which a drug distributes, VD, is  determined by injection of a standard dose of drug,  which is initially contained entirely in the vascular  system. The agent may then move from the plasma into  the interstitium and into cells, causing the plasma  concentration to decrease with time. Assume for  simplicity that the drug is not eliminated from the body;  the drug then achieves a uniform concentration that is  sustained with time.  The concentration within the  vascular compartment is the total amount of drug  administered, divided by the volume into which it  distributes. 
    15. 15. Apparent volume of distribution : total amount of drug in the body VD = ---------------------------------------------- drug blood plasma concentration Therefore the dose required to give a certain plasma  concentration can be determined if the VD for that drug  is known.  The VD is not a physiologic value; it is more a reflection  of how a drug will distribute throughout the body  depending on several physicochemical properties, e.g.  solubility, charge, size, etc.
    16. 16. For example : If 25 mg of a drug (D = 25 mg) are  administered and the plasma  concentration is 1 mg/L, then         VD = 25 mg/1 mg/L = 25 L.
    17. 17. Distribution of drug when elimination is present: In reality, drugs are eliminated from the body, and a plot of  concentration versus time shows two phases. The initial  decrease in plasma concentration is due to a rapid distribution  phase in which the drug is transferred from the plasma into the  interstitium and the intracellular water. This is followed by a  slower elimination phase during which the drug leaves the  plasma compartment and is lost from the body  For example, by renal or biliary excretion or by hepatic  biotransformation.  The rate at which the drug is eliminated is usually proportional  to the concentration of drug, C; that is, the rate for most drugs  is first-order and shows a linear relationship with time if  ln C  (where ln C is the natural log of C, rather than C) is plotted  versus time . This is because the elimination processes are not  saturated.
    18. 18. Calculation of drug concentration if distribution is instantaneous: Assume that the elimination process began at the time  of injection and continued throughout the distribution  phase. Then, the concentration of drug in the plasma,  C, can be extrapolated back to time zero (the time of  injection) to determine C0, which is the concentration  of drug that would have been achieved if the  distribution phase had occurred instantly.  For example, if 10 mg of drug are injected into a  patient and the plasma concentration is extrapolated to  time zero, the concentration is C0 = 1 mg/L  and then  VD = 10 mg/1 mg/L = 10 L.
    19. 19. Uneven drug distribution between compartments: The apparent volume of distribution assumes that the drug distributes  uniformly, in a single compartment. However, most drugs distribute  unevenly, in several compartments, and the volume of distribution does  not describe a real, physical volume, but rather, reflects the ratio of drug  in the extraplasmic spaces relative to the plasma space. Nonetheless, Vd   is useful because it can be used to calculate the amount of drug needed to achieve a desired plasma concentration. For example, assume the  arrhythmia of a cardiac patient is not well controlled due to inadequate  plasma levels of digitalis. Suppose the concentration of the drug in the  plasma is C1  and the desired level of digitalis (known from clinical  studies) is a higher concentration, C2 . The clinician needs to know how  much additional drug should be administered to bring the circulating  level of the drug from C1  to C2 :   The difference between the two values is the  additional dosage needed, which equals VD (C2   C1 ).
    20. 20. Concept of “Half Life”  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
    21. 21. Concept of “Half Life” Time [hours] 0 4 8 12 16 20 24 Conc.[mg/L] 0 1 2 3 4 5
    22. 22. Dependence of Half-life on Clearance and Volume
    23. 23. For a given dose rate, the blood drug concentration is inversely proportional to clearance
    24. 24. Bioavailability: The rate and extent to which the parent compound reaches the general circulation. Absolute Bioavailability  requires I.V. administration  Ratio of the oral:intravenous AUC values normalized for dose  Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral) Relative Bioavailability  no I.V. reference  comparison AUC values (ratio) of different dosage forms / formulations  Frel = (AUC a / AUC b) * (Dose b /Dose a) Bioavailability and Its Assessment
    25. 25. The VD may also be used to determine how readily a drug will displace into the body tissue compartments relative to the blood: VD = VP + VT ( fu / fuT ) Where: VP = plasma volume VT = apparent tissue volume fu = fraction unbound in plasma fu = fraction unbound in tissue
    26. 26.  Pharmacokinetics  “what the body does to the drug” • Absorption • Distribution • Metabolism • Elimination  Pharmacodynamics  “what the drug does to the body” • wanted effects - efficacy • unwanted effects - toxicity disposition
    27. 27. Dose regimen ResponseExposure Site of action Pharmacokinetics Pharmacodynamics
    28. 28.  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) General Outline
    29. 29. Basic Concepts  Easy to understand using intravenous route  No absorption phase  Simple to follow  Concepts clear with less assumptions  Need some math background  algebra, log scale, Simple linear Equations etc  complex math (differential equations, statistical concepts etc) for Modeling, Population PK, PK-PD etc. Drug Product Drug in Blood Distribution to Tissue and Receptor sites MetabolismExcretion
    30. 30. IV administration, contd.,  Following dose administration, we need to follow its drug’s disposition to understand 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 Dosing Sampling at Pre-determined Time intervals Bio-analytics Conc. vs time profiles Blood withdrawal
    31. 31. Concentration versus Time Profiles One- Compartment Model Assumes body as one compartment 1 Two-Compartment Model Central compartment (drug entry and elimination) Tissue compartment (drug distributes) 1 2 k k Dose Dos e Broadly the concentration – time profiles can be viewed as two different ways
    32. 32. Concept of “Half Life”  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
    33. 33. Concept of “Half Life” Time [hours] 0 4 8 12 16 20 24 Conc.[mg/L] 0 1 2 3 4 5
    34. 34. Dependence of Half-life on Clearance and Volume
    35. 35. For a given dose rate, the blood drug concentration is inversely proportional to clearance
    36. 36. Bioavailability: The rate and extent to which the parent compound reaches the general circulation. Absolute Bioavailability  requires I.V. administration  Ratio of the oral:intravenous AUC values normalized for dose  Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral) Relative Bioavailability  no I.V. reference  comparison AUC values (ratio) of different dosage forms / formulations  Frel = (AUC a / AUC b) * (Dose b /Dose a) Bioavailability and Its Assessment
    37. 37. Time [hours] 0 4 8 12 16 20 24 Conc.[mg/L] 0 1 2 3 4 5 Time [hours] 0 4 8 12 16 20 24 Conc.[mg/L] 0 1 2 3 4 5 Solution Capsule 20 mg administered as an i.v. bolus (Diovan) 80 mg given as a solution and a capsule (Diovan)
    38. 38. Thank you
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×