Bioavailability

It is measurement of rate and extent to which the therapeutically active drug reaches the systemic circulation and becomes available at the site of action.

l       It is difficult to measure the concentration of drug at the site of action. Therefore, the concentration of drug in the plasma is taken as an indicator of the extent of drug at the site of action. So, bioavailability is sometimes referred as “SYSTEMIC AVAILABILITY”.

l       For drugs that are not intended to be absorbed into blood stream in significant amounts, bioavailability is assessed by measurements intended to reflect the rate and extent to which the drug becomes available at the site of action.

Factors Affecting Bioavailability

(1) Route of Administration

l       In case of intravenous administration, bioavailability will be 100% or F is equal to unity, as drug is directly placed into systemic circulation.

l       In case of oral administration, F may vary from a value of 0 (no absorption) to 1(complete absorption).

F = Bioavailable dose / Administered dose

(2) Gastric Emptying

l       Although not true in all cases, gastric emptying enhances the bioavailability of orally administered drugs.

l       Gastric emptying is affected by;

Ø       Volume of liquid fluid intake

Ø      Volume of solid food

Ø      Stress and aggression

Ø      Drugs

Ø      Diseased state

(3) Presystemic Metabolism

l       First-pass metabolism of drugs by liver such as Propranolol, Paracetamol etc

l       Intestinal metabolism by enzymes in the proximal small intestine (e.g. Aspirin)

l       Degradation of acid labile drugs in stomach (e.g. Penicillin & erythromycin)

(4) Complex Formation

l       Complexes are usually unable to penetrate biological membranes.

l       E.g. tetracyclines form complexes with calcium.

(5) Formulation Factors

l       Excipients,

Ø      Binders (starch, acacia)

Ø      Disintegrants (carboxy methyl cellulose)

Ø      Lubricants (Ca or Magnesium stearate)

l       Manufacturing process,

Ø      Compression pressure

Ø      Compression time, etc

PURPOSE OF BIOAVAILABILITY STUDIES

v      Bioavailability studies are used to define the effect of changes in the physiochemical properties of the drug substance on the pharmacokinetics of the drug.

v      In approving a drug product for marketing, FDA ensures that;

Ø      Product is safe and effective,

Ø      Must meet all applicable standards of identity, strength, quality and purity

 

v      Bioavailability studies are performed for both approved active drug ingredients (new formulation or dosage forms) and therapeutic moieties not yet approved for marketing by FDA.

v      For marketed drugs that have NDA approval, purpose of study is to characterize the pharmacokinetic of new formulation, new dosage form or new salt relative to a reference formulation.

 

v      Bioavailability studies may be designed to provide information regarding the effect of food and other nutrients on absorption of drugs.

v      Bioavailability studies is of great importance in case of drugs that have a narrow margin of safety e.g. Digoxin, anticonvulsants. Differences in the rate of absorption of drug products from different manufacturers may cause patient to be over medicated or under medicated.

Relative & Absolute Bioavailability

Relative Bioavailability

l       Relative bioavailability is availability of the drug from a drug product as compared to a recognized standard

l       The availability of the drug in formulation is compared to the availability of drug in a standard dosage form, usually a solution of the pure drug.

l       It can be determined as;

 

i) Using plasma data:

  Relative availability = [AUC]∞A

           [AUC]∞B

  A=Test product, B=Reference standard

 For different doses:

    % R.A = [AUC] A / Dose A X 100

        [AUC] B / Dose B

ii) Using urinary data:

   Relative availability = [Du]∞A

            [Du]∞B

 _{[Du]∞ = Total amount of drug excreted in urine.}

Absolute bioavailability

l       It is the systemic availability of the drug after extra vascular administration compared to i.v dosing.

l       It is usually measured by comparing the respective AUCs after extra vascular administration to that after intravenous administration.

l       It can be determined by;

 i) Using plasma data:

  Absolute bioavailability= [AUC] p.o / dose p.o

             [AUC] i.v / dose i.v

 ii) Using urinary data:

  Absolute bioavailability= [Du]∞ p.o / dose p.o

             [Du]∞ i.v / dose i.v

BIOAVAILABILITY ASSESSMENT METHODS

 

v    Pharmacokinetic parameters that give information on the amount of drug reaching the systemic

Circulation (extent), and the time taken to reach the systemic circulation (rate) are used as measures for assessing bioavailability.

 (A) Direct Measures:

Ø      Based on plasma drug concentration

 (B) Indirect Measures:

Ø       Based on urinary excretion data

Ø       Based on acute Pharmacodynamic effect

Ø       From well controlled clinical trials

Ø       In-vitro dissolution studies

(1)From plasma drug concentration

Ø      Direct and most reliable

Ø      Blood samples are drawn at specific time intervals, analyzed for free drug.

Ø      A profile (curve) is constructed showing the concentration of drug in blood to the corresponding time intervals.

Ø      Key parameters,

§       AUC

§       Cmax

§       Tmax  

 

AUC:

Ø       It is the measure of the extent of bioavailability.

Ø      AUC is area under plasma level – time curve from t=0 to t=∞,

      

  [AUC]∞_{O =} ∫_O∞ cp.dt ----- (1)

l       AUC can be calculated as,

      

  [AUC]_O∞ ₌ FD _{0 / Clearance ----- (2)}

 

   _{Clearance = Kel .Vd}

          

  [AUC]_O∞ ₌ FD _{0 / Kel .Vd ------(3)}

_Where,

 _{F= fraction of dose absorbed, Do = dose,}

 _{Kel= elimination rate constant , Vd= vol of distribution}

 

l        From eq. (2),

    

    F= Cl . (AUC) / Do ---- (4)

 

l       Units of AUC are µg / ml . hr (concentration. x time)  

Ø       AUC can be determined by numerical methods, such as “ TRAPEZOIDAL RULE METHOD”.

 

l       Area of trapezoid = Cn-1 +C n/ 2 × (tn–tn-1)

l       _{Area of triangle =} c x t

       2

 

 t_max:

Ø      At tmax, peak drug absorption occurs

Ø      Rate of drug absorption exactly equals the rate of drug elimination.

Ø      Drug absorption continues after tmax is reached, but at slower rate.

Ø      tmax is inversely dependant on absorption rate.

 

 Cmax

Ø      Maximum plasma drug concentration

Ø      Cmax is directly dependant on absorption rate.

Ø      Cmax indicates ,

•        Drug is sufficiently absorbed to provide a therapeutic response.

•        Provides warning of possible toxic levels of drug

Ø      Units: µg/ml or ng/ml

(2)Using urinary excretion data

Ø      This method is applicable when,

 _ urinay excretion is the main mechanism of elimination.

 _ drug must be excreted in significant quantities as unchanged drug.

Ø      Urine samples are collected , analyzed for free drug.

Ø      A graph is constructed relating cumulative amount of drug excreted to collection time interval.

Ø      Parameters to note are [Du]∞, dDu/dt, t∞.

 

 Du∞         

Ø      Cumulative amount of drug excreted in the urine.

Ø      Directly related to the amount of drug absorbed.

Ø      As plasma concentration approaches zero, maximum amount of drug excreted in urine, Du∞ is obtained.

 

 Corresponding Plots

 Relating the Plasma level-time curve & rate of Urinary Drug Excretion

 

 dDu / dt:

Ø      Rate of urinary drug excretion is dependent on Kel and Cp , as drugs are mostly eliminated by first - order rate process.

Ø      In fig.2, maximum rate of urinary excretion will be at point B , and minimum at A & C.

 

 

 

l       t∞

 Total time required for the absorption and complete excretion (point C; Fig 1B).

(3) Acute Pharmacodynamic effect

 

l       To estimate bioavailability by this method, following criteria should meet,

§        An established Dose-response curve

§        An easily measurable pharmacological response such as heart rate, blood pressure, pupil diameter

l       Pharmacological effect is measured at different time intervals after drug administration, and a plot relating Pharmacodynamic effect verses time is made.

l       Pharmacodynamic parameters;

Ø      Total AUC under Pharmacodynamic effect – time curve,

Ø      peak Pharmacodynamic effect,

Ø      Time to peak Pharmacodynamic effect

(4)Clinical observations

l       Well controlled clinical trials are used that establish safety and effectiveness.

l       Least accurate, least sensitive of the approaches used for determining in-vivo bioavailability.

l       Clinical studies are

Ø      Complex

Ø      Expensive

Ø      Time consuming

l       Response is often quite variable because a large test population is applied.  

 

 

 

(5) In-vitro dissolution studies

 

l        Ideally in-vitro dissolution rate should correlate with in-vivo drug bioavailability.

l        performed on several test formulations of the same drug

l       The test formulation that demonstrates the most rapid drug dissolution in vitro will generally has most rapid rate of bioavailability in vivo.