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Pharmacokinetic Parameters: Elimination rate constant Biological Half life Rate constant of absorption Apparent volume of distributions Area under the curve
Example : 1
The plasma concentration after the 250 mg intravenous bolus dose of an antibiotic is given below. Plot the data and describe the pharmacokinetic model.
Time (hrs) Conc (mcg/ml) 1.0 2.0 8.0 6.3
3.0
4.0 5.0-
4.9
4.0 3.2
6.0
7.0
2.5
1.9
Graph
Slope =
- 1.6095 7.0 hr
= - 0.2299/ hr
Biological half-life :
Ke = 0.693 t1/2 , 0.693 Ke = 0.693 0.2299/hr
therefore
t =
= 3.01 hr
AUC0-7.0 ,
AUC 7.0- =
AUC0- =
Volume of distribution :
Vd = Dose Co
250 mg
= 10 mcg / ml = 250 mg 10 mg/L = 25 L
Description of model :
It shoes that a 250mg dose is administered intravenously. The apparent volume of distribution is 25 L and the rate constant of elimination (Ke) is 0.2299 / hr. since biological half-life is 3.01 hr.
intravenous
250 mg
injection
25 LITRES
0.2299 / hr
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Example 2
The plasma concentration versus time data following the administration of a single 250 mg rapid intravenous bolus dose of a drug is represented by the biexponential equation; C = 1.5e-0.13t + 12.5 e1.3t. Draw a schematic of the pharmacokinetic model, assuming concentration is in mcg / ml and time is in hours.
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Solution
From the biexponential equation, the following parameters of the two compartment pharmacokinetic model are deduced : b= 0.13/hr (because the smallest hybrid rate constant always b), and B = 1.5 mcg/ml (because B is yintercept corresponding to b). therefore a must be equal to 1.3/hr, and A = 12.5mcg/ml. In order to draw a schematic of the pharmacokinetic model, the following parameters need to be calculated: rate constants K10, K12, K21,, and apparent volumes of distribution Vc, and Vt.
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Rate constants
K 21 = Ab + Ba B+A
1.625 + 1.95
= 1.5 + 12.5 =
3.575
14.0
= 0.2554/hr
ab K10 = K21
(17.857 L) (0.5433 / hr+ 0.2554 / hr) 14.2624 L = 55.843 L = Vd = 0.2554 / hr 0.2554 Vt = Vd Vc (Vc) (K12) Vt = K21 = 55.843 L 17.857 L = 37.986 L
Schematic representation :
This schematic shows that the 250 mg dose can was given intravenously. The apparent volume of the central and tissue compartment are 17.857 L and 37.986 L, respectively. The first-order rate constant of transfer of the from the central compartment into the tissue compartment is 0.5433 /hr and the first-order rate constant of transfer of drug from the tissue compartment in to the central compartment is 0.2554 / hr. the first-order rate constant of elimination of drug from the central compartment is 0.6617 / hr.
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0.6617 /hr
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Example -3
The following data were obtained when a 500 mg dose of an antibiotic was given orally. Calculate the pharmacokinetic parameters, assuming 100% of the administered dose was absorbed.
TIME (Hr) Concentration (mcg/ml)
1
2 3
26.501
36.091 37.512
4
5 6 8
36.055
32.924 29.413 22.784
16
18 20
7.571
5.734 4.343
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Graph
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Solution:
Elimination rate constant:
The rate constant of elimination is calculated from the terminal linear portion of plasma profile. To determine it, we need to calculate slope of the straight line having y-intercept = B. if natural log are used the rate constant of elimination (b) = negative slope of this straight line. Therefore ln 5.734 - ln 4.343 0.2778 = 0.139/ hr ==b = - slope 2 hr (18 - 20) hr
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0.693 0.139/hr
= 4.98 hr
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The Y-intercept, B
The Y-intercept of this straight line is B and is determined using the first order equation ln Ct = ln B bt Which upon rearrangement gives ln B = ln Ct + bt = ln 4.343 + (0.139/hr)(20hr) =1.4686 + 2.78 = 4.2486 B = Inverse ln 4.2486 = 70.0 mcg/ml
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Graph
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The residual conc. at 1 hr is obtained by subtracting from this concentration at 1 hr provided in the data. therefore the residual concentration at 1hr is, 1 hr = 60.916 26.501 = 34.415mcg/ml
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=-
= - 0.71/ hr
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(Vd) =
AUC =
AUC = 503.597 mcg hr/ml 98.592 mcg hr /ml = 405.005 mcg hr/ml
A a
70 mcg/ml 0.71/hr
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0.71 /hr
500 mg
8.88 LITRS
0.139 / hr
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Example -3.1
From the data given Calculate the time when administered drug dose reaches its maximum concentration in the plasma.
TIME (Hr) Concentration (mcg/ml)
1
2 3 4 5 6 8 16 18 20
26.501
36.091 37.512 36.055 32.924 29.413 22.784 7.571 5.734 4.343
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From the pharmacokinetic parameters found, the firstorder rate constant of absorption, Ka = 0.71/hr and the first order rate constant elimination, Ke = 0.139/hr.
t max = ln Ka ln Ke Ka Ke
ln 0.71 /hr ln 0.139 /hr t max = 0.71 /hr 0.139 /hr 0.3425 (- 1.9733) = 0.571 /hr 1.6308 0..571 /hr
t max =
= 2.856 hr
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Example -3.2
From the data given Calculate the maximum concentration of the drug in plasma attained after the administration of the dose.
TIME (Hr) Concentration (mcg/ml)
1
2 3 4 5 6 8 16 18 20
26.501
36.091 37.512 36.055 32.924 29.413 22.784 7.571 5.734 4.343
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Example -4
The following data were obtained when a 500 mg dose of an antibiotic was given orally calculate the pharmacokinetic parameters, assuming 100% of the administered dose was absorbed.
TIME (Hr) Concentration (mcg/ml)
2
4 6 8 10 16 18 20 24 28
3.915
8.005 7.321 5.803 4.403 1.814 1.344 0.996 0.546 0.300
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graph
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=-
0.5988 4 hr
= 0.15/ hr
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The y-intercept, b, of this straight line is determined using the first-order rate equation :
B = Ct e bt
= 20 mcg/ml
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To obtained the straight line which represents absorption phase, the technique of feathering is used. The plasma profile is feathered with respect to the straight line having y-intercept = B. To feather the first concentration point, the concentration at 2 hr on the straight line having yintercept = B is subtracted from the data concentration at 2 hr.
C = Be-bt = (20 mcg/ml)e-(1.5/hr)(2hr) C = (20 mcg/ml) (0.7408) = 14.816 mcg/ml
0.693 0.15/hr
= 4.62hr
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Ka = a = - slope
=-
= 0.65/ hr
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Lag-Time
Since the value of the y-intercept A is not equal to the value of the y-intercept B, the dosage from exhibits lagtime. The lag-time (L) is determined using equation
ln A ln B L =
ab
ln 40 mcg/ml ln 0.20 mcg/ml 0.65 0.15 0.693 0.5 / hr 1.386 hr
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= =
The equation for calculating the time of maximum concntration of drug in plasma in presence of lag-time, tmax (L), is
t max = ln A ln B + ln a ln b a-b
ln 40 ln 20 + ln 0.65 ln 0.15 t max = 0.65 /hr 0.15 /hr 1.4663 0.5 /hr
t max =
= 4.319 hr
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C max (L) = Be-bt Ae-at) C max (L) = (20 mcg/ml) (e-(0.15/hr))(4.319 hr) e-(0.65 /hr)(4.319 hr)) C max (L) = (20 mcg/ml) (0.5253) (40 mcg /ml) (0.0604) C max (L) = 10.463 mcg/ml 2.415 mcg /ml
C max (L) =
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Measurement of bioavailability
Pharmacokinetic methods ( indirect )
1. Blood analysis 2. Urinary excretion data
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Blood analysis
Plasma level time studies or The plasma concentration time curve or blood level curve. A direct relationship exists concentration of drug at the site of action & concentration of drug in the plasma. Serial blood samples are taken after drug administration & analyzed for drug concentration. A typical blood level curve obtained after oral administration of drug.
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Parameters determined
Pharmacokinetic parameters
Peak Plasma Concentration (Cmax) Time of Peak concentration (tmax). Area Under Curve (AUC)
Pharmacodynamics parameters
Minimum Effective Concentration (MEC) / Minimum Inhibitory Concentration (MIC). Maximum Safe Concentration (MSC) / Maximum Safe Dose (MSD). Duration of action Onset of action. Intensity of action.
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Parameters determined
AUC or Extent of absorption can be measured by 3 methods 1.Planimeter Instrument for mechanically measuring the area 2. Cut & weigh method AUC is cut & weighed on analytical balance. The weight obtained is converted to proper unit by dividing it by the wt of a unit area of same paper. 3. Trapezoidal method
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Parameters determined
3. Trapezoidal method
AUC = ( C1 + C2) (t2 t1) + (C2 + C3) (t3 t2) +. (C n-1 + C n ) (tn tn-1 ) C = Concentration t = time subscript= sample number AUC = Area Under Curve
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Parameters determined
Relative bioavailability F rel = ( AUC) drug . (Dose) standard (AUC) standard .(Dose) drug
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From the following blood data obtained after the oral administration of 50mg of drug A. calculate the AUC?
Parameters determined
Plasma drug con in mcg/ml
Time in hr
1 2 3 4
5 6
(7.1 +2.2) (6-5)
7.3 2.2
AUC = (5.5 +9.2) (2-1) + (9.2+14.9) (3-2) + (14.9+10.3) (4-3) (1AUC = AUC = (5.5 +9.2) (2-1) + (9.2+14.9) (3-2) + (14.9+10.3) (4-3) (5.5 +9.2)7.1)(5-4)(9.2+14.9) (3-2) + (6-5) (10.3+ (2-1) + + (7.1 +2.2) (14.9+10.3) (4-3) (10.3+ 7.1)(5-4) + AUC = 45.35 mcg/ml hr hr AUC = 45.35 mcg/ml
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Parameters determined
The AUC of a new sustained release diclofenac sodium developed in the lab after giving in a dose of 100mg was found to be 250.30 mcg/ml hr.The AUC of the standard marketed sustained release tablets of the same at the same dose was found to be 261.35 mcg/ml hr. what is the the relative bioavailability of he same drug.
F rel = 250.30 X 100 261.35 X 100 = 0.9577 or 95.77%
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Parameters determined
The AUC of salbutamol sulphate from a 10 mg IV dose was found to be 94.6mcg/ml hr.when the same dose was given orally, the AUC was found to be 60.5 mcg/ml hr. What is the absolute bioavailability of the drug? Fabs = 60.5 X 10 94.6 X 10 Fabs = 0.6395 or 63.95
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Advantages
Useful when there is lack of sufficiently sensitive analytical techniques to measure concentration of drug in plasma. Noninvasive method therefore better subject compliance. Convenience of collecting urine samples in comparison to drawing of blood periodically. If any case the urine drug concentration is low, assaying of larger sample volume is relatively more. Direct measurement of bioavailability, both absolute & relative is possible without the necessity of fitting the data to the mathematical model.
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Advantages
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Advantages
Bioavailability is determined by.
F= (U (U U
) oral . D IV ) IV . D oral
= Cumulative amt of unchanged drug excreted in urine D IV = IV dose D oral = oral dose F = absolute bioavailability
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When drug A was administered IV to a group of volunteers, 80% of the 500mg dose was recovered unchanged in the urine. When the same drug was administered to the same volunteers orally.280 mg was recovered unchanged in urine. What is the absolute bioavailability of Drug A following oral administration. Absolute bioavailability = (cumulative amt.of drug excreted)sample (cumulative amt.of drug excreted)IV = 280 400 = 0.7 or 70%
Advantages
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Therapeutic response
This method is based on the observing the clinical response to a drug formulation given to a patients suffering from disease for which it is intended to be used. Ex for anti inflammatory drugs, the reduction in the inflammation is determined. The major DRAWBACK is quantification of observed response is too improper to allow for reasonable assessment of relative bioavailability between two dosage forms of a same drug.
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Rate of Absorption
AUC/dose gives an average extent of bioavailability. The rate of absorption is usually also important for the onset of drug action. The time of peak plasma concentration is used often as a measure of the rate of drug absorption. The peak plasma concentration is also an important parameter - for keeping the drug concentration within the therapeutic window. Absorption can be characterized by evaluating the absorption rate constant Ka from the plasma concentration time data.
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AG
Ka
AB
Kc
AE
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C=
K a F X0 Vd ( Ka KE )
kEt
[ e kEt e Kat ]
-A e Kat
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Where C is the back extrapolated plasma concentration value. A plot of log C versus t yields a biexponential curve with a terminal linear phase having slope KE/ 2.303.
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The technique works best when the difference between Ka & KE is large ( Ka >= 3)
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