Absorption Model Pk Concordia Cayetano C0029 Oct 2017 Pedro Zavala In Class Posting
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ABSORPTION MODEL PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
1
SOURCES
Some portions of lecture notes extracted from SHARGEL & DIPIRO
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
2
OBJECTIVES 1. Explain the absorption model
2. Recognize pchem and clinical PK terms in the absorption model 3. Calculate pchem and clinical PK parameters using the absorption model
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
3
SECTIONS A. ABSORPTION MODEL B. EQUATION RECOGNITION EXAMPLE C.
TERMS
D. IN CLASS EXERCISES PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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4
A.
ABSORPTION MODEL
1 compartment model ; V = volume of distribution (L) ka = Absorption rate constant (first order, h-1) k = Elimination rate constant (first order, h-1) PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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5
ABSORPTION MODEL
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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ABSORPTION MODEL ❖ Previous diagram shows absorption phase, elimination phase, Cmax , tmax ❖ More exact name: 1st Order Absorption, 1st Order Elimination, 1 Compartment Model ❖ Absorption Model Characteristics ❖ One compartment ❖ First order absorption ❖ First order elimination PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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ABSORPTION MODEL ❖ dC/dt = Rate In – Rate Out ❖ dC/dt = Change in system [drug] per time ❖ Rate In = Drug absorption rate (from GI into system) ❖ Rate Out = Drug elimination rate (from system) Comment: Model typically used for oral absorption but applies to other EV routes, e.g., skin patches, suppositories, IM PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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8
ABSORPTION MODEL
C = V= F = ka = k =
Drug plasma level (mg/L) Volume of distribution (L) Bioavailability ; D = Administered dose (mg) absorption rate constant (h-1) elimination rate constant (h-1) PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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9
ABSORPTION MODEL
Resembles Where A’ is a constant
Note: A’ is used as a constant, do not confuse with A used for amounts PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
10
ABSORPTION MODEL Model equation can be written in different ways
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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11
B.
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE
ABSORPTION MODEL EXAMPLE PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE Following oral intake of three 500 mg tablets of a cardiac drug (bioavailability 45%), patient plasma drug levels (mg/L) vs. time (h) were given by
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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13
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE 1)
What is k ?
2)
What is ka ?
3)
What is the elimination t1/2 ?
4)
What is the absorption t1/2 ?
5)
What is C0 ?
6)
What is V ? PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE Compare general & patient specific equations:
1) k = 0.1 h-1 2) ka = 0.9 h-1 PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE 3) Elimination t1/2 = ln 2 / k = 0.693/k = 0.693/0.1 = 6.93 h 4) Absorption t1/2 = ln 2 / ka = 0.693/ka = 0.693/0.9 = 0.77 h 5) C0 = 0 (initial concentration at t = 0)
MATH: If t = 0 is substituted in the absorption model equation C = 0 GRAPH: Looking at absorption model plot C vs. t it can be seen that initial concentration is zero PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE 6) Comparing general & patient specific equations
ANSWER :
V = 13.6 L
Comment: Only one volume of distribution for one compartment model PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE COMMENTS (a)
can be written as
(b) A’ = 56 mg/L (units !!) (c) ka >> k
In example:
0.9 h-1 >> 0.1 h-1
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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18
C.
ABSORPTION MODEL TERMS
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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19
ABSORPTION MODEL TERMS
Cmax & tmax
LAG TIME
FLIP FLOP KINETICS
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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ABSORPTION MODEL TERMS
Cmax tmax PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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21
Cmax
and tmax
Cmax is highest [drug] (peak level) which occurs at time tmax (peak time)
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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22
Cmax
and tmax
QUESTIONS For previous cardiac drug example
1.
What is tmax ?
2.
What is Cmax ? PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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23
Cmax
and tmax
1.
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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24
Cmax
and tmax
2.
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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25
Cmax
and tmax
Comments:
➢ See Cmax , tmax , and C0 in C vs. t plot ➢ Do estimated results for above parameters make sense? ➢ Shouldn’t Cmax be 56 mg/L ? PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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ABSORPTION MODEL TERMS
LAG TIME FLIP FLOP KINETICS PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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LAG TIME
Delay in time for absorption , e.g., for an orally ingested drug
Causes for delay include stomach emptying time, intestinal motility, others
See graph with lag time
For this course lag time calculations are not considered PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
28
FLIP FLOP KINETICS Not common in marketed products, can be seen in some drugs with very fast elimination ( k >> ka ) For this course flip flop calculation cases are not considered PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
29
D.
ABSORPTION MODEL IN CLASS EXERCISES
IN CLASS EXERCISES
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA I
DATA I PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA I Patient levels vs. time after oral administration of four 250 mg antibiotic capsules (F 0.65) Time (h) 0.2 0.5 1.0 2.0 3.0 4.0 6.0 8.0 12.0 PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
C (mg/L) 6.10 12.46 18.11 20.29 18.25 15.44 10.52 7.06 3.18 DR.
32
DATA I 1. 2. 3. 4. 5.
Estimate k , ka and A’ What are the general & patient specific equations ? What is tmax and Cmax? Looking at C vs. t plot do calculated Cmax and tmax make sense? Estimate V PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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33
DATA I 1.
From feathering analysis:
k = 0.19789 h-1 ka = 1.2239 h-1 A’ = 34.2797 mg/L Comment: Explain feathering qualitatively PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA I 2.
GENERAL
SPECIFIC
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA I 3.
tmax
Cmax
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA I 4. DATA I highest [ ] is 20.29 mg/L at 2 h. It is close to calculated Cmax 20.2 mg/L at tmax ~1.8 h using fitted curve, so calculated parameters make sense Comments: 1) Also look at C vs. t plot to check if calculated values make sense 2) Highest observed [ ] is not necessarily the real Cmax PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA I 5. Volume of distribution
V = 22.6 L PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA II
DATA II PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA II Patient levels vs. time after oral intake of four 500 mg cancer drug tablets (F 0.3 , AU∞ 250 mg) Time (h) 0.2 0.5 1.0 2.0 3.0 4.0 6.0 8.0 12.0
C (mg/L) 2.42 5.17 8.05 10.25 10.37 9.78 8.19 6.73 4.52
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
40
DATA II
Estimate
1. 2. 3.
CL AUC CLR PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
41
DATA II From feathering analysis:
k = 0.09697
h-1
ka = 1.031626 h-1 A’ = 14.5394
mg/L
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
42
DATA II GENERAL
SPECIFIC
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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43
DATA II 1.
CLEARANCE CL = kV (k 0.0970 h-1, find V)
V = 45.55 L CL = kV = 0.0970 * 45.55 = 4.42 L/h PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA II 2. AUC = FD/CL = 0.3 * 2000 mg / 4.42 L/h = 136 mg-h/L 3.
CLR = fR CL
fR = AU∞/FD = 250 mg /(0.3*2000) = 0.42 CLR = 0.42*4.42 = 1.84 L/h PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
45
DR.
1
SOURCES
Some portions of lecture notes extracted from SHARGEL & DIPIRO
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
2
OBJECTIVES 1. Explain the absorption model
2. Recognize pchem and clinical PK terms in the absorption model 3. Calculate pchem and clinical PK parameters using the absorption model
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
3
SECTIONS A. ABSORPTION MODEL B. EQUATION RECOGNITION EXAMPLE C.
TERMS
D. IN CLASS EXERCISES PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
4
A.
ABSORPTION MODEL
1 compartment model ; V = volume of distribution (L) ka = Absorption rate constant (first order, h-1) k = Elimination rate constant (first order, h-1) PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
5
ABSORPTION MODEL
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
6
ABSORPTION MODEL ❖ Previous diagram shows absorption phase, elimination phase, Cmax , tmax ❖ More exact name: 1st Order Absorption, 1st Order Elimination, 1 Compartment Model ❖ Absorption Model Characteristics ❖ One compartment ❖ First order absorption ❖ First order elimination PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
7
ABSORPTION MODEL ❖ dC/dt = Rate In – Rate Out ❖ dC/dt = Change in system [drug] per time ❖ Rate In = Drug absorption rate (from GI into system) ❖ Rate Out = Drug elimination rate (from system) Comment: Model typically used for oral absorption but applies to other EV routes, e.g., skin patches, suppositories, IM PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
8
ABSORPTION MODEL
C = V= F = ka = k =
Drug plasma level (mg/L) Volume of distribution (L) Bioavailability ; D = Administered dose (mg) absorption rate constant (h-1) elimination rate constant (h-1) PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
9
ABSORPTION MODEL
Resembles Where A’ is a constant
Note: A’ is used as a constant, do not confuse with A used for amounts PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
10
ABSORPTION MODEL Model equation can be written in different ways
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
11
B.
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE
ABSORPTION MODEL EXAMPLE PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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12
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE Following oral intake of three 500 mg tablets of a cardiac drug (bioavailability 45%), patient plasma drug levels (mg/L) vs. time (h) were given by
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
13
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE 1)
What is k ?
2)
What is ka ?
3)
What is the elimination t1/2 ?
4)
What is the absorption t1/2 ?
5)
What is C0 ?
6)
What is V ? PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
14
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE Compare general & patient specific equations:
1) k = 0.1 h-1 2) ka = 0.9 h-1 PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
15
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE 3) Elimination t1/2 = ln 2 / k = 0.693/k = 0.693/0.1 = 6.93 h 4) Absorption t1/2 = ln 2 / ka = 0.693/ka = 0.693/0.9 = 0.77 h 5) C0 = 0 (initial concentration at t = 0)
MATH: If t = 0 is substituted in the absorption model equation C = 0 GRAPH: Looking at absorption model plot C vs. t it can be seen that initial concentration is zero PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
16
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE 6) Comparing general & patient specific equations
ANSWER :
V = 13.6 L
Comment: Only one volume of distribution for one compartment model PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
17
EQUATION RECOGNITION ABSORPTION MODEL EXAMPLE COMMENTS (a)
can be written as
(b) A’ = 56 mg/L (units !!) (c) ka >> k
In example:
0.9 h-1 >> 0.1 h-1
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
18
C.
ABSORPTION MODEL TERMS
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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19
ABSORPTION MODEL TERMS
Cmax & tmax
LAG TIME
FLIP FLOP KINETICS
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
20
ABSORPTION MODEL TERMS
Cmax tmax PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
21
Cmax
and tmax
Cmax is highest [drug] (peak level) which occurs at time tmax (peak time)
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
22
Cmax
and tmax
QUESTIONS For previous cardiac drug example
1.
What is tmax ?
2.
What is Cmax ? PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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23
Cmax
and tmax
1.
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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24
Cmax
and tmax
2.
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
25
Cmax
and tmax
Comments:
➢ See Cmax , tmax , and C0 in C vs. t plot ➢ Do estimated results for above parameters make sense? ➢ Shouldn’t Cmax be 56 mg/L ? PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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26
ABSORPTION MODEL TERMS
LAG TIME FLIP FLOP KINETICS PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
27
LAG TIME
Delay in time for absorption , e.g., for an orally ingested drug
Causes for delay include stomach emptying time, intestinal motility, others
See graph with lag time
For this course lag time calculations are not considered PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
28
FLIP FLOP KINETICS Not common in marketed products, can be seen in some drugs with very fast elimination ( k >> ka ) For this course flip flop calculation cases are not considered PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
29
D.
ABSORPTION MODEL IN CLASS EXERCISES
IN CLASS EXERCISES
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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30
DATA I
DATA I PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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31
DATA I Patient levels vs. time after oral administration of four 250 mg antibiotic capsules (F 0.65) Time (h) 0.2 0.5 1.0 2.0 3.0 4.0 6.0 8.0 12.0 PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
C (mg/L) 6.10 12.46 18.11 20.29 18.25 15.44 10.52 7.06 3.18 DR.
32
DATA I 1. 2. 3. 4. 5.
Estimate k , ka and A’ What are the general & patient specific equations ? What is tmax and Cmax? Looking at C vs. t plot do calculated Cmax and tmax make sense? Estimate V PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
33
DATA I 1.
From feathering analysis:
k = 0.19789 h-1 ka = 1.2239 h-1 A’ = 34.2797 mg/L Comment: Explain feathering qualitatively PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
34
DATA I 2.
GENERAL
SPECIFIC
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA I 3.
tmax
Cmax
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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36
DATA I 4. DATA I highest [ ] is 20.29 mg/L at 2 h. It is close to calculated Cmax 20.2 mg/L at tmax ~1.8 h using fitted curve, so calculated parameters make sense Comments: 1) Also look at C vs. t plot to check if calculated values make sense 2) Highest observed [ ] is not necessarily the real Cmax PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA I 5. Volume of distribution
V = 22.6 L PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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38
DATA II
DATA II PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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39
DATA II Patient levels vs. time after oral intake of four 500 mg cancer drug tablets (F 0.3 , AU∞ 250 mg) Time (h) 0.2 0.5 1.0 2.0 3.0 4.0 6.0 8.0 12.0
C (mg/L) 2.42 5.17 8.05 10.25 10.37 9.78 8.19 6.73 4.52
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
40
DATA II
Estimate
1. 2. 3.
CL AUC CLR PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
41
DATA II From feathering analysis:
k = 0.09697
h-1
ka = 1.031626 h-1 A’ = 14.5394
mg/L
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
42
DATA II GENERAL
SPECIFIC
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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43
DATA II 1.
CLEARANCE CL = kV (k 0.0970 h-1, find V)
V = 45.55 L CL = kV = 0.0970 * 45.55 = 4.42 L/h PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
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DATA II 2. AUC = FD/CL = 0.3 * 2000 mg / 4.42 L/h = 136 mg-h/L 3.
CLR = fR CL
fR = AU∞/FD = 250 mg /(0.3*2000) = 0.42 CLR = 0.42*4.42 = 1.84 L/h PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017
DR.
45
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