A population pharmacokinetic-pharmacodynamic analysis to assess food
effect on PK and PD of fimasartan in healthy male subjects
Jongtae Lee, Sangil Jeon, Seunghoon Han, Dong-Seok Yim
Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary’s Hospital, Seoul, Korea; Department of
Pharmacology, College of Medicine, the Catholic University of Korea, Seoul, Korea
BACKGROUND & OBJECTIVE
Fimasartan is a novel non-peptide angiotensin II receptor antagonist which selectively blocks the AT1 receptor. A clinical
trial was performed in healthy subjects to assess the effect of food on the PK of fimasartan. To explore the exposureresponse relationship and the influence of food intake on it, a PK-PD model was developed.
METHODS
A randomized crossover trial of 240 mg tablet of fimasartan was performed in 24 healthy volunteers to evaluate the food
effect. Extensive PK sampling was done (at 0, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12 and 24 h after dose) as well as systolic and
diastolic blood pressure measurements at 0, 4, 8, 12 and 24 h. The results were analyzed using mixed effect methods
NONMEM (Ver.6.2).
RESULTS
DEMOGRAPHICS
Characteristics
variable
PK-PD MODEL
group
unit
No.
Total
P-value2)
A
B
12
12
24
-
Age1)
years
30.3±5.8
30.8±7.5
30.6±6.5
0.9999
Height1)
cm
176±9.0
177±7.1
176±8.0
0.5126
Weight1)
Kg
69.3±12.3
72.7±6.8
71.0±9.9
0.3506
SBP1)
mmHg
121±7.2
123±9.2
122±8.1
0.5878
DBP1)
mmHg
77.3±5.2
78.3±5.7
77.8±5.3
0.7101
PR1)
bpm
80.3±10.3
79.3±16.1
79.8±13.2
0.9999
1) mean ± SD ( SBP: Systolic BP, DBP: Diastolic BP, PR: Pulse Rate )
2) Wilcoxon rank sum test
BASIC GOODNESS-OF-FIT PLOT OF PK
FINAL PK PARAMETER ESTIMATES
Parameter
Estimate
% RSE
Bootstrap median (95% CI)
CL
178 L/h
8.31
173 (136-222)
V2
558 L
18.3
501 (305-760)
Q
56.3
19.0
60.9 (40.6-89.7)
V3
348 L
11.9
361 (280-454)
D2
0.531 h
5.42
0.573 (0.287-0.823)
Ka
0.483
15.5
0.428 (0.277-0.745)
WB = 1-EXP(-((Ka*TAD)**γ))
γ
4.1
5.63
3.99 (2.85-5.50)
Relative Bioavailability(F1)
0.63
4.54
0.613 (0.513-0.746)
V2 = θ2 * (70/WT) ** θ9
θ9
0.433
58.2
0.531 (0.01-1.99)
ωCL
47.2 %
14.9
0.417 (0.213-0.577)
ωV2
84.6 %
28.4
0.703 (0.364-0.976)
ωKa
148 %
10.4
0.929 (0.52-1.40)
ωγ
75.9 %
11.2
0.669 (0.444-0.943)
ωF1
33.4 %
26.5
0.295 (0.003-0.438)
ρCL~V2
0.917
Fixed effect
Interindividual variability
0.904 (0.642-0.978)
Residual error
0.429
7.29
0.425 (0.377-0.481)
VISUAL PREDICTIVE CHECK OF PK MODEL
Parameter
fed VPC
% RSE
Estimate (DBP)
% RSE
E0
113 mmHg
1.12
75.3 mmHg
1.67
MTT
0.758 h
10.9
1.35 h
156
Emax
0.146
8.43
0.211
10.1
EC50
4.95
20.4
3.06
62.4
ωE0
4.01 %
25.2
5.56 %
15.6
ωEmax
25.5 %
21.8
NE
NE
5.79
4.65
5.25
6.11
200
300
400
Observed value
95 percentile
50 percentile
5 percentile
Interindividual variability
0
0
200
100
Concentration (ng/mL)
1200
400
600
800
1000
Observed value
95 percentile
50 percentile
5 percentile
Estimate (SBP)
Fixed effect
500
1400
fasting VPC
Concentration (ng/mL)
FINAL PD PARAMETER ESTIMATES
0
5
10
15
TAD,hr
20
25
Residual error
0
5
10
15
20
25
σadd
TAD,hr
BASIC GOODNESS-OF-FIT PLOT OF PD
DBP
Simulated DBP
Simulated SBP
140
SBP
VISUAL PREDICTIVE CHECK OF PD MODEL
100
σprop
fasting
fed
80
40
80
50
60
70
DBP(mmHg)
100
SBP(mmHg)
120
90
fasting
fed
10
15
20
Time(hr)
25
30
10
15
20
25
30
Time(hr)
CONCLUSION
Because of the alteration of PK property in absorption phase, different PK models were used to characterize the food
effect. However, the final PK-PD model demonstrated that PK changes by the food had little effect on blood pressure.