Transcript Pharmacokinetics comparison (pediatrics/adults)

Olmesartan medoxomil dosing schedule
justification in pediatric hypertensive patients
Authors: SaeHeum Song*, Raymond Miller, Daniel Salazar
Daiichi Sankyo Pharma Development, Edison, NJ, USA
Objectives
0.2
0.0
0
1.0
0.8
0.6
0.4
D OSE (mg/Kg)
2000 4000 6000 8000
0.4
0.2
0.0
0
0.6
p
p
p
1.0
0.8
D OSE (mg/Kg)
2000 4000 6000 8000
p
pp
pppp
pp
pp
ppp
p
pp
p
pp
ppp
p
p
p
p
ppp
pp p
p
p
p
p
p
p
p
p
p
p
p
p
p
p
0.2
0.0
p
p p
p
p
p p
p
p ppp
p
p
pp ppp p p p
p
p
pp
pp p
p
p
p
1.0
0.8
0.6
0.4
0
20
D OSE (mg/Kg)
2000 4000 6000 8000
0
0
2000 4000 6000 8000
2000 4000 6000 8000
0
p
p
p
p
p
p
-80 -60 -40 -20
p pp
p
p
pp
pp
p pppp
pp
p pp
p pp p
pp p p
p
AU C (ng/mL hr)
0.3 mg/Kg
Summary of peak, baseline and predose blood pressure and their differences in pediatric patients in
CS0866-A-U301 study
>=6 years, <35 Kg >=6 years, >=35 Kg
20 mg
unit
40 mg
Subject & Observation
Diastolic
N
Systolic
75 subjects & 103 observations
Mean (SD)
(Low Dose)
2.5 mg
5 mg
Peak
mmHg
65.72 (11.64)
115.85 (15.05)
(High Dose)
20 mg
40 mg
Base
mmHg
73.74 (9.5)
122.69 (10.96)
Predose
mmHg
68.46 (9.92)
116.55 (14.47)
Steady State Peak –Baseline
mmHg
-8.32 (10.48)
-6.99 (11.32)
Steady State Peak –Predose
mmHg
-2.68 (7.77)
-0.59 (9.26)
Peak and Trough BP measurement
Comparison to Peak
dSBP (post-base) and OM Dose
Steady(1-3
State
Peak
Changes in BP at Peak OM exposure
hr Post
Dose)–Baseline
and OM Dose (mg/Kg)
0.0
0
1.0
2000
4000
500
6000
AUC (ng/mL
1000hr)
8000
1500
10000
0
4000
500
6000
AUC (ng/mL
1000hr)
8000
6000
1.0
20
30
40
50
60
Weight [kg]
*) Horizontal lines: Red: 20 mg, and green: 40 mg QD OM with mean(solid) and 90
% CI (Dotted) in adult population
10
0
-20
-40
2000
10000
1500
2000
0.8
1.0
dDBP (post-pre) and OM Dose
dDBP (post-base) and OM concentration
0.0
0
0.2
500
0.4
0.6
1000
DOSE (mg/Kg)
Conc (ng/mL)
0.8
1500
1.0
2000
0
2000
4000
6000
8000
10
20
100
-20
0
-20 -40 -10
500
0
6000
1000
AUC (ng/mL hr)
Conc (ng/mL)
4000
2000
0
8000
1500
10000
2000
10
20
dDBP (post-pre) and OM concentration
10000
AUC (ng/mL hr)
0
dSBP (post-pre) and OM concentration
500
0
dDBP (post-base) and OM concentration
dDBP (post-pre) and OM concentration
-10
10000
2000
dDBP
dDBP
20
20
0 1010
8000
1500
6000
1000
AUC (ng/mL hr)
Conc (ng/mL)
4000
2000
0
2000
dDBP (post-pre) and OM concentration
2000
0.6
-20
1.0
dDBP (post-base) and OM concentration
0
0.8
1500
dSBP=0 * AUC (ng/mL hr) -0.5376
0.6
0.8
500
1000
1500
DOSE (mg/Kg)
Dose) andConc
OM(ng/mL)
AUC
0.6
1000
DOSE (mg/Kg)
Conc (ng/mL)
dSBP (post-base) and OM concentration
dSBP (post-pre) and OM concentration
20
0.4
0.4
10
(1-3 hr Post
2000
0
2000
4000
6000
8000
10000
AUC (ng/mL hr)
Conc (ng/mL)
0
10
20
dDBP (post-pre) and OM concentration
-10
dDBP
dSBP=0 * AUC (ng/mL hr) -0.5376
dSBP (post-pre) and OM concentration
4000
500
0
0.2
Exposure dependent Sys/Dia blood pressure
lowering effects at week 2-3 compared to
baseline
2000
0.2
-30 -10
-20 -100
-20
dDBP=-0.0039
dDBP=1.5646 ** Conc
DOSE
(mg/Kg)-6.7532
-3.2082
dSBP(ng/mL)
dBP
20
0 1010
0
-10-20
-40
-20
dDBP
dDBP
0.0
0
10
20
dSBP (post-pre) and OM concentration
dDBP (post-pre) and OM Dose
dDBP (post-base) and OM concentration
-40
-10
0.6
0.8
1.0
500
1000
1500
2000
DOSE (mg/Kg)
(ng/mL)
ChangesConc
in BP
at Peak OM exposure
-20
0.4
No Exposure dependent Changes in Sys/Dia
blood pressures at peak exposure at week 23 compared to those at predose exposure
QD dosing is not likely to cause dosing interval
dependent fluctuations in blood pressure
lowering effects
8000
10000
-20
-20
2
0
10
0.4
Changes in BP at Peak OM exposure (1-3 hr Post Dose) and OM AUC
dDBP
dDBP
-20
0
10 0
0.2
dSBP=-0.0004
* AUC
(ng/mL
hr) -5.6583
dSBP=0.0014
* Conc
(ng/mL)
-1.4651
1010 20 20
00
20
10
0.8
DOSE (mg/Kg)
-10
0
dBP
10
0.6
0
2000
4000
6000
8000
10000
AUC (ng/mL hr)
Conclusions:
8
4
6
AUCss [mg/L*h]
0
150
0.4
dSBP (post-pre) and OM Dose
dSBP (post-base) and OM concentration
dDBP
0.2
Changes in BPat Peak OM exposure (1-3 hr Post Dose) and OM Peak Conc
AUC (ng/mL hr)
st
u
86 dym
86 6-3 g
63 18
-3 -20
86 012
86 6-3 0
63 18
-3 -40
01
-4
0
12
st
86 udy
86 6-3 -mg
6 1
86 3-3 8-2
86 6-3 01- 0
63 18 20
-3 -4
01 0
-4
0
10
8
6
4
20 mg
0.2
DOSE (mg/Kg)
dSBP=-0.002 * Conc (ng/mL) -6.2488
dSBP=-0.3369 * DOSE (mg/Kg) -0.4738
dDBP
dDBP
-40
-20
0 10
-20
-10
0
10
20
0.0
-30-20-20 -10
-10
dSBP
dBP
0.0
0
dDBP=-5.89 * DOSE (mg/Kg) -6.2982
dSBP
dBP
-30 -20 -10 0
10 20
-20
-10
0
10
20
10
0
-20
1.0
dSBP (post-pre) and OM Dose
dSBP (post-base) and OM concentration
0
0.6 mg/kg dose
0.3 mg/kg dose
0.0
dSBP=-0.0004
* AUC(ng/mL)
(ng/mL-1.4651
hr) -5.6583
dSBP=0.0014
* Conc
0.8
dSBP=-0.002
dSBP=-0.3369* *Conc
DOSE
(ng/mL)
(mg/Kg)
-6.2488
-0.4738
Conc
 WT [kg ]i 
V2,i [ L]  34.6  

 48 
Median, 90%CI for pediatric population
1.0
-10
0.6
DOSE (mg/Kg)
1.17
1-5 years
0.8
-20
0.4
dDBP=-0.0006
* AUC
(ng/mL hr) -6.5448
dDBP=0.0031
* Conc
dBP(ng/mL) -4.2715
0.2
dDBP (post-base) and OM Dose
Conc (ng/mL)
>= 6years
0.6
Steady State Peak –Predose
dDBP=0.0003 * AUC (ng/mL hr) -3.4955
0.0
0
Simulated and observed olmesartan exposure in pediatric subjects
age >=6 years old (left) and below 6 years (right) old.
0.4
Changes in BPat Peak OM exposure (1-3 hr Post Dose) and OM Peak Conc
-40
0
-30 -20 -10
dSBP
10
20
dSBP (post-base) and OM Dose
dDBP
dSBP=-5.2657 * DOSE (mg/Kg) -5.1795
Dose
0
Pharmacokinetic Comparison(Pediatrics/Adults)
0.2
DOSE (mg/Kg)
dBPdSBP
-20 -10
010 10 2020
-20 -30 -10
0
 WT [kg ]i 
CLi [ L / h]  5.11  

 48 
0.803
dDBP
20
10
0
0.0
dSBP (post-base) and OM concentration
Pediatric Pharmacokinetics of OM
-30 -20 -10
dSBP
Olmesartan weight adjusted dose, Peak Concentration and Daily exposure 0effects on peak pd
effects in comparison with baseline and predose blood pressure level
AUC
Results
dDBP (post-base) and OM Dose
•2 BLQ measurements were observed as a postdose
•2 Week 3 Trough measurements as actual post dose samples by time recording
•28 Samples on Visit 2 week 2 in 1-3 hr post dose
Analysis
Pharmacokinetics comparison (pediatrics/adults):
Pediatric pharmacokinetics of olmesartan were simulated based on the
population pharmacokinetic analysis utilizing CS866-102 and CS866-301
study based on the dosage regimen intended for the pediatric use CS866301.
The simulated observations were compared to posthoc estimated adult
pharmacokinetic exposures from previous research.
Pharmacodynamic comparison (pediatrics/adults):
Dose and pharmacokinetic exposures (AUC) and observed blood pressure
lowering effects in pediatrics and adults were compared graphically .
Evaluation of the Peak drug effects:
For the comparison of the peak drug effect in pediatrics population:
observed plasma concentration at the time of 1-3 hour post administration
and posthoc estimated AUC were used to evaluate peak drug effects.
The blood pressures at the peak drug exposure (1-3 hr post dose) were
compared to those at baseline and predose .
Changes in BP at Peak OM exposure (1-3 hr Post Dose) and OM Dose (mg/Kg)
dSBP=-5.2657 * DOSE (mg/Kg) -5.1795
(CS866-A-U301 Study)
Blood Pressure Measurement with matching pharmacokinetic
samples were collected after
1-8 hours post dose in visit 2, week 2 and predose, and
1-3 hours post dose in visit 2, week 3
dDBP=-5.89 * DOSE (mg/Kg) -6.2982
CS866-A-U301
12
p
dDBP=-0.0039 * Conc (ng/mL) -6.7532
dDBP=1.5646 * DOSE (mg/Kg) -3.2082
0.3 mg/Kg
2
p
dDBP=-0.0006
* AUC(ng/mL)
(ng/mL-4.2715
hr) -6.5448
dDBP=0.0031
* Conc
CS866-A-U102
Weight [kg]
p
p
2000 4000 6000 8000
0
AU C (ng/mL hr)
AU C (ng/mL hr)
p
p
p
p
p
ppp
p
pp
pp
p
pp
ppp
dDBP=0.0003 * AUC (ng/mL hr) -3.4955
<6 years
100
1.0
40
20
p pp
p
p
pp
pp
p pppp
pp
p pp
p pp p
pp p p
p
2000 4000 6000 8000
0
p
pp
pp
pp
p
p
pp
p
p
p
p
p
p
ppppp
ppp
ppp
pp
pp p
0
p
p
p
p
p
p
p
ppp
p
pp
pp
p
pp
ppp
-80 -60 -40 -20
20
p pp
p
p pp pp
pp
p pp p
p pp
p pp p
pp p p
p
2000 4000 6000 8000
AU C (ng/mL hr)
AU C (ng/mL hr)
p
pp
pp
pp
p
p
pp
p
p
p
p
p
p
ppppp
ppp
ppp
pp
pp p
0
p
p
60
866-419 & Pediatric s
60
8663-301 & Pediatric s
40
p
p
pp
p p pp p pp p
p pp p p
p
pp p p p
p
p
p
p
D OSE (mg/Kg)
2000 4000 6000 8000
866-318 & Pediatric s
p
p
p
p
p
ppp
p
pp
pp
p
pp
ppp
p
p
0.8
0.6
0.4
0.2
0.0
p
p p
p
p
p p
p
p ppp
p
p
pp ppp p p p
p
p
p p
pp p
AU C (ng/mL hr)
dSBP
p
ppp
p
pp
p
p
pp
pp
ppp
pp
p
pp
pp
pp
p
p
pp
p
p
p
p
p
p
ppppp
ppp
ppp
pp
pp p
p
p
p
p
p
p
p
p
p
p
p
p
p
p
AU C (ng/mL hr)
-80 -60 -40 -20
p
p
p
pp
p ppp
pp
pp
pp
pp
p
pppp
ppp
pp
p
p
p
ppp
pp p
AU C (ng/mL hr)
dSBP
p
p
pp
p p pp p pp p
p pp p p
p
pp p p p
p
p
p
ppp
p
pp
p
p
pp
pp
ppp
pp
pp
p
20
p
p
p
0
p
pp
866-419
0
40
60
40
20
p
p
-60
0
2000 4000 6000 8000
p
p
p
p
p pp
p
p
ppp
ppppppp
p
pppp
pppp
pp
pp p
-80 -60 -40 -20
p
866-419 & Pediatric s
dSBP
p
8663-301 & Pediatric s
0
p
p
AU C (ng/mL hr)
866-419 & Pediatric s
60
60
p
p p
p
p
p p
p
p ppp
p
p
pp pp p p p p
p
p
pp
pp p
8663-301
dSBP
dSBP
-80 -60 -40 -20 0
20 40
-80 -60 -40 -20 0
20 40 60
p
8663-301 & Pediatric s
dSBP=-0.0009 * DOSE(mg/Kg) -11.7275
pp p
p
p
pp p
p
p
p
p
p
p
p
p
p
p
p
p
p
p
dSBP
dSBP
-80 -60 -40 -20 0
20 40
-80 -60 -40 -20 0
20 40 60
p p ppp p
pppppp
p
p pp
p
p
p
pp
p ppp
pp
pp
ppp
p
p
pp
ppp
pp
p
p
p
p
p
ppp
pp p
dSBP
20
0
-80 -60 -40 -20
dSBP
20
0
-80 -60 -40 -20
dSBP
60
p
866-318
dSBP=-0.0016 * AUC(ng/mL hr) -9.7355
p
dSBP
dSBP
-80 -60 -40 -20 0
20 40
-80 -60 -40 -20 0
20 40 60
-200
-40
-20
p
p
p
p
p
p
p
p
p
p
p
p
p
p
p
dDBP=-0.0005 * DOSE(mg/Kg) -3.0866
020
20
40
40
1.0
0.8
0.6
0.4
p
p
p
p
p pp
p
pp
p
ppppppp
p
p ppppp
ppp
ppp
pp p
-60
-40
p
-60
pp p
p
p
pp p
dDBP dDBP
p p ppp p
pppppp
p
p pp
p
p
866-419
D OSE (mg/Kg)
Peak exposure and Blood Pressure lowering effects
Study ID
50
dSBP=-8.0081 * DOSE(mg/Kg) -6.0071
60
40
60
40
dSBP=-20.933 * DOSE(mg/Kg) -10.3483
40
60
dDBP=-6.5106 * DOSE(mg/Kg) -3.0648
40
20
0
-40
-20
dDBP
-60
866-318 & Pediatric s
AU C (ng/mL hr)
AU C (ng/mL hr)
Dose and Administration
AUCss [mg/L*h]
866-419 & Pediatric s
1.0
0.8
0.6
0.4
0.2
D OSE (mg/Kg)
D OSE (mg/Kg)
p
-20
p
p p pp p pp p
p pp p p
p
pp p p p
p
p
p
ppp
p
pp
p
p
pp
pp
ppp
pp
p
-60
0
*) POP-PK subjects .
10 mg
866-419
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
D OSE (mg/Kg)
p
-40
p
p
dDBP
40
20
p
p
p
p
p pp
p
p
ppp
ppppppp
p
pppp
pppp
pp
pp p
0
p
pp
p
p
p
D OSE (mg/Kg)
2000 4000 6000 8000
-40
steady State
steady State
steady State
-20
no
no
Sparse
-40
487
153
1773
p
p
-60
3
4
3
dDBP
0
Adult
CS866-318
CS866-419
CS8663-A-U301
8663-301
AUC (mg/Kg) –Response (BP lowering effects)
866-318 & Pediatric s
p
p
p
p
p pp
p
p
ppp
ppppppp
p
pppp
pppp
pp
pp p
p
p
p
p
p
p
p
p
p
p
p
p
0.2
0.0
0
dDBP
not done
Steady state
40
Dense
Sparse
20
24
362 (74*)
p
p
p
p
ppp
p
pp
p
ppppppp
p
p pppp
ppp
ppp
pp p
dDBP=-0.0006 * DOSE(mg/Kg) -7.3438
20
40
020
D OSE (mg/Kg)
2000 4000 6000 8000
AU C (ng/mL hr)
1
3
dDBP=-10.8841 * DOSE(mg/Kg) -6.9982
40
20
0
40
1.0
0.8
0.6
0.4
0.2
0.0
-200
p
p
-40
-20
pp p
p
p
pp p
p
p
8663-301
p
-60
-40
BP measurement
8663-301 & Pediatric s
-20
020
p
p
p
p
p
p
p
p
p
p
p
p
-40
-20
-200
p
p
p
p
p
p p pp p
ppppp p
p
p pp
p
-60
p
p
p
p
p pp
p
pp
p
ppppppp
p
p ppppp
ppp
ppp
pp p
dDBP dDBP
20
40
p
dDBP=-0.0007 * AUC(ng/mL hr) -10.9418
866-318
p
0
CS866-A-U102
CS866-A-U301
-20
-60
-40
dDBP
20
0
-60
-40
-20
dDBP
40
866-318 & Pediatric s
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
D OSE (mg/Kg)
-60
-40
PK sampling
-60
n
866-318
Dose (mg/Kg) –Response (BP lowering effects)
D OSE (mg/Kg)
dDBP dDBP
Phase
866-419
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
Clinical Studies
Study ID
8663-301
Effect of olmesartan dose (top) and exposure (bottom) on diastolic blood pressure lowering
effects in adult and pediatrics. in lower figures ‘p’ indicates diastolic blood pressure lowering
effects in pediatric population. Corresponding olmesartan doses were normalized by their body
weights.
Method
Population
Pediatric
dDBP=-7.7643 * DOSE(mg/Kg) -11.5003
40
866-318
dSBP=-15.8691 * DOSE(mg/Kg) -11.3224
Pharmacodynamic Comparison(Pediatrics (p)/Adults (black dots))
dSBP=-0.0008 * DOSE(mg/Kg) -5.2739
To compare olmesartan pharmacokinetics between pediatric and adult hypertensive
patients
To compare olmesartan exposure-response between pediatric and adult patients
To evaluate peak blood pressure lowering effects (PD effects) in comparison to when
maximum drug exposures were achieved in pediatric patients.
To aid olmesartan dosage regimen decision for hypertensive pediatric population at ages
above 1 year old.
•PK, and PK/PD of olmesartan in pediatrics were similar to those of adults.
•Recommended starting dose regimen based on the PKPD relationship is

Once Daily,

10 mg in body weight 20-35 Kg,

20 mg in body weight 35 Kg and above and

0.3 mg/Kg below 20 Kg above one years old.