Transcript Document

A Population-based Analysis of Dalteparin Pharmacokinetics in Pediatric Patients at Risk for Thromboembolic Events
J.S. Barrett, L.G. Mitchell, D. Patel, P. Cox, P. Vegh, M. Castillo, P. Massicotte
Division of Clinical Pharmacology and Therapeutics, Children’s Hospital of Philadelphia; Pediatric Thrombosis Program and Critical Care Unit , Stollery Childrens Hospital;
Hospital for Sick Children, Toronto, Canada
Study Design
An open-label, dose-finding trial in children (>36 weeks gestational
age-16 years) with objectively confirmed TE, requiring therapeutic
dosages of anticoagulants
Dose Adjustment phase: 1-7 days until a prophylactic plasma anti-Xa
level is achieved.
Maintenance phase: additional 5 (+3) days (following dose adjustment
phase) during which detailed pharmacokinetic assessments will be
performed.
Follow-up Phase: For up to 90 days with prophylactic doses of
dalteparin or until the end of required anticoagulation treatment,
whichever comes first (prophylactic dose is adjusted monthly to
ensure prophylactic anti-Xa levels are maintained).
Model Building
• A PPK model was developed using anti-Xa data from all phases of
the study (mostly from the dose adjustment phase)
• The model was developed using NONMEM (version 6) and was
based on a 2 CPM with first order absorption (ADVAN4 TRANS4)
with allometrically-scaled CL and V, a proportional CV error model
and endogenous anti-Xa activity.
• FOCE with - interaction used for method/estimation
6
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227
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25
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0
23
15
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8
-2
0.1
0.2
0.3
0.4
Predicted Plasma Fragmin (IU/mL)
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12
15
15
7
7
0.0
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5
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2
4
18 2
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14
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518
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9
19 12 11 8
1711
18
12
19
17
7 7
23
31
2
30
10
0.2
0.4
0.6
0.8
Observed Plasma Fragmin (IU/mL)
12
14
22
27
-2
0.0
7
7
13
13
30
3 12
22
25
2618
27
23
11
6 26
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1
1
5 2
0
0.0
0.2
0.4
0.6
0.8
Observed Plasma Fragmin (IU/mL)
8
23
7
7 12
8
13
12
7
15
13
7
2
Weighted Residuals
16
8
8
0.6
Weighted Residuals
12
16
4
7
12
23
3
7
1378
127 7
87
1312 7
7 13
513 8
13
168
12
14
13
10 8
30
11
218 4
31
21
11588
27
37
92522
21
12
13
29
122
21
12
425
8 3
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11
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1
13
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10
24 22
18
2
29
16
26
423
25
26
122
29
26
111
24
20
71 86 7
20
10
3
17
10
31
261 12
11
14
20
19
226
19
5
30
24
24
16
1022
10
622
10
14
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25
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25
18
27
14
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24
28
5
27
183
11
16
8
112
119
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31
30
19
3
22
1
7
19
14
3
19
23
5
15
8 16
500
1000
1500
Time (minutes)
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11
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1
13
10
24
2
26
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4
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1
1
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76
10
3 17
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6
6
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1
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158
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11
5
7
7
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0.6
7
12
0.4
0.2
8
0.0
10
15
20
Time After Dose (minutes)
5
0.8
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5
2000
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F
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4
1
61
E
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0
0.5
Observed and Predicted Plasma Fragmin (IU/mL)
0.2
7
Individual Predicted Plasma Fragmin (IU/mL)
0.4
10
1 12 111
1
1 10 11
1010
14
11
1
10
22
18 25
18 822
25
11
18 5
1
5
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1016
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627
23 3
3
Implications for Monitoring Practices and Dose Adjustment in Children
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0.8
Figure 2: Diagnostic plots confirm the
suitability of the model to describe sources of
variation in dalteparin PK across pediatric
subpopulations: (A) PRED vs DV, (B) IPRED
vs DV, (C) WRES vs PRED, (D) WRES vs
TIME, (E) WRES vs TAD and (F) DV, PRED
vs TAD. Some under-predicted high
concentrations were observed (primarily after
the initial dose adjustment phase) and
unassociated with measured covariates.
RESULTS
DESIGN / METHODS
0.6
0.0
* Other (Native Canadian, Aboriginal, East Indian, Asian, missing)
2. To examine the PK of prophylactic doses of dalteparin and document
the long-term safety up to 90 days administration
0.8
0.0
0.1
16.3
22.6
2.6 100.0
Categorical Covariates, N (% total)
Race
Sex
Caucasian, 17 (%)
Male = 21 (%)
Black = 2 (%)
Female = 10 (%)
Asian = 4 (%)
Other* = 8 (%)
Sampling Density Across Age Strata
D
15
7.4
Overall
6
16
Continuous Covariates
Age (mos or yr)
Weight (kg)
Mean Min Max
Mean Min Max
0.7
0.1
1.9
3.2
2.6
3.9
7.1
2.9
10.9
6.6
4.7
9.3
2.9
1.1
4.4
12.1
6.4
14.6
7.3
5.5
9.6
22.5
13.7
34.3
14.2
11.5
16.3
58.1
41.4 100.0
Age Category
1: 0-2 mos (n=5)
2: 2-12 mos (n=9)
3: 1-5 yr (n=4)
4: 6-10 yr (n=5)
5: 11-18 yr (n=8)
OBJECTIVES
1. To determine the dose of dalteparin required to achieve satisfactory
prophylactic anti-factor Xa level in children at increased risk of TEs.
A
Table 1: Study demographics (N=31 evaluable patients)
Population Predicted Plasma Fragmin (IU/mL)
• Low-molecular-weight heparins (LMWHs) are increasingly being
used for prophylaxis and treatment of thromboembolic events (TE)
in children.
• The LMWH dalteparin offers the advantage of once-daily dosing.
• Prior to this trial, dalteparin has not been studied in pediatric
patients and appropriate dosing or pharmacokinetics is not known.
• Anti-Xa activity is used as a surrogate for active dalteparin moieties
(< 2000 D fraction) in plasma.
• A target peak exposure of 0.10-0.40 Anti-Xa IU/mL (C4h, based on
adult experience) has been used as the de facto dosing guidance for
dalteparin though this has not been challenged clinically nor have
dosing adjustment strategies been defined.
RESULTS (continued)
RESULTS (continued)
B
C
DESIGN / METHODS (continued)
Weighted Residuals
BACKGROUND
8 5
15
13
8
13
71 2
11
1
7
7
12 214
22 12
31 1
16
11
1
18 8 128
14
18
16
28
16
4 2
21
3
12
7
15 8
11
2 29
913
726
25
19
413
7222 28 23
291
10
14
10
22
5
610
1
2
26
1
29
1
3 14
724
2
13
10 20
10
14
25
12
14
22
15
31
3128
10
8
7
313
5
19
17
18
25
330
1
24
14
18
10
7
7
11
26
24
24
36
619
2
6
4
27
19
27
19 27
17
30
23
69
17
19
22
2
5
7
13
7 12
30
25
7
11 20
27
618 23
19
9
3
26
24
2
10
0
25
31
15
10
1 8
13
12
14
78
5
3
12
225 25
27
18
116
26
23
11
16
20
10
15
20
Time After Dose (minutes)
25
Table 3: Model-Derived Secondary Parameters
Figure 1: The more rigorous, sparse
sampling design yielded adequate
data density to define a structural
model characterizing the entire
dalteparin disposition profile.
Sampling frequency for each age
strata shown – Categories: (1) 0-2
months, (2) 2-12 months, (3) 1-5 yrs,
(4) 6-10 yrs and (5) 11-18 yrs. The
final dataset included 31 patients and
193 Anti-Xa observations.
Table 2: Parameter estimates of the final model
Estimate
SE
%RSE
%CV
Final Model Parameter
CL
(mL/h)
θCL
1410
165
11.7
-
V
(mL)
θV
9470
1310
13.8
-
Q
(mL/h)
θQ
202
10.7
5.3
-
V2
(mL)
θV2
42.3
24.8
58.6
-
KA
(IU/mL)
θKA
0.511
0.127
24.9
-
ENDO
(IU/mL)
θENDO
0.0342
0.00226
6.6
-
Inter-individual Variance
0-2 months
(n=5)
2-12 months
(n=6)
1-5 years
(n=3)
5-10 years
(n=4)
10-16 years
(n=8)
Cmax
[IU/mL]
0.13
(0.03-0.36)
0.264
(0.04-0.92)
0.255
(0.05-0.82)
0.285
(0.025-0.76)
0.335
(0.01-0.9)
Tmax
[h]
1.59
(1.48-1.83)
1.80
(1.69-2.61)
2.077
(1.93-2.15)
2.28
(2.00-2.41)
2.55
(2.22-3.10)
T1/2
[h]
0.50
(0.45-0.63)
0.61
(0.55-1.13)
0.77
(0.68-0.81)
0.90
(0.72-0.99)
1.08
(0.85-1.5)
AUCtau
(IU/h)
0.002
(0.001-0.003)
0.002
(0-0.005)
0.003
(0.002-0.005)
0.003
(0.001-0.006)
0.003
(0.001-0.013)
V/F
[L/h/kg]
0.038
(0.022-0.066)
0.036
(0.008-0.049)
0.036
(0.017-0.044)
0.033
(0.019-0.080)
0.032
(0.012-0.072)
CL/F
[L/h/kg]
0.046
(0.03-0.072)
0.032
(0.005-0.053)
0.031
(0.018-0.042)
0.024
(0.017-0.076)
0.019
(0.007-0.032)
Table 4: Clinical Performance – Achieving Target Exposure
0-2 mos
(n=5)
2-12 mos
(n=6)
1-5 yrs
(n=3)
5-10 yrs
(n=4)
10-16 yrs
(n=8)
Maintenance dose
[IU]
316
(260-390)
585
(447-876)
730
(640-1400)
1825
(1370-2500)
3445
(2500-5500)
Maintenance dose
[IU/kg]
100
(100)
100
(50-100)
100
(50-100)
87.5
(73-100)
62.5
(25-100)
Time to achieve
target range [days]
1
(1-3)
1
(1-2)
1
(1)
1
(1-3)
1.5
(1-3)
% of Patients in target range (cumulative)
ETA1
ω 2CL
0.436
0.106
24.3
66.0
ETA2
ω 2V
0.123
0.0967
78.6
35.1
1 day
80
83.3
100
50
50
ETA3
ω 2KA
0.458
0.207
45.2
67.7
2 days
80
100
100
75
87.5
ETA4
ω 2Q
7.93
5.96
75.2
281.6
3 days
100
100
100
100
100
EPS1
ω 2prop
0.0999
0.0166
16.6
31.6
> 3 days
100
100
100
100
100
Figure 3: The discrete sampling practice of measuring Anti-Xa activity at 4h
as a surrogate for peak exposure may mask age-related changes in Tmax.
The concentration at 4 hours across the various age strata (left panel) does
not discriminate the age-related changes in Tmax (right panel). Younger
children reach peak exposure sooner and hence the concentration at 4 hours
may underestimate peak anti-Xa activity and recommend dose adjustment
when not warranted.
DISCUSSION AND CONCLUSIONS
• The PPK model is well predicted; pediatric anti-Xa exposure of
dalteparin is well characterized by a 2 CPM structural model with
allometrically scaled CL and V, a proportional residual error
model and an additive term for endogenous anti-Xa activity.
• MAP Bayes estimates from the final model suggests that agerelated differences exist in the Tmax of SC administered
dalteparin. This has been poorly studied with other LMWHs due
to the reliance on TDM-based, discrete sampling around the
presumed Cmax (4 hours) based on adult data.
• Age-specific guidance on monitoring to assess the achievement of
therapeutic Anti-Xa levels may be warranted if peak exposure is
clinically relevant – this remains to be verified.
• The model will form the basis of additional covariate
identification in pediatric patients and used to support design of
future trials particularly with emphasis on managing toxicities.
• Likewise, an external validation is planned from both standard of
care dosing and TDM data and the results of a prospective dosefinding trial due to enroll by year’s end.