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BACKGROUND
OBJECTIVES
DESIGN / METHODS
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 age-related 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 dose-finding trial due to enroll by year’s end.
• 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.
1. To determine the dose of dalteparin required to achieve satisfactory prophylactic anti-factor Xa level in children at increased risk of TEs.
2. To examine the PK of prophylactic doses of dalteparin and document the long-term safety up to 90 days administration
J.S. Barrett, L.G. Mitchell, D. Patel, P. Cox, P. Vegh, M. Castillo, P. MassicotteDivision 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
A Population-based Analysis of Dalteparin Pharmacokinetics in Pediatric Patients at Risk for Thromboembolic Events
Table 1: Study demographics (N=31 evaluable patients)
RESULTS (continued)
Study DesignAn 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
RESULTS (continued)
RESULTS
Table 2: Parameter estimates of the final model
DESIGN / METHODS (continued)
Sampling Density Across Age Strata 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 4: Clinical Performance – Achieving Target Exposure
62.5(25-100)
87.5(73-100)
100(50-100)
100(50-100)
100(100)
Maintenance dose [IU/kg]
100100100100100> 3 days
1001001001001003 days
87.575100100802 days
505010083.3801 day
% of Patients in target range (cumulative)
1.5(1-3)
1(1-3)
1(1)
1(1-2)
1(1-3)
Time to achieve target range [days]
3445(2500-5500)
1825(1370-2500)
730(640-1400)
585(447-876)
316(260-390)
Maintenance dose [IU]
10-16 yrs(n=8)
5-10 yrs(n=4)
1-5 yrs(n=3)
2-12 mos(n=6)
0-2 mos(n=5)
62.5(25-100)
87.5(73-100)
100(50-100)
100(50-100)
100(100)
Maintenance dose [IU/kg]
100100100100100> 3 days
1001001001001003 days
87.575100100802 days
505010083.3801 day
% of Patients in target range (cumulative)
1.5(1-3)
1(1-3)
1(1)
1(1-2)
1(1-3)
Time to achieve target range [days]
3445(2500-5500)
1825(1370-2500)
730(640-1400)
585(447-876)
316(260-390)
Maintenance dose [IU]
10-16 yrs(n=8)
5-10 yrs(n=4)
1-5 yrs(n=3)
2-12 mos(n=6)
0-2 mos(n=5)
Continuous Covariates Age (mos or yr) Weight (kg)
Age Category Mean Min Max Mean Min Max 1: 0-2 mos (n=5) 0.7 0.1 1.9 3.2 2.6 3.9 2: 2-12 mos (n=9) 7.1 2.9 10.9 6.6 4.7 9.3 3: 1-5 yr (n=4) 2.9 1.1 4.4 12.1 6.4 14.6 4: 6-10 yr (n=5) 7.3 5.5 9.6 22.5 13.7 34.3 5: 11-18 yr (n=8) 14.2 11.5 16.3 58.1 41.4 100.0
Overall 7.4 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 (%)
* Other (Native Canadian, Aboriginal, East Indian, Asian, missing)
0.0 0.2 0.4 0.6 0.8
Observed Plasma Fragmin (IU/mL)
0.0
0.2
0.4
0.6
0.8
Po
pu
latio
n P
red
icte
d P
lasm
a F
rag
min
(IU
/mL
)
11
1
1
11
1
1
1
1
11 1
22
2
2
2
2
2
2
22
3
3
3
3
3
33
4
4
4
4
5 5 5
5
5
5
6
66
6
6
6
6
7
77
7
7
7
77
7
7
7
7
7
7
77
8
88
8
8
8
8
8
8
8
89
9
9
101010
10
10
1010
10
10
1111
11
11
11
11
12
12
12
12
12
12
12
12
12
12
12
13
13
13
13
1313
1313
1414 14
14
14
1414
15 1515
15
15
16
1616
16
16
16
16
17
17
17
18
18
18
18
18
1919
19
19
19 19 1920
20
20
21
21
22
22
22
22
2222
23
23
23
23
2424
24
24
24
2525
25
25
25
2626
26
2626
27
27
27
2727
28 28
2829 29
29
3030
30
31
31
3131
0.0 0.2 0.4 0.6 0.8
Observed Plasma Fragmin (IU/mL)
0.0
0.2
0.4
0.6
0.8
Ind
ivid
ua
l Pre
dic
ted
Pla
sma
Fra
gm
in (
IU/m
L)
1
1
1
1
11
1
1
1
1
11 1
22
2
2
2
2
2
2
2
23
3
3
3
3
33
4
4
4
4
5
5
5
5
5
5
6
6
6
66
6
6
7
7
7 7
7
7
77
7
7
7
7
7
7
77
8
8 8
8
8
8
8
8
8
8
8
9
99
1010
1010
10
10
1010
10
11
11
11
11
11
11
12
12
12
12
12
12
12
12
12
12
12
13
13
13
13
13
1313
13
14
14
1414
14
1414
15
15
15
15
15
16
16
16
1616
16
1617
17
17
18
18
18
18
18
19
19
19
19
19 19 19
20
20
20
21
2122
22
22
22
2222
23
23
23
23
24
24
24
24
24
2525
25
25
25
26
26
26
2626
27
27
27
2727
28
28
282929
29
3030
30
31
3131
31
0.0 0.1 0.2 0.3 0.4 0.5
Predicted Plasma Fragmin (IU/mL)
-2
0
2
4
6
We
igh
ted
Re
sid
ua
ls
1
1
11
1
11
1
1
1
1
1
1
22
22
22
2
2
2
2
3
3
33
3
3
3
4
4
4
4
5
5
5
5
5
56
6
666
6 6
7
7
7
7
7
7
7
77
7
7
7
7
7
7
7
8
8
8
8
8
88
8
8
8
8
9
9
9
10
10
10
10
10
10
10
10
10
11
11
11
1111
11
1212
12
12
12
12
12
12
12
12
12
13
13
1313 13
13
13
13
1414
14
14
1414
14
15
15
15
15
15
16
16
16
16
16
16
16
1717
17
18
18
18
18
18
19
19
19
1919
19
19
202020
2121
22
222222
22
22
23
23
23
23
24
24
24
24
24
25
2525
2525
262626
2626
27
27
27
2727 28
28282929
29
30
30
3031
31
31
31
0 500 1000 1500 2000
Time (minutes)
-2
0
2
4
6
We
igh
ted
Re
sid
ua
ls
1
1
11
1
11
1
1
1
1
1
1
2 2
22
22
2
2
2
2
3
3
33
3
3
3
4
4
4
4
5
5
5
5
5
56
6
66 6
6 6
7
7
7
7
7
7
7
77
7
7
7
7
7
7
7
8
8
8
8
8
88
8
8
8
8
9
9
9
10
10
10
10
10
10
10
10
10
11
11
11
1111
11
1212
12
12
12
12
12
12
12
12
12
13
13
131313
13
13
13
1414
14
14
1414
14
15
15
15
15
15
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16
16
1717
17
18
18
18
18
18
19
19
19
1919
19
19
202020
2121
22
222222
22
22
23
23
23
23
24
24
24
24
24
25
2525
2525
262626
2626
27
27
27
272728
2828292929
30
30
3031
31
31
31
0 5 10 15 20 25
Time After Dose (minutes)
-2
0
2
4
6
We
igh
ted
Re
sid
ua
ls
1
1
11
1
1 1
1
1
1
1
1
1
22
2 2
2 2
2
2
2
2
3
3
33
3
3
3
4
4
4
4
5
5
5
5
5
56
6
6 6 6
66
7
7
7
7
7
7
7
77
7
7
7
7
7
7
7
8
8
8
8
8
88
8
8
8
8
9
9
9
10
10
10
10
10
10
10
10
10
11
11
11
11 11
11
12 12
12
12
12
12
12
12
12
12
12
13
13
131313
13
13
13
1414
14
14
1414
14
15
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15
15
15
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16
16
16
16
16
1717
17
18
18
18
18
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19
19
1919
19
19
2020 20
2121
22
2222 22
22
22
23
23
23
23
24
24
24
24
24
25
25 25
25 25
26 2626
2626
27
27
27
272728
28 2829 29
29
30
30
3031
31
31
31
0 5 10 15 20 25
Time After Dose (minutes)
0.0
0.2
0.4
0.6
0.8
Ob
serv
ed
an
d P
red
icte
d P
lasm
a F
rag
min
(IU
/mL
)
11
1
1
1
1
1
1
1
1
1
1
1
22
2
2
2
2
2
2
2
2
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66
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77
77
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7
7 7
7
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1010
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1011
11
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1212
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2323
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27 27
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282929
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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.
A B C D
E F
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.
Implications for Monitoring Practices and Dose Adjustment in Children
31.616.60.01660.0999ω 2propEPS1
281.675.25.967.93ω 2QETA4
67.745.20.2070.458ω 2KAETA3
35.178.60.09670.123ω 2VETA2
66.024.30.1060.436ω 2CLETA1
Inter-individual Variance
-6.60.002260.0342θENDO(IU/mL)ENDO
-24.90.1270.511θKA(IU/mL)KA
-58.624.842.3θV2(mL)V2
-5.310.7202θQ(mL/h)Q
-13.813109470θV(mL)V
-11.71651410θCL(mL/h)CL
Final Model Parameter
%CV%RSESEEstimate
31.616.60.01660.0999ω 2propEPS1
281.675.25.967.93ω 2QETA4
67.745.20.2070.458ω 2KAETA3
35.178.60.09670.123ω 2VETA2
66.024.30.1060.436ω 2CLETA1
Inter-individual Variance
-6.60.002260.0342θENDO(IU/mL)ENDO
-24.90.1270.511θKA(IU/mL)KA
-58.624.842.3θV2(mL)V2
-5.310.7202θQ(mL/h)Q
-13.813109470θV(mL)V
-11.71651410θCL(mL/h)CL
Final Model Parameter
%CV%RSESEEstimate
Table 3: Model-Derived Secondary Parameters
0.032(0.012-0.072)
0.033(0.019-0.080)
0.036(0.017-0.044)
0.036(0.008-0.049)
0.038(0.022-0.066)
V/F[L/h/kg]
0.019(0.007-0.032)
0.024(0.017-0.076)
0.031(0.018-0.042)
0.032(0.005-0.053)
0.046(0.03-0.072)
CL/F[L/h/kg]
0.003(0.001-0.013)
0.003(0.001-0.006)
0.003(0.002-0.005)
0.002(0-0.005)
0.002(0.001-0.003)
AUCtau
(IU/h)
1.08(0.85-1.5)
0.90(0.72-0.99)
0.77(0.68-0.81)
0.61(0.55-1.13)
0.50(0.45-0.63)
T1/2[h]
2.55(2.22-3.10)
2.28(2.00-2.41)
2.077(1.93-2.15)
1.80(1.69-2.61)
1.59(1.48-1.83)
Tmax
[h]
0.335(0.01-0.9)
0.285(0.025-0.76)
0.255(0.05-0.82)
0.264(0.04-0.92)
0.13(0.03-0.36)
Cmax
[IU/mL]
10-16 years(n=8)
5-10 years(n=4)
1-5 years(n=3)
2-12 months(n=6)
0-2 months(n=5)
0.032(0.012-0.072)
0.033(0.019-0.080)
0.036(0.017-0.044)
0.036(0.008-0.049)
0.038(0.022-0.066)
V/F[L/h/kg]
0.019(0.007-0.032)
0.024(0.017-0.076)
0.031(0.018-0.042)
0.032(0.005-0.053)
0.046(0.03-0.072)
CL/F[L/h/kg]
0.003(0.001-0.013)
0.003(0.001-0.006)
0.003(0.002-0.005)
0.002(0-0.005)
0.002(0.001-0.003)
AUCtau
(IU/h)
1.08(0.85-1.5)
0.90(0.72-0.99)
0.77(0.68-0.81)
0.61(0.55-1.13)
0.50(0.45-0.63)
T1/2[h]
2.55(2.22-3.10)
2.28(2.00-2.41)
2.077(1.93-2.15)
1.80(1.69-2.61)
1.59(1.48-1.83)
Tmax
[h]
0.335(0.01-0.9)
0.285(0.025-0.76)
0.255(0.05-0.82)
0.264(0.04-0.92)
0.13(0.03-0.36)
Cmax
[IU/mL]
10-16 years(n=8)
5-10 years(n=4)
1-5 years(n=3)
2-12 months(n=6)
0-2 months(n=5)
