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![Page 1: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/1.jpg)
Sotalol Pediatric Decision Tree and Exposure-Response
Relationship
Peter Hinderling, OCPB
Saul et al. JCP 2001;40:35-43Saul et al. CPT 2001;69:145-57
Shi et el. JPK PD 2001;28:555-75
![Page 2: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/2.jpg)
Sotalol
Adults
1992 : Life threatening VT, VF (Betapace ®)
2000 : Maintenance of SR in sympt. AFIB/AFL (Betapace AF ™)
PK: Linear
F: 90%
Ae/D=90 %
t1/2 = 12 h
PK-PD: Linear
dl Sotalol : Class III antiarrythmic act.
l Sotalol : -blocking act.
![Page 3: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/3.jpg)
Knowledge on Sotalol in Pediatrics in 1999
• Published, uncontrolled studies in children using adult doses adjusted for BSA or BW and =12 h
Breakthrough arrhythmias with =12 h
![Page 4: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/4.jpg)
Lipicky Paradigm (Pediatric Summit, Washington, 2002):
“ Do what is feasible in children, see what can be extracted and use it.”
“ In the case of antiarrhythmics where the demonstration of efficacy
even in adults is shaky, it is not reasonable to ask for efficacy in
children.”
![Page 5: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/5.jpg)
PD Biomarkers
• Class III / safety: QTc- Interval
• Class II /safety: Resting RR-Interval
![Page 6: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/6.jpg)
![Page 7: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/7.jpg)
Written Request
• PK : Open label, single dose study, 1 dose level, extensive
sampling, 6 N, 10 I, 10 PC, 10 SC
• PK-PD : Open label, multiple ascending dose study, 3 dose levels,
sparse sampling, 8 N or 8 I completing
![Page 8: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/8.jpg)
Study Protocols
Sampling
Study Dose Level, mg/m2 PK PDa Type
PK 30 0-36 h NA extensive
PK-PD 10, 30, 70 0-8 h 0-8 h sparse
a QT, RR intervals prior to and after drug administration, resting conditions
![Page 9: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/9.jpg)
Methods
• Formulation: Syrup, extemporaneous compounding procedure
• Assay: LC/MS/MS, 0.4 ml blood required
• ECG: Same type in all sites
Baseline values during 8 h dose interval
Blinded cardiologist, digitizing pad
QTc Fridericia, Bazett • Data analysis: Traditional and population approaches
PK: Linear 2 CM
PK-PD: Linear and Emax models
![Page 10: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/10.jpg)
Study Sites and Database
Sites
24 sites initiated for PK study
21 sites initiated for PK-PD study
59 patients enrolled (34 in PK study, 25 in PK-PD study)
54 SVT, 3 VT, 2 SVT & VT
Database
58 patients with analyzable PK data ( 9 N, 17 I, 9 PC, 23 SC)
22 patients with analyzable PD data ( 6 N, 8 I, 3 PC, 5 SC)
![Page 11: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/11.jpg)
Representative Semilogarithmic Plots of Sotalol
Plasma Concentrations
0 10 20 30 40
Time (h)
1
10
100
1000
10000
Patient 21
t 1/2 =10.2 h
0 10 20 30 40
1
10
100
1000
100000 10 20 30 40
1
10
100
1000
10000
Patient 6
t 1/2 =10.1 h
0 10 20 30 40
1
10
100
1000
10000
0 10 20 30 40
Time (h)
1
10
100
1000
10000
C (
ng
/mL
)
Patient 11
t 1/2 =9.1 h
0 10 20 30 40
1
10
100
1000
100000 10 20 30 40
1
10
100
1000
10000
C (
ng
/mL
)
Patient 1
t 1/2 =8.6 h
0 10 20 30 40
1
10
100
1000
10000
![Page 12: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/12.jpg)
Relationship between CL/f and Vc/f and BSA(Empirical Bayes Estimates)
0.0 0.5 1.0 1.5 2.0
BSA, m2
0
50
100
150
200
CL
/f, m
L/m
in
CL/f (mL/min)=-13+105xBSA (m2)
0.0 0.5 1.0 1.5 2.00
50
100
150
200
0.0 0.5 1.0 1.5 2.0
BSA, m2
0
20
40
60
80
100
Vc/
f, L
Vc/f (L)=-3.94+40.2xBSA (m2)
0.0 0.5 1.0 1.5 2.00
20
40
60
80
100
![Page 13: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/13.jpg)
Plot of Dose and BSA Normalized AUC vs. BSA for 58 Pediatric Patients and 40 Adults
0.0 0.5 1.0 1.5 2.0 2.5
BSA, m2
0
200
400
600
800
1000
AU
C,
hxm
2/10
00L
Pediatrics
Adults
POPULATION
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Dose-Response Relationship
10 30 70
Dose (mg/m2)
0
10
20
30
40
50
%de
lta E
max
(ob
serv
ed)
QTc
RR
10 30 70
Dose (mg/m2)
0
10
20
30
%de
lta A
UE
ss
QTc
RR
![Page 15: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/15.jpg)
Impact of BSA on PK
10 30 70
Dose (mg/m2)
0
1000
2000
3000
4000
Cmax
,ss (n
g/mL)
BSA>=0.33 m2
BSA< 0.33 m2
10 30 70
Dose (mg/m2)
0
10000
20000
30000
AUCs
s (h*
ng/m
L)
BSA>=0.33 m2
BSA< 0.33 m2
![Page 16: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/16.jpg)
Consequential Impact of BSA on PD
10 30 70
Dose (mg/m2)
0
5
10
15
20
%de
lta A
UEss
(QTc
)
BSA>=0.33 m2
BSA< 0.33 m2
10 30 70
Dose (mg/m2)
0
10
20
30
40
%de
lta A
UEss
(RR)
BSA>=0.33 m2
BSA< 0.33 m2
![Page 17: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/17.jpg)
Representative Plots of Observed QTc Intervals vs. (Empirical Bayes) Predicted Sotalol Concentrations in 4 Individuals
Subject 48003
Predicted C, ng/ml
Obse
rve
d Q
Tc, m
sec
0 200 400 600 800 1000 1200
400
420
440
460
480
Age: 0.052 year
Subject 47001
Predicted C, ng/ml
Obse
rve
d Q
Tc, m
sec
0 500 1000 1500 2000 2500
400
450
500
Age: 0.44 year
Subject 47003
Predicted C, ng/ml
Obse
rve
d Q
Tc, m
sec
0 500 1000 1500 2000
400
420
440
460
Age: 1.1 years
Subject 35002
Predicted C, ng/ml
Obse
rve
d Q
Tc, m
sec
0 500 1000 1500 2000 2500
440
460
480
500
520
540
Age: 7.3 years
![Page 18: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/18.jpg)
Representative Plots of Observed RR Intervals vs. (Empirical Bayes) Predicted Sotalol Concentrations in 4
Individuals Subject 48004
Predicted C, ng/ml
Obse
rved R
R, m
sec
0 1000 2000 3000
400
450
500
Age: 0.03 year
Subject 47003
Predicted C, ng/ml
Obse
rved R
R, m
sec
0 500 1000 1500 2000
450
550
650
Age: 1.1 year
Subject 37002
Predicted C, ng/ml
Obse
rved R
R, m
sec
0 500 1000 1500 2000
500
600
700
800
Age: 2.6 years
Subject 32003
Predicted C, ng/ml
Obse
rved R
R, m
sec
0 500 1000 1500 2000
1000
1200
1400
1600
Age: 12 years
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Summary of Results
• PK
- Linear and dose proportionate
- t1/2 10 hours, independent of BSA
- CL/f and Vc/f linearly dependent on BSA
- BSA most important covariate
- Greater exposure of smallest children (BSA < 0.33 m2 )
• PD, PK-PD• - Doses tolerated well
- Responses increase dose dependently
- Pharmacologically important effects:
Class III at 70 mg/m2, -blocking at 30 and 70 mg/m2
- Trend for greater effects in smallest children
- Effects linearly correlated with concentrations
-blocking effect increases with BSA
![Page 20: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/20.jpg)
Additional Dose Adjustment Factor in N and I
![Page 21: Sotalol Pediatric Decision Tree and Exposure-Response Relationship Peter Hinderling, OCPB Saul et al. JCP 2001;40:35-43 Saul et al. CPT 2001;69:145-57.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649e6c5503460f94b6b39c/html5/thumbnails/21.jpg)
Conclusions
Exposure-response analysis in children using biomarkers:
PS and SC: “Small adults”, similar exposure and response as
adults, BSA based dose adjustment appropriate
N and I: Subpopulation with larger exposure and response
Maturation of kidney
Additional dose adjustment required