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

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.

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

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.”

PD Biomarkers

• Class III / safety: QTc- Interval

• Class II /safety: Resting RR-Interval

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

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

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

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)

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

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

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

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

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

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

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

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

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

Additional Dose Adjustment Factor in N and I

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