# Presentation: 472298

## 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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 TM)**
**           ****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

**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.”

**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

**PD Biomarkers**
**Class III / safety:**** ****QTc- Interval**
**Class II /safety: Resting  RR-Interval**

- <date/time>

##    
    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 

**    ****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

- <date/time>

## 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

**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)

_** **__**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

- <date/time>

**            **Representative Semilogarithmic Plots of Sotalol
-                                Plasma Concentrations

## Relationship between CL/f and Vc/f and BSA(Empirical Bayes Estimates)

- <date/time>

- Relationship between CL/f and Vc/f and BSA(Empirical Bayes Estimates)

## Plot of Dose and BSA Normalized AUC vs. BSA for 58 Pediatric Patients and 40 Adults

- <date/time>

**Plot of Dose and BSA Normalized AUC vs. BSA for 58 Pediatric Patients and 40 Adults**

## Dose-Response Relationship   

- <date/time>

- Dose-Response Relationship

## Impact of BSA on PK

- <date/time>

**Impact of BSA on PK**

## Consequential Impact of BSA on PD

- <date/time>

**Consequential Impact of BSA on PD**

## Representative Plots of Observed QTc Intervals vs. (Empirical Bayes) Predicted Sotalol Concentrations in 4 Individuals

- <date/time>

## Representative Plots of Observed RR Intervals vs. (Empirical Bayes) Predicted Sotalol Concentrations in 4 Individuals 

- <date/time>

- Representative Plots of Observed RR Intervals vs. (Empirical Bayes) Predicted Sotalol Concentrations in 4 Individuals

## 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 m****2**** )**
**PD, PK-PD**
**-  Doses tolerated well**
**     ****-  Responses increase dose dependently**
**     ****-  Pharmacologically important effects:**
**            ****Class III at 70 mg/m****2****, ********-blocking  at 30 and 70 mg/m****2**
-      **- ** **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

- <date/time>

**        ****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

** **
**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**
**      **
**      **