Sotalol

1. Sotalol Pediatric Decision Tree and Exposure-ResponseRelationshipPeter Hinderling, OCPBSaul et al. JCP 2001;40:35-43Saul et al. CPT 2001;69:145-57Shi et el. JPK PD 2001;28:555-75

2. 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.

3. 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

4. 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.”

5. PD Biomarkers • Class III / safety:QTc- Interval • Class II /safety: Resting RR-Interval

7. 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

8. Study Protocols

9. 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

10. 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)

11. Representative Semilogarithmic Plots of Sotalol Plasma Concentrations

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

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

14. Dose-Response Relationship

15. Impact of BSA on PK

16. Consequential Impact of BSA on PD

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

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

19. 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

20. Additional Dose Adjustment Factor in N and I

21. Conclusions Exposure-response analysis in children using biomarkers: PS and SC: “Small adults”, similar exposure and responseas adults, BSA based dose adjustment appropriate N and I: Subpopulation with larger exposureand response Maturation of kidney Additional dose adjustment required