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

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Sotalol Pediatric Decision Tree and
Exposure-ResponseRelationshipPeter
Hinderling, OCPBSaul et al. JCP
20014035-43Saul et al. CPT 200169145-57Shi
et el. JPK PD 200128555-75
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Sotalol

• Adults
• 1992 Life threatening VT, VF
  (Betapace )
• 2000 Maintenance of SR in sympt.
  AFIB/AFL (Betapace AF )
• PK Linear
• F 90
• Ae/D90
• t1/2 12 h
• PK-PD Linear
• dl Sotalol Class III
  antiarrythmic act.
• l Sotalol ?-blocking
  act.

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• 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

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• 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.

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

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• 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

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Study Protocols
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• 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

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• 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)

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• Representative Semilogarithmic Plots
  of Sotalol
• Plasma
  Concentrations

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Relationship between CL/f and Vc/f and
BSA(Empirical Bayes Estimates)
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Plot of Dose and BSA Normalized AUC vs. BSA for
58 Pediatric Patients and 40 Adults
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Dose-Response Relationship
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Impact of BSA on PK
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Consequential Impact of BSA on PD
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Representative Plots of Observed QTc Intervals
vs. (Empirical Bayes) Predicted Sotalol
Concentrations in 4 Individuals
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Representative Plots of Observed RR Intervals vs.
(Empirical Bayes) Predicted Sotalol
Concentrations in 4 Individuals
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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 lt 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

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• Additional Dose Adjustment Factor in N
  and I

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• 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