Tetrabenazine Prestwick Pharmaceuticals NDA 21894

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TetrabenazinePrestwick PharmaceuticalsNDA 21894

• Peripheral and Central Nervous System Drugs
  Advisory Committee Meeting
• Beltsville, Maryland
• December 6, 2007
• Venkatesh Atul Bhattaram
• Pharmacometrics, Office of Clinical Pharmacology

Center for Drug Evaluation and Research
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Key Review Questions

• Does the dose and change in total chorea scores
  (TCS) relationship provide confirmatory evidence
  of effectiveness?
• Yes, there is a significant linear dose-TCS
  relationship for doses up to 100 mg.
• The changes in TCS are internally consistent
  across trials
• What is the QT prolongation potential?
• Single dose studies at 50 mg showed a maximum
  prolongation of 7.3 msec (4.5, 10 msec).
  Prolongation after multiple doses with
  interacting drugs is not studied.

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Pharmacokinetic Characteristics of TBZ
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Pharmacokinetic Characteristics of TBZ

• Absorption
• 75 after oral administration
• Metabolism
• Rapidly converted to ?-HTBZ and ?-HTBZ
• ?-HTBZ and ?-HTBZ predominantly metabolized by
  CYP2D6
• Half-life for
• ?-HTBZ 5 h
• ?-HTBZ is 4 h

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Does the dose and change in total chorea scores
(TCS) relationship provide confirmatory evidence
of effectiveness?
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Clinical studies analyzed

• Study TBZ 103,004 (Placebo Controlled)
• Dose levels 12.5 100 mg
• Study TBZ 103,007
• Open label extension of TBZ 103,004
• Dose levels 12.5 - 200 mg
• Study TBZ 103,005
• Withdrawal design
• Dose levels Up to 150 mg
• Study TBZ 103,006
• Open label extension of TBZ 103,005
• Dose levels Up to 150 mg

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Change in TCS are internally consistent across
studies
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Distribution of TBZ doses at week 12 (TBZ 103,004)
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Dose and time are not confounded for TBZ studies

• Pharmacokinetic half-life for TBZ is 5-6 hours.
  Pharmacokinetic steady state is achieved after
  first dose.
• 26/30 patients in placebo group have no
  systematic changes in total chorea scores over
  time. Change from baseline in placebo group at
  Week 12 is not significantly different from zero
  (p0.10)
• TBZ elicits it effect on total chorea scores
  within one week post dose change. In Study TBZ
  103,005, upon withdrawal of TBZ, the total chorea
  scores are at baseline levels within 3 days.
  Chorea scores at every weekly visit demonstrate
  full effect at that dose.

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Relationship between dose and change in TCS is
linear between 12.5 and 100 mg
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Effects of TBZ on QT prolongation
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QT prolongation potential of TBZ in healthy
volunteers

• Study TBZ 104,015
• Thorough QT study with a single dose of 25 and 50
  mg
• Study TBZ 107,018
• Single dose of 50 mg with multiple doses of
  paroxetine (CYP2D6 inhibitor)

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Mean change in QTcF, corrected for baseline,
placebo
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Key Review Questions

• Does the dose and change in total chorea scores
  (TCS) relationship provide confirmatory evidence
  of effectiveness?
• Yes, there is a significant linear dose-TCS
  relationship for doses up to 100 mg.
• The changes in TCS are internally consistent
  across trials
• What is the QT prolongation potential?
• Single dose studies at 50 mg showed a maximum
  prolongation of 7.3 msec (4.5, 10 msec).
  Prolongation after multiple doses with
  interacting drugs is not studied.

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Acknowledgments

• Pharmacometrics Group, Office of Clinical
  Pharmacology, FDA.
• Sally Yasuda, Ramana Uppoor, Mehul Mehta,
  Division of Clinical PharmacologyI, Office of
  Clinical Pharmacology, FDA.
• IRT QT Team, FDA.