# Presentation: 673350

## TetrabenazinePrestwick PharmaceuticalsNDA 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**** **

## 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.**

## Pharmacokinetic Characteristics of TBZ

## 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**

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

## 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**

## Change in TCS are internally consistent across studies

## Distribution of TBZ doses at week 12 (TBZ 103,004)

## 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 (p=0.10)**
**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.**

## Relationship between dose and change in TCS is linear between 12.5 and 100 mg

## Effects of TBZ on QT prolongation

## 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)**

## Mean change in QTcF, corrected for baseline, placebo

## 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.**

## Acknowledgments

**Pharmacometrics Group, Office of Clinical Pharmacology, FDA.**
**Sally Yasuda, Ramana Uppoor, Mehul Mehta, Division of Clinical Pharmacology–I, Office of Clinical Pharmacology, FDA.**
**IRT – QT Team, FDA.**