205122Orig1s000

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

205122Orig1s000

CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S)

4. Appendices 4.3 Individual Study Reviews

Study Report # Title Investigator/ Center Study Dates Objectives Formulation

Study Design

PK Assessment Statistical Analysis

Bioanalytical Methods

P09-001 Randomized, Single-Center, Open-Label, Five-Way Crossover Study to Evaluate the Dose-Proportionality of USL255 in Healthy Adult Subjects

Aziz L. Laurent, MD, PPD Phase I Clinic, 7551 Metro Center Drive, Building 10, Suite 200, Austin TX 78744

September 02, 2009 - March 30, 2010

To evaluate the PK, dose-proportionality, safety and tolerability of single dose of

25, 50, 100, 200, and 400 mg of USL255

TPM ER

Batch #

USL255-25-MD

268046

USL255-50-MD

268047

USL255-100-MD

268048

USL255-200-MD

268049

? Phase 1, randomized, single-center, open-label, single-dose, 5-way crossover (using A standard 5 ? 5 Latin square) study in 30 eligible healthy males and females (N=6 per cohort), aged 18-65 years

? Screening period: 4 weeks; washout period: at least 3 weeks between periods; duration: 18 weeks

? Plasma samples: predose and at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 36, 48, 72, 96, 120, 168, 216, 264, and 336h postdose

? AUC0-t, AUC0-, Cmax, Tmax, kel, and t?. ? Descriptive statistics were used to summarize the PK parameteres

? Power Model (

) was used to assess the dose-

proportionality for 25-400mg dose range. The Rdnm was the model-predicted

ratio of dose-normalized geometric means for highest dose relative to lowest

dose, with 0.8 and 1.25 being lower and upper limits, respectively.

? Dose linearity was tested by fitting the model: log(PK parameter) = a + b*log(dose) + Dose

? Additional analysis using power model was performed to test doseproportionality for 100-400mg doses

? Additional analysis was performed to test dose-normalized Cmax and AUC using ANOVA model on log-transformed exposure measures between 400mg vs. 200mg, and between 200mg vs. 100mg. Point estimates and 90% CI for geometric mean ratios between treatments, judged by BE acceptance criteria of 80-125%. Dose proportionality would be concluded if all 90% CIs fall within 80-125%.

Table. Assay performance

Analyte

Topiramate (plasma)

Method: Standard Curve:

Range: R:

HPLC/MS/MS

10.00 ? 10000 ng/mL 0.9992

2

Reference ID: 3464886

Population/ Demographics

PK Results

Precision: 4.10 ? 9.13%

Accuracy: -1.82 ? 2.42%

LOQ:

10 ng/mL

QC:

30 ng/mL 80 ng/mL 300 ng/mL 1200 ng/mL 7500 ng/mL

Precision:

8.35%

6.70% 6.94%

6.57%

5.65%

Accuracy:

-2.66%

-0.43% -1.01% -0.098% 1.57%

? Bioanalytical site:

(b) (4)

Comment: The bioanalytical methods were found acceptable, with inter-day and

intra-day accuracy and precision being ................
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