PhRMA Web Synopsis
Protocol A9451169 – 13July2011 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
For publications based on this study, see associated bibliography.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Neurontin ® (Gabapen ®)/Gabapentin
THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See United States
Package Insert (USPI)NATIONAL CLINICAL TRIAL NO.: NCT00785772
PROTOCOL NO. : A9451169
PROTOCOL TITLE: A post-marketing clinical pharmacokinetics study of gabapentin inJapanese epileptic subjects with renal impairment

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Study Center: 1 center in Japan
Study Initiation Date and Completion Dates: 16 March 2010 to 1 April 2010
Phase of Development: Phase 4
Study Objective(s): To confirm the pharmacokinetics of gabapentin after administration toJapanese epileptic subjects with renal impairment and investigate if there are differences
between values obtained from a simulation with a population pharmacokinetic (PK) modelthat was used as a rationale for dose adjustment in subjects with renal impairment andobserved plasma concentration, and to evaluate the safety throughout the study.
METHODS
Study Design: This study was planned as a multicenter, open-label, post-marketing clinicalstudy in epileptic subjects with renal impairment or on hemodialysis. The subjects of thestudy were epileptic subjects with renal impairment (subjects with a creatinine clearance of
5 to 59 mL/min or who require hemodialysis) who had no deviation from inclusion
criteria/exclusion criteria and who consented for study participation. The creatinine clearance
was calculated using the Cockcroft-Gault equation. Duration of observation was 15 days
from screening if the subject had already been treated with gabapentin and 28 days fromscreening if the subject was treated with gabapentin for the first time. In case gabapentin
treatment was completed or discontinued in the study, the subject was to be observed 7 days
after completion or discontinuation of the study as well.
Number of Subjects (Planned and Analyzed):
Planned: 10 subjects

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Protocol A9451169 – 13July2011 – FinalAnalyzed: 1 subject
The target sample size of the study was 10 subjects. As a result of a consultation with
Pharmaceuticals and Medical Devices Agency, however, the study was completed with anenrollment of 1 subject because prolongation of the study period or a change in the inclusion
criteria (the upper limit of age was deleted) did not lead to further enrollment of subjects.
Diagnosis and Main Criteria for Inclusion: Epileptic subjects aged 20 years or older
indicated for the treatment with gabapentin (combined therapy with an antiepileptic forpartial seizure [including secondary generalized seizure] in epileptic subjects in whom otherantiepileptics had been inadequate) with renal impairment defined as a creatinine clearanceof 5 to 59 mL/min at baseline or on hemodialysis.
Study Treatment: The study drugs used were GABAPEN® tablets 200 mg, 300 mg, and400 mg. Descriptions in the package insert were followed as much as possible, and dosage
regimens were adjusted depending on the creatinine clearance. However, changes in dose
based on clinical symptoms or laboratory test results were allowed during the study.
Efficacy Evaluations: No efficacy evaluations were performed for this study.
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Pharmacokinetic Evaluations: Observed plasma gabapentin concentration
Plasma gabapentin concentrations were measured to investigate if there were differencesfrom values obtained from a simulation with a population PK model that was used as arationale for dose adjustment in subjects with renal impairment.
Safety Evaluations: Adverse events, laboratory tests (including hematology, serum
chemistry, and urinalysis), physical examination, blood pressure, pulse rate, body weight
Statistical Methods: In the tabulation of the pharmacokinetic and safety analyses, the day ofthe start of the study treatment was defined as Day 1.
Pharmacokinetics Analysis: Based on the obtained data on plasma gabapentin concentrations,
population mean estimates were simulated by demographic factor and dose for each subject
using a currently established population PK model and compared with actual measurements.
Individual parameters were also determined by the Bayesian method and the deviations fromthe population parameters were evaluated.
Safety Analysis: The summaries and lists of safety data and other parameters were tabulated
in accordance with the Pfizer Data Standard, which specifies the sponsor’s standard methods
for data collection and reporting concerning safety information.
RESULTS
Subject Disposition and Demography: A subject who had already been taking gabapentin
was enrolled in the study, received study treatment, and completed the study. The
demographic factors of this subject were as follows: 62 year-old male, weight 61.8 kg, height161.00 cm, BMI 23.8 kg/m2, and duration of epilepsy 5.98 years. The subject was onPage 2PhRMA Web Synopsis
Protocol A9451169 – 13July2011 – Finalhemodialysis, receiving a maintenance dose of 300 mg twice daily. No supplemental dosing
was performed immediately after hemodialysis.
Efficacy Results: No efficacy evaluations were performed in this study.
Pharmacokinetic Results: The plasma drug concentration of the subject was 38.4 and44.64 µg/mL at Visit 2 (Day 8) and Visit 3 (Day 15), respectively. The observed plasma
concentration was 2.16- and 2.59-fold of the plasma concentration estimated from thepopulation mean and 1.15- and 1.37-fold of the individual estimate on Day 8 and Day 15,respectively. The observed values were higher than the plasma concentrations calculated
from the population means and individual estimates.
Safety Results: No adverse events or laboratory test parameters with significant changes
were observed in the study. No clinically significant changes were observed in bloodpressures, pulse rate, body weight, or physical findings.

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CONCLUSION(S): The observed plasma gabapentin concentrations after administration ofgabapentin at 300 mg twice daily to one Japanese epileptic subject (CLcr = 7.49 mL/min)receiving hemodialysis three times a week were higher than the plasma concentrations
calculated from the population mean and individual estimates.
No adverse events developed, and no clinically significant changes were observed in thesafety evaluation in the study.

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