Pharmacokinetic (PK) Study in Japanese Non-epileptic Renal Impaired Patients

Phase 4

Completed

Conditions: Healthy Subjects
Renal Impairments

Interventions: Drug: Levetiracetam 500 mg
Drug: Levetiracetam 250 mg

Registration Number: NCT01491113

Lead Sponsor: UCB Pharma

Brief Summary: This is a human pharmacology, single-dose study to investigate the pharmacokinetics of orally administered Levetiracetam (LEV) in Japanese subjects with normal renal function and in Japanese subjects with various degrees of impaired renal function.

Detailed Description: The primary objective of this study is to evaluate the plasma and urine PK of Levetiracetam (ucb L059) and its metabolite (ucb L057) after a single dose of LEV 250 mg or LEV 500 mg in Japanese subjects with normal renal function and in Japanese subjects with various degrees of renal impairment.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Healthy subjects with normal renal function
Subject is Japanese
Subjects with creatinine clearance within 1 of 3 Groups (CLcr[mL/min/1.73 cm^2]: Group B: 50 - <80, Group C: 30 - <50, Group D: <30), or for Group E, subjects with end-stage renal failure undergoing hemodialysis

Exclusion Criteria

Subjects has taken any drug treatment, disease or injury to influence Levetiracetam PK except for renal impairments

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: Normal renal function	Levetiracetam 500 mg	Subjects who have normal renal function (CLcr \>80 mL/min/1.73 m\^2). Subjects will be orally administered Levetiracetam (LEV) 500 mg once. After LEV administration, safety assessments and blood and urine samplings will be taken through to Day 4 during the Treatment Period, and safety follow-up assessments will be performed on Day 8 according to the schedule of study assessments. * Blood samples for Pharmacokinetics (PK): Predose (Baseline), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 hours postdose * Urine samples for PK: 0 - 6, 6 - 12, 12 - 24, 24 - 48, 48 - 72 hours postdose
Group B: Mild renal impairment	Levetiracetam 500 mg	Patients who have mild renal impairment (50\<CLcr \<80 mL/min/1.73 m\^2). Subjects will be orally administered (Levetiracetam) LEV 500 mg once. After LEV administration, safety assessments and blood and urine samplings will be conducted through Day 5 during the Treatment Period, and safety follow-up assessments will be performed on Day 8 according to the schedule of study assessments. * Blood samples for Pharmacokinetics (PK): Predose (Baseline), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96 hours postdose * Urine samples for PK: 0 - 6, 6 - 12, 12 - 24, 24 - 48, 48 - 72, 72 - 96 hours postdose
Group C: Moderate renal impairment	Levetiracetam 250 mg	Patients who have moderate renal impairment (30\<CLcr \< 50 mL/min/1.73 m\^2). Subjects will be orally administered Levetiracetam (LEV) 250 mg once. After LEV administration, safety assessments and blood and urine samplings will be conducted through Day 6 during the Treatment Period, and safety follow-up assessments will be performed on Day 8 according to the schedule of study assessments. * Blood samples for Pharmacokinetics (PK): Predose (Baseline), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours postdose * Urine samples for PK: 0 - 6, 6 - 12, 12 - 24, 24 - 48, 48 - 72, 72 - 96, 96 -120 hours postdose
Group D: Severe renal impairment	Levetiracetam 250 mg	Patients who have severe renal impairment (CLcr \<30 mL/min/1.73 m\^2). Subjects will be orally administered Levetiracetam (LEV) 250 mg once. After LEV administration, safety assessments and blood and urine samplings will be conducted through Day 7 during the Treatment Period, and safety follow-up assessments will be performed on Day 8 according to the schedule of study assessments. * Blood samples for Pharmacokinetics (PK): Predose (Baseline), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 hours postdose * Urine samples for PK: 0 - 6, 6 - 12, 12 - 24, 24 - 48, 48 - 72, 72 - 96, 96 -120, 120 - 144 hours postdose
Group E: End-stage renal disease	Levetiracetam 250 mg	Group E will receive Levetiracetam (LEV) 500 mg on Day 1, 44 hours (h) before the first hemodialysis. As a supplementary dose LEV 250 mg will be administered 1 h after the end of the first hemodialysis on Day 3. The 4-h Hemodialysis are scheduled as follows: 1. Dialysis: 44 h to 48 h after the first dose (Day 3) 2. Dialysis: 92 h to 96 h after the first dose (Day 5) 3. Dialysis: 140 h after the first dose (Day 7) Safety assessments and blood samplings will be conducted until Day 7. Safety follow-up assessments will be performed on Day 10. Blood samples for Pharmacokinetics (PK): Predose (Baseline), and 0.5, 1, 2, 4, 6, 8, 12, 24, 30, 44\, 44.25\, 44.5\, 45\, 46\, 47\, 48\, 49, 49.5, 50, 51, 53, 55, 57, 61, 73, 92, 96, 120, 140 hours post first dosing. 49 h-sample should be taken before the additional dose. The 44 h, 92 h, and 140 h sample should be taken before the start of the hemodialysis. \Inflow blood, outflow blood, and dialysate fluid will be collected.
Group E: End-stage renal disease	Levetiracetam 500 mg	Group E will receive Levetiracetam (LEV) 500 mg on Day 1, 44 hours (h) before the first hemodialysis. As a supplementary dose LEV 250 mg will be administered 1 h after the end of the first hemodialysis on Day 3. The 4-h Hemodialysis are scheduled as follows: 1. Dialysis: 44 h to 48 h after the first dose (Day 3) 2. Dialysis: 92 h to 96 h after the first dose (Day 5) 3. Dialysis: 140 h after the first dose (Day 7) Safety assessments and blood samplings will be conducted until Day 7. Safety follow-up assessments will be performed on Day 10. Blood samples for Pharmacokinetics (PK): Predose (Baseline), and 0.5, 1, 2, 4, 6, 8, 12, 24, 30, 44\, 44.25\, 44.5\, 45\, 46\, 47\, 48\, 49, 49.5, 50, 51, 53, 55, 57, 61, 73, 92, 96, 120, 140 hours post first dosing. 49 h-sample should be taken before the additional dose. The 44 h, 92 h, and 140 h sample should be taken before the start of the hemodialysis. \Inflow blood, outflow blood, and dialysate fluid will be collected.

Primary Outcome Measures

Name	Time	Method
Maximum Observed Plasma Concentration (Cmax) of Ucb L059 (LEV) for Groups A to D	From Baseline up to 144 hours post first dose	Cmax refers to the maximum observed concentration of L059 (Levetiracetam). Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Area Under the Concentration-time Curve (AUC(0-t)) of Ucb L059 (LEV) From Baseline to the Last Quantifiable Concentration for Groups A to D	From Baseline up to 144 hours post first dose	AUC(0-t) refers to the area under the plasma concentration versus time curve, which provides information on the exposure. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Maximum Observed Plasma Concentration (Cmax) of Ucb L057 for Groups A to D	From Baseline up to 144 hours post first dose	Cmax refers to the maximum observed concentration of ucb L057. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Area Under the Concentration-time Curve (AUC(0-t)) of Ucb L057 From Baseline to the Last Quantifiable Concentration for Groups A to D	From Baseline up to 144 hours post first dose	AUC(0-t) refers to the area under the plasma concentration versus time curve, which provides information on the exposure. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Maximum Observed Plasma Concentration (Cmax) of Ucb L059 (LEV) for Group E During First Period	From Baseline to 44 hours post first dose	Cmax refers to the maximum observed concentration of ucb L059 (Levetiracetam).
Area Under the Concentration-time Curve (AUC(0-t)) of Ucb L059 (LEV) From Baseline to 44 Hours for Group E	From Baseline to 44 hours post first dose	AUC(0-t) refers to the area under the plasma concentration versus time curve, which provides information on the exposure.
Maximum Observed Plasma Concentration (Cmax) of Ucb L057 for Group E During First Period	From Baseline to 44 hours post first dose	Cmax refers to the maximum observed concentration of ucb L057.
Area Under the Concentration-time Curve (AUC(0-t)) of Ucb L057 From Baseline to 44 Hours for Group E	From Baseline to 44 hours post first dose	AUC(0-t) refers to the area under the plasma concentration versus time curve, which provides information on the exposure.

Secondary Outcome Measures

Name	Time	Method
Total Amount Excreted in Urine (Ae) of Ucb L057 for Groups A to D	From Baseline up to 144 hours post first dose	Ae refers to the total amount of ucb L057 excreted in urine. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Total Amount Excreted in Urine (Ae) of Ucb L059 (LEV) for Groups A to D	From Baseline up to 144 hours post first dose	Ae refers to the total amount of ucb L059 (Levetiracetam) excreted in urine. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Time to Reach Maximum Plasma Concentration (Tmax) of Ucb L057 for Groups A to D	From Baseline up to 144 hours post first dose	tmax refers to the time to reach maximum plasma concentration (tmax). Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Fraction of Dose Excreted in Urine (fe) of Ucb L059 (LEV) for Groups A to D	From Baseline up to 144 hours post first dose	fe refers to the fraction of dose excreted in urine of L059 (Levetiracetam). Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Time to Reach Maximum Plasma Concentration (Tmax) of Ucb L059 (LEV) for Groups A to D	From Baseline up to 144 hours post first dose	tmax refers to the time to reach maximum plasma concentration of ucb L059 (Levetiracetam). Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Area Under the Concentration-time Curve (AUC) of Ucb L059 (LEV) From Baseline to Infinite for Groups A to D	From Baseline up to 144 hours post first dose	AUC(0-t) refers to the area under the plasma concentration versus time curve, which provides information on the exposure. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Terminal Half-life (t1/2) of Ucb L059 (LEV) for Groups A to D	From Baseline up to 144 hours post first dose	Terminal half-life refers to the time it takes for the concentrations to decrease by half. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Area Under the Concentration-time Curve (AUC) of Ucb L057 From Baseline to Infinite for Groups A to D	From Baseline up to 144 hours post first dose	AUC(0-t) refers to the area under the plasma concentration versus time curve, which provides information on the exposure. Geometric mean and CV was not calculated since the extrapolated part of the AUC was greater than 20 %. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Terminal Half-life (t1/2) of Ucb L057 for Groups A to D	From Baseline up to 144 hours post first dose	Terminal half-life refers to the time it takes for the concentrations to decrease by half. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Time to Reach Maximum Plasma Concentration (Tmax) of Ucb L059 (Levetiracetam) for Group E During First Period	From Baseline to 44 hours post first dose	tmax refers to the time to reach the maximum plasma concentration of ucb L059 (Levetiracetam).
Area Under the Concentration-time Curve (AUC) of Ucb L059 (LEV) From Baseline to Infinite for Group E	From Baseline to 140 hours post first dose	AUC(0-t) refers to the area under the plasma concentration versus time curve, which provides information on the exposure. Geometric mean and CV was not calculated since the extrapolated part of the AUC was greater than 20 %.
Renal Clearance (CLR) of Ucb L059 (LEV) for Groups A to D	From Baseline up to 144 hours post first dose	Renal clearance describes the removal of drug from a volume of plasma in a given unit of time by the kidneys. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Nonrenal Clearance (CLNR) of Ucb L059 (LEV) for Groups A to D	From Baseline up to 144 hours post first dose	The Non-Renal Clearance (CLNR) describes the removal of drug by organs other than the kidneys. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Apparent Total Body Clearance (CL/F) of Ucb L059 (LEV) for Groups A to D	From Baseline up to 144 hours post first dose	Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). It indicates the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time period. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Renal Clearance (CLR) of Ucb L057 for Groups A to D	From Baseline up to 144 hours post first dose	Renal clearance describes the removal of drug from a volume of plasma in a given unit of time by the kidneys. Group A: Baseline to 72 hours; Group B: Baseline to 96 hours; Group C: Baseline to 120 hours; Group D: Baseline to 144 hours
Apparent Total Body Clearance (CL/F) of Ucb L059 (LEV) for Group E During First Period	From Baseline to 44 hours post first dose	Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). It indicates the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time period. Geometric mean and Coefficient of Variation (CV) was not calculated since the extrapolated part of the AUC was greater than 20 %.
Terminal Half-life (t1/2) of Ucb L059 (LEV) for Group E During First Period	From Baseline to 44 hours post first dose	Terminal half-life refers to the time it takes for the concentrations to decrease by half. Geometric mean and CV was not calculated since the extrapolated part of the AUC was greater than 20 %.
Time to Reach Maximum Plasma Concentration (Tmax) of Ucb L057 for Group E During First Period	From Baseline to 44 hours post first dose	tmax refers to the time to reach maximum plasma concentration (tmax).
Hemodialysis Clearance (CLD) of Ucb L059 (LEV) During First Dialysis for Group E	From 44 hours to 48 hours post first dose	Calculated by the Arterio - Venous difference method and cumulative dialysate method.
Ultrafiltration Clearance (CLUF) of Ucb L059 (LEV) During First Dialysis for Group E	From 44 hours to 48 hours post first dose	Calculated by the Arterio - Venous difference method and cumulative dialysate method.
Hemodialysis Clearance (CLHD) of Ucb L059 (LEV) During First Dialysis for Group E	From 44 hours to 48 hours post first dose	Calculated according: CLHD=CLD+CLUF.