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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Single-Dose Pharmacokinetics of Orally Administered Levetiracetam (LEV) in Japanese Subjects With Normal Renal Function and Various Degrees of Renal Impairment Using a Dosing Regimen Adjusted to Renal Function (250 mg or 500 mg)

Conditions
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Healthy Subjects, Renal Impairments

Intervention / Treatment
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* Drug: Levetiracetam 250 mg
* Drug: Levetiracetam 500 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Normal renal function<br>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 | Drug: Levetiracetam 500 mg<br>* Tablet containing Levetiracetam 500 mg<br>* Other names: E-Keppra;|
| Experimental: Group B: Mild renal impairment<br>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 | Drug: Levetiracetam 500 mg<br>* Tablet containing Levetiracetam 500 mg<br>* Other names: E-Keppra;|
| Experimental: Group C: Moderate renal impairment<br>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 | Drug: Levetiracetam 250 mg<br>* Tablet containing Levetiracetam 250 mg<br>* Other names: E-Keppra;|
| Experimental: Group D: Severe renal impairment<br>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 | Drug: Levetiracetam 250 mg<br>* Tablet containing Levetiracetam 250 mg<br>* Other names: E-Keppra;|
| Experimental: Group E: End-stage renal disease<br>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: Dialysis: 44 h to 48 h after the first dose (Day 3) Dialysis: 92 h to 96 h after the first dose (Day 5) 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. | Drug: Levetiracetam 250 mg<br>* Tablet containing Levetiracetam 250 mg<br>* Other names: E-Keppra;Drug: Levetiracetam 500 mg<br>* Tablet containing Levetiracetam 500 mg<br>* Other names: E-Keppra;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Amount Excreted in Urine (Ae) of Ucb L059 (LEV) for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Fraction of Dose Excreted in Urine (fe) of Ucb L059 (LEV) for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Renal Clearance (CLR) of Ucb L059 (LEV) for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Apparent Total Body Clearance (CL/F) of Ucb L059 (LEV) for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Nonrenal Clearance (CLNR) of Ucb L059 (LEV) for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Total Amount Excreted in Urine (Ae) of Ucb L057 for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Renal Clearance (CLR) of Ucb L057 for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Apparent Total Body Clearance (CL/F) of Ucb L059 (LEV) for Group E During First Period | 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 %. | From Baseline to 44 hours post first dose | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Ucb L059 (LEV) for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Area Under the Concentration-time Curve (AUC) of Ucb L059 (LEV) From Baseline to Infinite for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Terminal Half-life (t1/2) of Ucb L059 (LEV) for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Ucb L057 for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Area Under the Concentration-time Curve (AUC) of Ucb L057 From Baseline to Infinite for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Terminal Half-life (t1/2) of Ucb L057 for Groups A to D | 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 | From Baseline up to 144 hours post first dose | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Ucb L059 (Levetiracetam) for Group E During First Period | tmax refers to the time to reach the maximum plasma concentration of ucb L059 (Levetiracetam). | From Baseline to 44 hours post first dose | 
| Area Under the Concentration-time Curve (AUC) of Ucb L059 (LEV) From Baseline to Infinite for Group E | 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 %. | From Baseline to 140 hours post first dose | 
| Terminal Half-life (t1/2) of Ucb L059 (LEV) for Group E During First Period | 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 %. | From Baseline to 44 hours post first dose | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Ucb L057 for Group E During First Period | tmax refers to the time to reach maximum plasma concentration (tmax). | From Baseline to 44 hours post first dose | 
| Hemodialysis Clearance (CLD) of Ucb L059 (LEV) During First Dialysis for Group E | Calculated by the Arterio - Venous difference method and cumulative dialysate method. | From 44 hours to 48 hours post first dose | 
| Ultrafiltration Clearance (CLUF) of Ucb L059 (LEV) During First Dialysis for Group E | Calculated by the Arterio - Venous difference method and cumulative dialysate method. | From 44 hours to 48 hours post first dose | 
| Hemodialysis Clearance (CLHD) of Ucb L059 (LEV) During First Dialysis for Group E | Calculated according: CLHD=CLD+CLUF. | From 44 hours to 48 hours post first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Levetiracetam, Oral administration, Japanese, Non-epileptic, Healthy, Renal impaired subjects