A Single Dose Study of Tamiflu in Volunteers in Dialysis And in Volunteers With Reduced Creatinine Clearance

Study Overview
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Brief Summary
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This open-label, prospective, single dose study will evaluate the pharmacokinetics and safety of Tamiflu (oseltamivir) in volunteers on dialysis and in volunteers with a creatinine clearance from 10 to 30 mL/min. Volunteers will receive a single oral dose of Tamiflu.

Official Title
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An Open Label, Prospective, Single Oral Dose Study Evaluating the Pharmacokinetics, Safety, and Tolerability of Oseltamivir in Adult Subjects on Peritoneal Dialysis (PD) Using a Rapid Cycle Regimen to Simulate APD and in Adult Subjects With Creatinine Clearance From 10 to 30 mL/Min Not on Dialysis

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Drug: Tamiflu (oseltamivir)
* Drug: Tamiflu (oseltamivir)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General Adult volunteers, aged 19 to 90 years Medically stable with no hospitalization for a significant disease in the 3 months before study start Volunteers on dialysis A documented and well-established dialysis therapy Volunteers with reduced creatinine clearance Creatinine clearance from 10 to 30 mL/min Stable renal function Exclusion Criteria: Clinically significant and unstable disease (e.g., cardiac, hepatic, pulmonary) Medical history of concurrent medical condition that would compromise participation in the study Hypotensive episodes or symptoms of fainting, dizziness or lightheadedness in the 4 weeks before screening Uncontrolled hypotension or hypertension Infection with hepatitis B, hepatitis C or human immunodeficiency virus

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 90 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Volunteers on dialysis<br> | Drug: Tamiflu (oseltamivir)<br>* Single dose of Tamiflu in volunteers on dialysis<br>|
| Experimental: Volunteers with reduced creatinine clearance<br> | Drug: Tamiflu (oseltamivir)<br>* Single dose of Tamiflu in volunteers with creatinine clearance from 10 to 30 mL/min<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Dialysate Clearance for Automated Peritoneal Dialysis (CLDAPD) of Oseltamivir and Oseltamivir Carboxylate for 75 mg Dose | CLDAPD is the total dialysate clearance for automated peritoneal dialysis, attributable to both continuous cycler-assisted peritoneal dialysis (CCPD) and continuous ambulatory peritoneal dialysis (CAPD), which was calculated with the recovery method over the dense blood sampling collection interval from 0 to 48 hours post-dose. CLDAPD = the amount excreted into dialysate from 0 to 48 hours (Aed[0-48])/ plasma area under the concentration-time curve from time zero through 48 hours (AUC[0-48]) CLDCCPD = mean of CLDCCPD from the 2 CCPD sessions, calculated as CLDCCPD = (Aed[0-8]/AUC[0-8] + Aed[24-32]/AUC[24-32]) / 2 CLDCAPD = mean of CLDCAPD from the 3 CAPD sessions, calculated as CLDCAPD = (Aed[8-16]/AUC[8-16] + Aed[16-24]/AUC[16-24] + Aed[32-48]/AUC[32-48]) / 3 | CCPD: pre-dose (0)-2.67, 2.67-5.33, 5.33-8; CAPD: 8-16, 16-24; CCPD: 24-26.67, 26.67-29.33, 29.33-32; CAPD: 32-40, 40-48 hrs post-dose for urine; CCPD and CAPD:0.5, 1.33, 2, 2.5, 3, 4, 5, 6.67, 8, 10, 12, 14, 16, 20, 24, 28, 32, 48 hrs post-dose for blood | 
| AUC120, AUC168 and AUCinf of Oseltamivir and Oseltamivir Carboxylate for 75 mg Dose | AUC120 is defined as the area under the plasma concentration-time curve from time zero through 120 hours post-dose, AUC168 is defined as the area under the plasma concentration-time curve from time zero through 168 hours post-dose, and AUCinf is defined as the area under the plasma concentration-time curve from time zero extrapolated to infinity. Oseltamivir carboxylate is a clinically active metabolite of oseltamivir. | Pre-dose; 0.5, 1.33, 2, 2.5, 3, 4, 5, 6.67, 8, 10, 12, 14, 16, 20, 24, 28, 32, 48, 72, 96, 120, 144, and 168 hrs post-dose | 
| AUCinf of Oseltamivir and Oseltamivir Carboxylate for 30 mg Dose | AUCinf is defined as the area under the plasma concentration-time curve from time zero extrapolated to infinity. Oseltamivir carboxylate is a clinically active metabolite of oseltamivir. | Pre-dose; 0.5, 1.33, 2, 2.5, 3, 4, 5, 6.67, 8, 10, 12, 14, 16, 20, 24, 28, 32, 48, 72, 96, 120, 144, and 168 hrs post-dose | 
| Cmax of Oseltamivir and Oseltamivir Carboxylate | The Plasma Concentration (Cmax) is defined as maximum observed analyte concentration. Oseltamivir carboxylate is a clinically active metabolite of oseltamivir. | Pre-dose; 0.5, 1.33, 2, 2.5, 3, 4, 5, 6.67, 8, 10, 12, 14, 16, 20, 24, 28, 32, 48, 72, 96, 120, 144, and 168 hrs post-dose | 
| C120h, C168h and Clast of Oseltamivir and Oseltamivir Carboxylate for 75 mg Dose | C120h is defined as the plasma concentration at 120 hours post-dose. C168h is defined as the plasma concentration at 168 hours post-dose. Clast is defined as the plasma concentration corresponding to the time of the last measureable (positive) plasma concentration. Oseltamivir carboxylate is a clinically active metabolite of oseltamivir. | Pre-dose; 0.5, 1.33, 2, 2.5, 3, 4, 5, 6.67, 8, 10, 12, 14, 16, 20, 24, 28, 32, 48, 72, 96, 120, 144, and 168 hrs post-dose | 
| Tmax and T1/2 of Oseltamivir and Oseltamivir Carboxylate | The Time of observed maximum plasma concentration (Tmax) is defined as actual sampling time to reach maximum observed analyte concentration. The Elimination Half-Life Period (T1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. Oseltamivir carboxylate is a clinically active metabolite of oseltamivir. | Pre-dose; 0.5, 1.33, 2, 2.5, 3, 4, 5, 6.67, 8, 10, 12, 14, 16, 20, 24, 28, 32, 48, 72, 96, 120, 144, and 168 hrs post-dose | 
| Renal Clearance (CLR) of Oseltamivir and Oseltamivir Carboxylate | CLR is calculated as the cumulative amount of drug excreted into urine from 0 to time t hours (Ae0-tlast) / area under the concentration-time curve from time zero through the last quantifiable concentration time (AUC0-t). | Pre-dose; 0.5, 1.33, 2, 2.5, 3, 4, 5, 6.67, 8, 10, 12, 14, 16, 20, 24, 28, 32, 48, 72, 96, 120, 144, and 168 hrs post-dose for blood; pre-dose and 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hrs post-dose for urine. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AEs) and Any Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the intervention. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. | Approximately 7 weeks | 
| Number of Participants With Marked Abnormality in Laboratory Measurements | Laboratory analysis included: hematology (hemoglobin, hematocrit, reticulocyte, red blood cell, platelet and white blood cell count, mean corpuscular volume, mean corpuscular hemoglobin), prothrombin and activated partial thromboplastin time, biochemistry (sodium, potassium, bicarbonate, phosphate, chloride, calcium, urea, serum creatinine, bilirubin, cholesterol, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase [ALT], gamma-glutamyl transferase, protein, albumin, amylase, creatinine, lipase), random glucose, and urinalysis. Laboratory test result values falling outside of the marked abnormality range that also represent a defined change from baseline were considered as marked laboratory abnormalities. A marked reference range for sodium is 130-150 millimole (mmol)/L, chloride is 95-115 mmol/L, phosphate is 0.75-1.60 mmol/L, calcium is 2-2.90 mmol/L, glucose is 2.8-11.10 mmol/L, bicarbonate is 18-28 mmol/L, and ALT is 0-110 Unit/L. | Approximately 7 weeks | 
| Number of Participants With Change From Baseline in Marked Abnormality in Electrocardiogram (ECG) Parameters at Follow-up Visit | ECG parameter included QT interval, QTcB interval and QTcF interval (all intervals are measured in millisecond [msec]). Marked abnormality in ECG is predefined for QT, QTcB, and QTcF interval as <=30, >30-60, and >60 msec increase from baseline. | From Baseline (Day -1) to Follow-up visit (Days 15 to 22) | 
| Number of Participants With Abnormal Shifts in Vital Signs | Vital signs included pulse rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), and body temperature. Vital sign with abnormal shifts from normal at baseline to high or low at post-baseline time points were recorded. Blood pressure was recorded in millimeter of mercury (mmHg), and temperature in degrees Celsius. Low blood pressure defined as <=70 mmHg (SBP) and <=40 mmHg (DBP); high blood pressure defined as >=140 mmHg (SBP) and >=90 mmHg (DBP); low temperature defined as <=36.5 degrees Celsius and high temperature defined as >=37.5 degrees Celsius. | Days 1 (post-dose), 2, 3, 4, 5, 6, 7, 8; and Follow-up visit (Days 15 to 22) |