Pharmacokinetic and Safety Study of Daclatasvir in Patients With Renal Impairment

AUC(INF) was estimated by summing the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and the extrapolated area, computed by the quotient of the last observable concentration and elimination rate constant. The pharmacokinetic (PK) analysis was based on Cockcroft-Gault (C-G) creatinine clearance (CLcr) grouping method: normal renal function, end stage renal disease (ESRD), moderate and severe renal impairment. Mild participants were counted as per their original allocation.

AUC(INF)u was calculated by multiplying the area under the plasma concentration-time curve from time zero extrapolated to infinite time by mean fraction of unbound drug from 1 hour post-dose time point.

Maximum observed plasma concentration following drug administration from the raw plasma concentration-time data. The plasma samples were analyzed for daclatasvir by using a validated liquid chromatography tandem mass spectrometric (LC-MS/MS) assay.

Unbound Maximum observed plasma concentrations (Cmaxu) was calculated by multiplying maximum observed plasma concentrations by mean fraction of unbound drug from 1 hour post-dose time point.

AUC(0-T) was calculated as the sum of linear trapezoids using non-compartmental analysis.

Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration-time data.

Terminal half-life was the time required for one half of the total amount of administered drug eliminated from the body.

Apparent total body clearance was calculated by dividing the dose by area under the plasma concentration-time curve from time zero extrapolated to infinite time.

The CLU/F was calculated by dividing the apparent total body clearance by mean fraction of unbound drug from 1 hour post dose time point.

The percentage of daclatasvir recovered in the urine was determined by using validated liquid chromatography-tandem mass spectrometry methods. The sum of the percentage of dose recovered in urine from all intervals was calculated to obtain the total percentage of urinary excretion.

The CLR was calculated by dividing the total amount excreted in the urine from 0 to 96 hours by the area under the plasma concentration-time curve from time zero extrapolated to infinite time.

The Vd/F was calculated by dividing the product of the dose and mean residence time by area under the plasma concentration-time curve from time zero extrapolated to infinite time.

Adverse event (AE) was defined as any new unfavorable symptom, sign, or disease or worsening of a pre-existing condition that does not necessarily have a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalisation.

Significant laboratory abnormalities were defined as any test results which were observed beyond the clinically acceptable limits as per the discretion of investigator.

The number of participants with clinically relevant changes in ECG which were considered as adverse events was determined.

The total number of participants with abnormal range vital signs which were considered as adverse events was determined.