Drug Discov Ther. 2014;8(2):89-95. (DOI: 10.5582/ddt.8.89)

Exploring the influence of renal dysfunction on the pharmacokinetics of ribavirin after oral and intravenous dosing.

Gupta SK, Kantesaria B, Glue P

Although ribavirin is minimally cleared by renal elimination, its pharmacokinetics are substantially altered in patients with chronic renal impairment. This open-label study assessed the pharmacokinetics of single 400-mg oral and intravenous (IV) doses of ribavirin in two healthy volunteers and 12 patients with varying degrees of chronic renal impairment. Blood and urine samples were collected pre-dose and up to 168 h post-dose for pharmacokinetic analyses. Ribavirin area under the plasma concentration-time curve from time zero to time of final quantifiable sample and maximum plasma concentration values were increased, and total plasma clearance (CL), renal clearance (CL_r), non-renal clearance (CL_nr), volume of distribution at steady state (Vd_ss), and amount excreted values were reduced in patients with renal dysfunction compared with those who had normal renal function. Following IV administration, mean CL_r was 54%, 23%, and 10% in patients with mild, moderate, and severe renal dysfunction, respectively, relative to control subjects, and was 56%, 28%, and 9% of control values after oral dosing. After IV dosing, mean CL_nr was 94%, 76%, and 75% of control values in patients with mild, moderate, and severe renal dysfunction, respectively, and was 54%, 48%, and 27% of control values after oral dosing. Mean oral bioavailability of ribavirin was 35%, 60%, 57%, and 71% in control subjects and patients with mild, moderate, and severe renal dysfunction, respectively. These data indicate that there are multiple mechanisms (increased oral bioavailability, reduced CL_r and CL_nr, reduced Vd) contributing to altered ribavirin pharmacokinetics in chronic renal impairment.

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