title: Exploring the influence of renal dysfunction on the pharmacokinetics of ribavirin after oral and intravenous dosing.
abstract: 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 (CLr), non-renal clearance (CLnr), volume of distribution at steady state (Vdss), and amount excreted values were reduced in patients with renal dysfunction compared with those who had normal renal function. Following IV administration, mean CLr 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 CLnr 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 CLr and CLnr, reduced Vd) contributing to altered ribavirin pharmacokinetics in chronic renal impairment.
authors.affiliation: Departments of Drug Metabolism/Pharmacokinetics and Clinical Pharmacology, Merck Research Lab.
authors.forename: Samir
authors.initials: S
authors.lastname: K Gupta
authors.forename: Bhavna
authors.initials: B
authors.lastname: Kantesaria
authors.forename: Paul
authors.initials: P
authors.lastname: Glue
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001682:Biological Availability; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D012254:Ribavirin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D012720:Severity of Illness Index
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin