Pharmacokinetics and Absolute Bioavailability of Ribavirin in Healthy Volunteers as Determined by Stable-Isotope Methodology

Abstract

Ribavirin has recently been demonstrated to have efficacy in combination with alpha interferon for treatment of relapsed hepatitis C. The marked improvement in the response rate after treatment with the combination regimen (10-fold higher versus that from monotherapy with alpha interferon) highlights the importance of determining the absolute bioavailability of ribavirin as a first step in beginning to investigate the pharmacodynamics of the combination. The objective of this study was to determine the absolute bioavailability of ribavirin with an intravenous formulation containing ribavirin labeled with the stable isotope 13 C 3 ( 13 C 3ribavirin) and unlabeled oral ribavirin. Six healthy volunteers received 150 mg of intravenous 13 C 3 -ribavirin followed 1 h later by a 400-mg oral dose of ribavirin. Samples of blood and urine were collected up to 169 h postdosing. Concentrations of 13 C 3 -ribavirin and unlabeled ribavirin were determined by a high-performance liquid chromatography tandem mass spectrometric method. All plasma and urine data were comodeled for labeled and unlabeled ribavirin by using both the two-and three-compartment models in the program ADAPT II. A three-compartment model was chosen for the pharmacokinetic analysis with the Akaike Information Criterion. The mean maximum concentrations of drug in plasma for intravenous and oral ribavirin were 4,187 and 638 ng/ml, respectively. The mean bioavailability was 51.8% ؎ 21.8%, and the mean ␥-phase half-life was 37.0 ؎ 14.2 h. The mean renal clearance, metabolic clearance, and volume of distribution of the central compartment were 6.94 liters/h, 18.1 liters/h, and 17.8 liters, respectively. The use of the stable-isotope methodology has provided the best estimate of the absolute bioavailability of ribavirin that is currently available, as there was neither a period bias nor a washout effect to confound the data. The study demonstrated that the mean bioavailability for a 400-mg dose of ribavirin was 52%, which is higher than that previously reported in other investigations.

Successful treatment of parainfluenza virus 3 pneumonia with oral ribavirin and methylprednisolone in a bone marrow transplant recipient

“…The dose and duration of oral ribavirin for the treatment of PIV3 pneumonia after HSCT have not been established. It is reported that the bioavailability of oral ribavirin is approximately 50% [20][21][22][23].…”

The metabolism, pharmacokinetics and mechanisms of antiviral activity of ribavirin against hepatitis C virus

“…The pharmacokinetic profile of ribavirin remained unchanged between patients with healthy livers and those with hepatic dysfunction, suggesting that the liver is not a major site of ribavirin metabolism [84]. Further, about 85% of the orally administered drug was found to be absorbed, although the absolute bioavailability of ribavirin is onlỹ 50% [86], which remains unchanged with hepatic dysfunction [84]. The gastrointestinal tract and not the liver thus appears to be the major site of first pass elimination [87].…”

“…Thus, parameters that describe single-dose pharmacokinetics may not be applicable to the multiple-dose case. Preston et al [86] have employed two and three compartment models to fit experimental ribavirin plasma drug concentration profiles and find that the three compartment model provides a superior fit. However, what these compartments represent physically remains unclear.…”

“…Thus, along with the underlying mechanism(s), the pharmacokinetic properties of ribavirin may hold key links to the identification of improved therapeutic protocols. The pharmacokinetic properties of ribavirin have been studied extensively [27,49,[80][81][82][83][84][85][86][87]. Ribavirin is typically administered orally in doses of 400, 500 or 600 mg twice daily.…”

Bioavailability and Bioequivalence

“…A stable isotope study was planned with ribavirin in order to avoid the risk of insufficient washout between the treatment phases of a crossover design. To estimate absolute bioavailability, the study design involved IV administration of [ 13 C]-ribavirin followed 1 h later by an oral dose of unlabeled drug [18]. The use of stable isotope methodology provided a robust estimate of ribavirin bioavailability (51.8%) without a period bias or a washout effect to confound the data.…”