Pharmacokinetics and tolerability of paritaprevir, a direct acting antiviral agent for hepatitis C virus treatment, with and without ritonavir in healthy volunteers.

AIMS: Paritaprevir is a direct acting antiviral agent for use as part of a multidrug hepatitis C virus infection treatment regimen. To characterize the pharmacokinetics, safety, and tolerability of paritaprevir and determine an optimal dosing regimen for subsequent evaluations, clinical studies were conducted with paritaprevir alone or with ritonavir, a cytochrome P450 3A4 inhibitor anticipated to increase paritaprevir exposure. METHODS: Two phase 1, double-blind, placebo-controlled, parallel group studies were conducted in healthy volunteers (NCT00850044 and NCT00931281). Single dose study participants (n = 87) were randomized to one time administration of either paritaprevir or placebo, or paritaprevir with ritonavir or placebo. Participants (n = 38) enrolled in the multiple dose study received paritaprevir with ritonavir or placebo once or twice daily for 14 days. Pharmacokinetics, safety and tolerability were assessed throughout the study treatment periods. RESULTS: After single or multiple dose administration, paritaprevir displayed non-linear pharmacokinetics, with maximum plasma concentration and area under the plasma concentration-time curve increasing in a greater than dose proportional manner. Concomitant administration of 100 mg ritonavir increased paritaprevir exposure from a 300 mg dose approximately 30- to 50-fold and extended paritaprevir half-life. The tolerability of paritaprevir was similar with or without ritonavir. Asymptomatic, transient increases in bilirubin were observed but were not associated with abnormalities in other liver function tests. CONCLUSIONS: Paritaprevir exhibits non-linear pharmacokinetics with greater than dose proportional increases in exposure after single or multiple dosing. Co-administration with ritonavir increases paritaprevir exposure and half-life without adversely influencing tolerability.

Journal pricing issues: an economic perspective.

Scientific journal prices have increased markedly in the past two decades, outpacing inflation by severalfold. Such increases challenge the librarian's ability to manage acquisitions resources effectively and threaten the mission of the health sciences library as a resource for present and future scientific information needs. Explanations for serial price increases vary with the point of view considered. Publishers, librarians, faculty, and consumers of scientific information perceive the situation differently. This paper provides an economic analysis of each group's views. Particular emphasis is given to the aspects of journal publishing and pricing that foster price increases. In addition, the paper examines the problems of dual-pricing structures and narrowly focused journals that cater to subspecialties of medicine. Suggested responses to subscription rate increases are offered to curtail further increases and to avoid the potential detrimental effects of reduced library collections. Since one of the underpinnings of education is threatened by reductions in library collections, actions must be taken by publishers, librarians, faculty, and professional associations to ameliorate the present situation and to limit additional increases in serial prices.