Viral safety of human plasma-derived medicinal products: impact of regulation requirements.

The viral safety of plasma-derived medicinal products is of paramount importance. This article aims to provide insight into the relative impact of different safety measures on achieving viral safety of finished products, derived from human plasma. Virus removal and/or inactivation during the production process is the most important safety measure, and model-based risk estimates show that with current safety measures, the risk of transmission of known blood-borne pathogens to plasma product recipients is extremely low. However, because the residual risk of virus transmissions is also influenced by the incidence rate of infection in the donor population, it makes sense to control these incidence rates, as well. The current measures are aiming in the right direction, but integration of guidelines is required to adequately address their common goal: controlling the risk of infectious disease transmission by plasma-derived medicinal products. By integration of guidelines, the combination of various types of safety measures to prevent virus transmission-donor selection, donation screening, quarantining, and virus removal and/or inactivation during production-may be consistently interpreted and adequately assessed.

A probabilistic model for analyzing viral risks of plasma-derived medicinal products.

BACKGROUND: The prevention of transmission of viral infections by plasma-derived medicinal products is of concern to manufacturers, legislators, and patient representative groups. Recent European legislation requires a viral risk assessment for all new marketing applications of such products. STUDY DESIGN AND METHODS: A discrete event Monte Carlo model was developed to determine the viral transmission risks of the plasma-derived medicinal products. The model incorporates donor epidemiology, donation intervals, efficiency of screening tests for viral markers, inventory hold period, size and composition of the manufacturing pool, production time, process virus reduction capacity, and product yield. With the model, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) contamination risks of a typical hypothetical plasma product were calculated, and the sensitivity of the risk to various model variables was analyzed. RESULTS: The residual HIV and HCV risks of the finished products are linear in change with viral incidence rate and inversely linear with product yield and process virus reduction capacity. For the product analyzed in this article, the residual risk is less sensitive to changes in screening test pool size, donation frequency, and inventory hold period. There is only a limited dependency on the donation type (apheresis or whole-blood donations) and a negligible dependency on the manufacturing pool size. CONCLUSIONS: The use of probabilistic model simulation techniques is indispensable when estimating realistic residual viral risks of plasma-derived medicinal products. In contrast to conventional deterministic residual risk estimations, the probabilistic approach allows incorporation of specific manufacturing decisions and therefore provides the only feasible alternative for a correct assessment of residual risks.

A phase I/IIa study with succinylated human serum albumin (Suc-HSA), a candidate HIV-1 fusion inhibitor.

BACKGROUND: Succinylated human serum albumin (Suc-HAS) is a negatively charged neo-glycoprotein that binds to the positively charged V3-loop of HIV-1 gp120, acting as HIV-1-fusion inhibitor in vitro (IC50: 0.5-5.0 microg/ml). Suc-HSA was safe in rats and monkeys, and showed antiretroviral effect in a human-to-mouse model. We evaluated safety and pharmacokinetics of single and multiple doses of Suc-HSA in HIV-1-infected individuals. METHODS: First, six untreated, chronically HIV-1-infected patients were randomized to a single dose of 1 or 10 mg/kg Suc-HSA intravenously. Second, five consecutive daily doses (10 mg/kg, based on the results of the single dose study) were given to four patients. Safety laboratory assessments, Suc-HSA plasma levels, plasma HIV-1 RNA (pVL), and CD4+ T-cell counts were determined. RESULTS: Increase of liver transaminases (grade 1/2) occurred in one of six patients in the single-dose phase and in three of four patients in the multiple-dosing phase. Suc-HSA plasma levels were undetectable 4 h after a single dose of 1 mg/kg. After a dose of 10 mg/kg, plasma levels were more sustained, but declined under the target plasma concentration (10 microg/ml) 12-24 h post-dosing. After multiple dosing, plasma levels reached peak values 2h post-dosing as predicted by our kinetic model. However, trough levels were below the target concentrations. There was no change in pVL or CD4+ T-cell count in either the single- or multiple-dosing phase. CONCLUSIONS: At the chosen dosing regimens, adequate antiviral plasma levels were not maintained, probably because the hepatic clearance was more rapid than expected. This may partially explain the lack of effect on pVL and CD4+ T-cell count. The observed liver transaminase increases prohibit further dose escalation.