Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets

Abstract

<jats:p> The pathogen inactivation process developed by Cerus and Baxter Healthcare Corporations uses the psoralen, S-59 (amotosalen) in an ex vivo photochemical treatment (PCT) process to inactivate viruses, bacteria, protozoans, and leukocytes in platelet concentrates and plasma. Studies were performed by intravenous infusion of S-59 PCT formulations-compound adsorption device (CAD) treatment and with non-UVA illuminated S-59, using doses that were multiples of potential clinical exposures. The studies comprised full pharmacokinetic, single and repeated-dose (up to 13 weeks duration) toxicity, safety pharmacology (CNS, renal, and cardiovascular), reproductive toxicity, genotoxicity, carcinogenicity testing in the p53<jats:sup>-</jats:sup> mouse, vein irritation, and phototoxicity. No specific target organ toxicity (clinical or histopathological), reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS, ECG, and phototoxicity only at supraclinical doses. Based on the extremely large safety margins (&gt;30,000 fold expected clinical exposures), the CNS and ECG observations are not considered to have any toxicological relevance. Additionally, after a complete assessment, mutagenicity and phototoxicity results are not considered relevant for the proposed use of INTERCEPT platelets. Thus, the results of an extensive series of in vitro and in vivo studies have not demonstrated any toxicologically relevant effects of platelet concentrates prepared by the INTERCEPT system. </jats:p>

Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial

“…Extensive toxicology, mutagenicity, carcinogenicity, phototoxicity, and pharmacologic studies established an adequate safety profile for PCT platelets. 24,25 In vitro platelet function of PCT platelets was preserved following up to 7 days of storage. 15,16 Recovery and survival of radiolabeled PCT platelets in healthy subjects were reduced compared with conventional untreated platelets but within acceptable therapeutic ranges.…”

Pathogen Inactivation of Human Serum Facilitates its Clinical Use for Islet Cell Culture and Subsequent Transplantation

“…In addition, different experimental studies indicated that in vitro culture reduces islet immuThe Intercept technology using amotosalen and UVA treatment, already in use in many European counnogenicity compared to freshly isolated islets (27,29,32). A period of culture has benefits not only for islet recovtries (50), has been reported to be safe in preclinical studies (9)(10)(11) and to be well tolerated in a wide range ery, as it replenishes islet ATP stores depleted during both cold ischemia period and the isolation procedure, of patients (22, 41,42,45,52,56). It has even been used to prevent transfusion transmission of Chikungunya virus but also increases posttransplant function of human islets transplanted into diabetic nude mice (2,5,23,26).…”

The Science of Safety: Toxicological Review of Amotosalen HCl

“…All the studies have been performed in compliance with Good Laboratory Practice requirements. Ciaravino et al have published a full account of the toxicity testing programme, the results obtained and a critical evaluation of these results [1]. The detailed findings discussed in this paper have been taken from this report.…”