The Science of Safety: Toxicological Review of Amotosalen HCl

Abstract

The strategy used to plan toxicity testing of the INTERCEPT Blood System platelets is discussed and the results of the comprehensive non-clinical studies as provided to regulatory agencies are presented. The studies covered the toxicity of the psoralen amotosalen HCl added to platelets, the effect of residual photoproducts after controlled UVA illumination and any induced change in platelet antigens. Independent studies had demonstrated the normality of the physiology, survival and functions of treated platelets. The formal toxicity tests covered the pharmacokinetics of amotosalen and its photoproducts, their actions in safety pharmacology, acute and chronic toxicity, genotoxicity, full reproduction toxicity and p53 carcinogenicity tests. Local irritancy, phototoxicity and sensitisation potential were also examined, as well as platelet neoantigenicity and any risk from the physical components of the system. The ‘safety margin’ between high dose effects in laboratory models and the exposure of patients in the clinic is 45- to >1,000-fold, factors much higher than for many medicines and substances in the diet.

Trends and targets in antiviral phototherapy

“…After the irradiation procedure, most of the amotosalen is photodegraded and a large portion consists of amotosalen dimers. 93b, 341,343 In the INTERCEPT process, these and other photoproducts, as well as remaining amotosalen in the treated blood products, are removed or at least reduced in a subsequent filtering step. 316,341,343 The remaining amotosalen photoproducts were not found to induce neoantigen formation, lowering the probability of adverse immune responses.…”

“…93b, 341,343 In the INTERCEPT process, these and other photoproducts, as well as remaining amotosalen in the treated blood products, are removed or at least reduced in a subsequent filtering step. 316,341,343 The remaining amotosalen photoproducts were not found to induce neoantigen formation, lowering the probability of adverse immune responses. 344 Amotosalen has proven to be active against a large number of both enveloped and non-enveloped viruses, i.e.…”

“…A concise overview is given in recent reviews. 18b,320,340b A description of multi-center clinical trials can be found in the review by Schlenke, 18b while the toxicology testing has been summarized by Dayan 341 and others. 18b,347 One issue in the safety-testing was of course genotoxicity.…”

Meeting the Challenges of Blood Safety in the 21st Century: Pathogen Inactivation

“…Compounds that target DNA and RNA necessarily have the potential not only for acute and chronic toxicity but also for genotoxicity of both the parent compound and its breakdown products. Results of toxicological studies with amotosalen are reviewed by A. D. Dayan [3], who concludes that there is no genotoxic risk to patients.…”