Etravirine (ETV) is a 2nd-generation Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) used against HIV-1. Although ETV addition to the set of treatment choices aimed to overcome the most common adverse effects of 1st generation NNRTIs, post-marketing reports of severe ETV-induced skin rash and hypersensitivity reactions have compelled the U.S. FDA to issue a safety alert. Since patients who start ETV-based therapies are typically debilitated by a history of virus resistance and previous drug-induced side effects, administration of a potentially (geno)toxic drug must be considered carefully. The development of reliable prognostic tools for early risk/benefit estimations is therefore urgent. Currently, little is known about the mechanisms underlying ETV-induced toxic outcomes; nonetheless, drug bioactivation is anticipated as a major cause of these events. To search for potential bioactivation pathways we performed ETV incubations with rat and human S9 fractions in the presence of bionucleophiles, and analyzed urines of HIV patients on ETV therapy. Using liquid chromatography coupled to quadrupole-time-of-flight (Q-ToF) mass spectrometry we obtained evidence of multiple bioactivation pathways leading to the formation of covalent adducts with glutathione and N-acetyl-cysteine. These results suggest that similar reactions can occur with cysteine residues of proteins, supporting a role for bioactivation at the onset of the toxic effects elicited by ETV.

Evidence of bioactivation of the anti-HIV drug etravirine to reactive metabolites in vitro and in vivo

254th National Meeting (2017)

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