Atazanavir/ritonavir increased tizoxanide exposure from oral nitazoxanide through pharmacokinetic interaction in healthy volunteers

Abstract

Nitazoxanide use is limited by gastrointestinal side effects associated with increasing dose. In this drug repurposing study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir. In this crossover drug-drug interaction study, 18 healthy participants received a single dose of 1000mg of nitazoxanide alone and in combination with 300/100mg atazanavir/ritonavir in period 1 and 2 re-spectively. On both days, blood samples for intensive pharmacokinetic analyses were collected at 0–12 hours post-dose. To explore the utility of dried blood spots (DBS) as alternative to plasma for tizoxanide quantification, 50µL of blood from some participants was spotted on DBS cards and correlated with plasma concentrations. Pharmacokinetic parameters were derived by non-compartmental analysis and compared between both periods. Co-administration of nita-zoxanide with atazanavir/ritonavir resulted in a significant increase in tizoxanide plasma exposure [GMR (90% CI) of AUC0-12h, Cmax and C12h being 1.872 (1.870–1.875), 2.029 (1.99–2.07) and 3.14 (2.268–4.352) respectively]. DBS concentration (%CV) was 46.3% (5.6%) lower than plasma con-centrations, and strong correlation (R = 0.95, P<0.001) between DBS-derived plasma concentration and plasma concentrations. Co-administration with atazanavir/ritonavir enhanced tizoxanide ex-posure with no report of adverse events in healthy volunteers.