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

Abstract

ABSTRACTAimsNitazoxanide is a broad-spectrum antiviral with potential application in a number of viral infections. Its use is limited by gastrointestinal side effects associated with increasing dose. In this study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir.MethodThis was a crossover drug-drug interaction study, 18 healthy participants received a single dose of 1000 mg of nitazoxanide alone in period 1 and in combination with 300/100 mg atazanavir/ritonavir in period 2 after a washout period of 21 days. On both days, blood samples for intensive pharmacokinetic analyses were collected before and at 0.25, 0.5, 1, 2, 4, 6, and 12 h after dose. To explore the utility of dried blood spots (DBS) as alternative to plasma for tizoxanide quantification, 50 µL of blood from some participants was spotted on DBS cards. Pharmacokinetic parameters were derived by non-compartmental analysis and compared between periods 1 and 2. The correlation between tizoxanide concentration in plasma and DBS was also evaluated.ResultsCo-administration of nitazoxanide with atazanavir/ritonavir resulted in a significant increase in tizoxanide plasma exposure. The geometric mean ratios (90% CI) of tizoxanide AUC0-12h, Cmaxand C12hwere 1.872 (1.870 – 1.875), 2.029 (1.99 – 2.07) and 3.14 (2.268 – 4.352) respectively, were all outside the 0.8 – 1.25 interval, implying clinically significant interaction. DBS concentration (%CV) was 46.3% (5.6%) lower than plasma concentrations, with a strong correlation (R = 0.89, P < 0.001). Similarly, DBS- derived plasma concentration and plasma concentrations displayed very strong correlation with linearity (R = 0.95, P<0.001).ConclusionCo-administration with atazanavir/ritonavir enhanced tizoxanide exposure with no report of adverse events in healthy volunteers.