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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 1000 mg of nitazoxanide alone and in combination with 300/100 mg atazanavir/ritonavir in period 1 and 2 respectively. On both days, blood samples for intensive pharmacokinetic analyses were collected at 0–12 h post-dose. To explore the utility of dried blood spots (DBS) as an alternative to plasma for tizoxanide quantification, 50 µL 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 nitazoxanide 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 concentrations, and there was strong correlation (R = 0.95, p < 0.001) between DBS-derived plasma concentration and plasma concentrations. Co-administration with atazanavir/ritonavir enhanced tizoxanide exposure with no report of adverse events in healthy volunteers. [ABSTRACT FROM AUTHOR]

Promising clinical efficacy results have generated considerable enthusiasm for the potential impact of adjuvant-containing subunit tuberculosis vaccines. The development of a thermostable tuberculosis vaccine formulation could have significant benefits on both the cost and feasibility of global vaccine distribution. The tuberculosis vaccine candidate ID93 + GLA-SE has reached Phase 2 clinical testing, demonstrating safety and immunogenicity as a two-vial point-of-care mixture. Earlier publications have detailed efforts to develop a lead candidate single-vial lyophilized thermostable ID93 + GLA-SE vaccine formulation. The present report describes the lyophilization process development and scale-up of the lead candidate thermostable ID93 + GLA-SE composition. The manufacture of three full-scale engineering batches was followed by one batch made and released under current Good Manufacturing Practices (cGMP). Up to 4.5 years of stability data were collected. The cGMP lyophilized ID93 + GLA-SE passed all manufacturing release test criteria and maintained stability for at least 3 months when stored at 37°C and up to 24 months when stored at 5°C. This work represents the first advancement of a thermostable adjuvant-containing subunit tuberculosis vaccine to clinical testing readiness., Competing Interests: 7Conflict of Interest CF and RK are co-inventors on patents claiming priority to WO/2015/103167, “Single Vial Vaccines,” and WO/2013/119856, “Improved Adjuvant Formulations Constituting TLR4 Agonists and Methods of Using Same.” TD and ET are/were employed by Lyophilization Technology, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.