Akinloye, Abdulafeez, Oyedeji, Timothy, Eniayewu, Oluwasegun, Adeagbo, Babatunde, Bolaji, Oluseye, Rannard, Steve 
ORCID: 0000-0002-6946-1097, Owen, Andrew ORCID: 0000-0002-9819-7651 and Olagunju, Adeniyi ORCID: 0000-0002-6588-5749
(2023)
Atazanavir/ritonavir increased tizoxanide exposure from oral nitazoxanide through pharmacokinetic interaction in healthy volunteers.
[Preprint]
Abstract
<jats:title>ABSTRACT</jats:title><jats:sec id="s45"><jats:title>Aims</jats:title><jats:p>Nitazoxanide 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.</jats:p></jats:sec><jats:sec id="s46"><jats:title>Method</jats:title><jats:p>This 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.</jats:p></jats:sec><jats:sec id="s47"><jats:title>Results</jats:title><jats:p>Co-administration of nitazoxanide with atazanavir/ritonavir resulted in a significant increase in tizoxanide plasma exposure. The geometric mean ratios (90% CI) of tizoxanide AUC<jats:sub>0-12h</jats:sub>, C<jats:sub>max</jats:sub>and C<jats:sub>12h</jats:sub>were 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).</jats:p></jats:sec><jats:sec id="s48"><jats:title>Conclusion</jats:title><jats:p>Co-administration with atazanavir/ritonavir enhanced tizoxanide exposure with no report of adverse events in healthy volunteers.</jats:p></jats:sec>
| Item Type: | Preprint |
|---|---|
| Uncontrolled Keywords: | Clinical Trials and Supportive Activities, Clinical Research |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 25 Sep 2023 08:19 |
| Last Modified: | 11 Apr 2024 17:09 |
| DOI: | 10.1101/2023.09.20.23295544 |
| Open Access URL: | https://doi.org/10.1101/2023.09.20.23295544 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3172994 |
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