Population Pharmacokinetics of the Interaction between Atazanavir/Ritonavir and Tizoxanide from Oral Nitazoxanide in Healthy Volunteers

Background

The potential benefit of co-administration of the antiparasitic agent, nitazoxanide (NTZ), and antiretroviral drug, atazanavir/ritonavir (ATV/r), was recently reported1. The exposure of NTZ active metabolite, tizoxanide (TIZ), improved with ATV/r co-administration by the latter inhibiting the glucuronidation conversion to a less active TIZ glucuronide. However, this was observed in a small cohort of volunteers, and larger population data are missing. Therefore, in this study, we developed a population pharmacokinetic (popPK) model to describe the pharmacokinetics of tizoxanide upon co-administration, explored possible covariate relationships, and described the variability across populations.

Methods

A total of 252 concentration-time points (126 pre- and 126 post- ATV/r co-administration) were analyzed. A one-compartment population pharmacokinetic (popPK) model was developed using Monolix 2024R1. Initial model validation was performed by comparing parameter estimates with data from a crossover study in healthy volunteers (n = 18). The covariates included age, body weight, and sex. The structural model incorporated transit compartments and first-order elimination, and parameters were estimated using the SAEM algorithm. Residual unexplained variability was described with a proportional error model. Model fit was assessed through diagnostic plots.

Results

ATV/r co-administration reduced apparent clearance (CL/F) by 47.8%, volume of distribution (V/F) by 50.54%, absorption rate constant (Ka) by 56.41%, and transit rate by 35.39%. High inter-individual variability was noted in Ka, with no significant covariate accounting for it. These results align with prior non-compartmental analysis showing a 69.05%¹ and 68%² increase in TIZ exposure upon ATV/r co-administration.

Conclusion

ATV/r significantly alters TIZ pharmacokinetics by inhibiting clearance and slowing absorption, resulting in increased systemic exposure. These findings support the need to re-evaluate NTZ dosing in HIV patients receiving protease inhibitors and highlight the value of popPK modelling in optimizing therapy amid complex drug-drug interactions³.

References

1. Akinloye, A., Oyedeji, T., Eniayewu, O., Adeagbo, B., Bolaji, O., Rannard, S., Owen, A., & Olagunju, A. (2024). Atazanavir/Ritonavir Increased Tizoxanide Exposure from Oral Nitazoxanide through Pharmacokinetic Interaction in Healthy Volunteers. Future Pharmacology, 4(1), Article 1. https://doi.org/10.3390/futurepharmacol4010011
2. Fowotade, A., Bamidele, F., Egbetola, B., Fagbamigbe, A. F., Adeagbo, B. A., Adefuye, B. O., Olagunoye, A., Ojo, T. O., Adebiyi, A. O., Olagunju, O. I., Ladipo, O. T., Akinloye, A., Onayade, A., Bolaji, O. O., Rannard, S., Happi, C., Owen, A., & Olagunju, A. (2022). A randomized, open-label trial of combined nitazoxanide and atazanavir/ritonavir for mild to moderate COVID-19. Frontiers in Medicine, 9. https://doi.org/10.3389/fmed.2022.956123
3. Zhou, C.-C., Huang, F., Zhang, J.-M., & Zhuang, Y.-G. (2023). Population Pharmacokinetics of Tigecycline: A Systematic Review. Drug Design, Development and Therapy, 16, 1885–1896. https://doi.org/10.2147/DDDT.S365512