Higher Atazanavir Plasma Exposure in Rats is Associated with Gut Microbiota Changes Induced by Cotrimoxazole

Background: Cotrimoxazole (TMP-SMX) is concomitantly used as a primary prophylaxis of opportunistic infections with antiretroviral agents, such as Atazanavir (ATV). Results from an ex vivo study showed changes in intestinal absorption of ATV when rats were pretreated with TMP-SMX. The objective of this in vivo study is to determine the effect of TMP-SMX on the pharmacokinetics of ATV in rats. We also studied changes in gut microbiota induced by TMP-SMX. Methods: We used the non-compartment analysis to compare the pharmacokinetics of ATV in a parallel group of rats treated with a low or therapeutic dose of TMP-SMX for nine days to untreated control rats. Gut microbiota was characterized using qPCR and High Throughput Sequencing of 16S rDNA. Results: Rats treated with TMP-SMX showed a much broader exposure to ATV compared to the control group (AUC(0-8h) (ng.mL(-1).h), 25975.9 +/- 4048.7 versus 2587.6 +/- 546.9, p=0.001). The main observation regarding the gut micmbiota was a lower proportion of enterobacteria related to the administration of TMP-SMX. Moreover, the Total Gastrointestinal Transit Time (TGTT) was longer in the TMP-SMX treated group. Conclusion: Concomitant administration of TMP-SMX and ATV significantly increased ATV exposure in rats. This increase could be the result of a prolonged TGTT leading to an increase in the intestinal residence time of ATV favoring its absorption. Gut microbiota changes induced by TMP-SMX could be at the origin of this prolonged TGTT. If demonstrated in humans, this potential interaction could be accompanied by an increase in the adverse effects of ATV.