In this study, we did not observe a clinically relevant PK interaction between DTG DT and F/TAF TOS for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC0–∞ and Cmax fell outside our acceptance criteria of 0.70–1.43.

For DTG, we found a GLSM ratio of 1.16 (90% CI 1.10–1.23) for Cmax, with all but one individual ratio above 1. This may indicate that there is a non-significant increase in the absorption of DTG when combined with F/TAF TOS. As there was no impact on AUC0–∞, and the Tmax was reached earlier (0.75 h in the test treatment versus 1 h in the reference treatment), this effect may occur in the absorption phase only. A significant higher Cmax of DTG has been observed and reported when the adult film-coated formulation of DTG was given with F/TAF, suggesting that this minor effect may be related to co-administration, but the actual mechanism for this potential effect is currently unknown (5, 10). Given that the safety data for DTG has been reassuring (11-13), and we expect not to reach the Cmax of 5.4 mg/L found in adults taking DTG 50 mg twice daily and which has been demonstrated to be safe (12), we see no cause for concern. Finally, we found comparable AUC0–∞ and Cmax values for DTG in our study after a single dose of 30-mg DT compared to other single-dose studies with the 50-mg adult DTG product, which is bioequivalent to the dose we gave (14, 15).

For FTC, there were no differences in Cmax and AUC0–∞ GLSM ratios compared to previous studies (5, 6, 16). In addition, the individual values are equally distributed; hence no trend was observed in higher or lower exposure in either of the treatments.

For TAF, we could not rule out a potentially relevant PK interaction between DTG DT and F/TAF TOS based on AUC0–∞ and Cmax GLSM ratios on 90% CIs. However, when evaluating the individual ratios of TAF in the test treatment versus the reference treatment, no consistent trend was seen in TAF exposure in either of the treatments: 50% of the participants in this study had a ratio below 1 and 50% had a ratio above 1. In contrast to our study, higher TAF exposure was reported when given with DTG as adult formulations (5, 6). Furthermore, as TAF is a pro-drug of TFV, and since TFV exposures were not impacted, the clinical impact was doubtful. It has been shown that higher concentrations of intracellular TFV diphosphate (TFV-DP) are found after administration of TAF compared to administration of TDF, with much lower TFV concentrations (6). TAF exhibits greater stability in the intestine and plasma compared to TDF; as a consequence, TAF has improved intracellular accumulation of TFV-DP in HIV target cells with lower circulating levels of TFV. Therefore, we expect that the lower exposure of TAF observed in our study is negligible in terms of clinical relevance. In addition, the AUC0–∞ levels observed within this study, were still within ranges that were found to be safe and effective in adults, indicating that the observed changes are not clinically relevant (17). We suggest that our results mainly reflect the high intersubject variation which has been reported for TAF. Previous studies measuring TAF (25-mg dose) administered to adults in a fasting state found PK results in the same order of magnitude as we found with a 22.5-mg TAF dose (6, 18), which reinforces confidence in the study results.

In conclusion, we did not find any clinically relevant PK interaction between DTG DT and F/TAF TOS for DTG, TFV, and FTC when co-administered, compared to products administered separately. Although TAF AUC0–∞ and Cmax 90% CIs fell outside the pre-defined criteria, no consistent effect on TAF PK was observed, likely due to high intersubject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we assume that we found no clinically relevant interactions in this study. These data will inform on the dose ratio as well as dose selection for a paediatric DTG/FTC/TAF FDC to be developed in the UNIVERSAL project.