Methods: This was a Phase 1, blinded, placebo-controlled, crossover study in 32 healthy subjects randomized 1:1 to either B/F/TAF or placebo QD for 9 days followed by a 3-day washout. Following 4 days of B/F/TAF or placebo, subjects received 850 mg MET at 12 hours postdose of B/F/TAF or placebo, and 500 mg BID for 4 additional days. Plasma and urine PK of MET were assessed on the last treatment day (Days 9 and 21 for B/F/TAF or placebo). Oral glucose tolerance test was performed before (Days 5 and 17) and after MET (Days 9 and 21). MET PD endpoints including plasma glucose, active Glucagon-Like Peptide 1 (GLP‑1) and lactate were assessed after glucose intake. Geometric mean ratios (GMR) and 90% confidence intervals (CIs) for MET PK were calculated for B/F/TAF vs placebo. Comparisons of PD responses within treatments (before vs after MET) and comparisons between treatments (B/F/TAF vs placebo) were done via nonparametric Wilcoxon signed-rank test (p> 0.05 denotes non-significance).
Results: MET plasma AUCtau was increased 39% (%GMR [90% CI]: 139 [131, 148]) with B/F/TAF vs placebo, with no change in median plasma t1/2 (B/F/TAF: 6.4 h; placebo: 7.1 h). MET renal clearance decreased 31% with B/F/TAF vs placebo. Following MET administration, statistically significant reduction of plasma glucose, and increase of plasma active GLP-1 and lactate levels relative to baseline were observed (p < 0.001) confirming their utility as PD endpoints. Importantly, PD responses were not statistically different when MET was administered with B/F/TAF vs placebo (p >0.05).
Conclusion: Inhibition of renal transporters OCT2/MATE1 by BIC led to a modest increase of MET plasma exposure upon coadministration with B/F/TAF; however, the PD characteristics of MET were not significantly affected by B/F/TAF relative to placebo. Based on these findings, prospective dose adjustment/restriction of MET is not required upon coadministration with B/F/TAF.
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