Bictegravir versus Metformin
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Study Design
This was a Phase 1, blinded, placebo-controlled, multiple-dose, 2- period, crossover study in healthy subjects. Thirty-two subjects were randomized in a 1:1 ratio to receive either B/F/TAF or placebo once daily for 9 days followed by a 3 days of washout. Following 4 days of B/F/TAF or placebo, subjects received 850 mg metformin at 12 hours postdose of B/F/TAF or placebo, and 500 mg twice daily for an additional 4 days. The evening dose of metformin on the last day was not given. Plasma and urine PK of metformin were assessed on the last day of treatment (Days 9 and 21 for B/F/TAF or placebo). Oral glucose tolerance test (OGTT) was performed before metformin (Days 5 and 17) and after the last dose of metformin (Days 9 and 21). Metformin PD endpoints including plasma glucose, active Glucagon-Like Peptide 1 (GLP-1) and lactate following OGTT were assessed. Safety was monitored throughout the study. Geometric least-squares mean (GLSM) ratios and 90% confidence intervals (CIs) for metformin plasma exposure were calculated for B/F/TAF vs placebo treatments. Comparisons of
PD responses within a treatment (before vs after metformin) as well as comparisons between treatments (B/F/TAF vs placebo) were evaluated using the nonparametric Wilcoxon signed-rank test (p> 0.05 denotes non-significance).
Study Results
Metformin plasma exposure (AUCtau) was increased by approximately 39% (%GLSM ratio [90% CI]: 139 [131, 148]) when coadministered with B/F/TAF relative to placebo. Median plasma t1/2 was similar between B/F/TAF (6.36 hrs) and placebo (7.06 hrs) treatments. Metformin renal clearance (CLR) decreased approximately 31% when coadministered with B/F/TAF vs placebo. Following metformin 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 for metformin. Importantly, clinically-relevant PD responses were not statistically different when metformin was administered with B/F/TAF vs placebo (p >0.05). Coadministration of metformin with B/F/TAF was generally safe and well tolerated.
Study Conclusions
The author’s concluded that inhibition of renal transporters OCT2 and/or MATE1 by BIC led to a modest increase of metformin plasma exposure following coadministration with B/F/TAF; however, the PD characteristics of metformin, such as glucose reduction, and active GLP-1 and lactate increases after OGTT were not significantly affected by B/F/TAF relative to placebo. Based on these findings, prospective dose adjustment or dose restriction of metformin is not required when it is coadministered with B/F/TAF.
References
Zhang H, West S, Vu A, Martin H, Graham H, Quirk E. Lack of clinically relevant effect of bictegravir on metformin pharmacokinetics and pharmacodynamics . International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
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