Coadministration of multiple dose of metformin (850 mg once daily followed by 500 mg twice daily and 500 mg once daily) was studied with bictegravir/emtricitabine/tenofovir alafenamide (50/200/25 mg once daily) in 32 subjects. Coadministration increased metformin Cmax and AUC by 28% and 39% due to inhibition of renal OCT2 and MATE1 transporters by bictegravir. The pharmacodynamic characteristics of metformin (including glucose reduction, increases in active GLP-1 and plasma lactate) were not affected by coadministration with bictegravir, emtricitabine and tenofovir alafenamide relative to placebo. In addition, no significant differences were observed in fasted blood glucose or HbA1c values before and after initiating bictegravir in HIV+ people with either normal or mildly impaired renal function receiving metformin at daily doses of 500-3000 mg. The US product label for Biktarvy refers to the Prescribing Information of metformin for assessing the benefit and risk of concomitant use of Biktarvy and metformin. This is particularly important in patients with renal impairment. The European product label for Biktarvy indicates that no dose adjustment is required upon coadministration in patients with normal renal function, but for patients with moderate renal impairment, close monitoring should be considered when starting coadministration of bictegravir with metformin, due to increased risk for lactic acidosis in these patients and a dose adjustment of metformin should be considered if required.

Coadministration with ferrous sulfate has not been studied. As with other HIV integrase inhibitors, bictegravir may be subject to chelation by high concentrations of divalent cations which may result in reduced bictegravir concentrations. The simultaneous administration of ferrous fumarate (324 mg) and bictegravir with food did not significantly impair bictegravir exposure whereas exposure was decreased by 63% during simultaneous administration in fasted conditions. A similar effect may occur with ferrous sulfate. It is recommended to administer bictegravir and ferrous sulfate simultaneously with food.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Venlafaxine is mainly metabolized by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19 and 2C9. Bictegravir does not inhibit or induce P450 enzymes; emtricitabine and tenofovir alafenamide do not interact with venlafaxine’s metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quetiapine is primarily metabolized by CYP3A4. Bictegravir does not inhibit or induce P450 enzymes; emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). Bictegravir does not inhibit or induce UGTs enzymes. A large proportion of furosemide is also eliminated unchanged renally (via OATs). In vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/OAT3 but this is unlikely to significantly impact tenofovir concentration as tenofovir alafenamide results in 90% lower systemic levels of tenofovir compared to tenofovir-DF. Emtricitabine is unlikely to interact as it is eliminated by different renal transporters. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Studies have shown no evidence that bictegravir solubility is impacted by changes in pH and therefore can be coadministered with PPIs or H2-antagonists without dose adjustment or separation. Emtricitabine and tenofovir alafenamide are not impacted by lansoprazole.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9 which is not affected by bictegravir, emtricitabine or tenofovir alafenamide.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Folic acid is metabolized to dihydrofolic acid and tetrahydrofolic acid with the aid of reduced diphosphopyridine nucleotide and folate reductases.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of vitamin D to active metabolites occurs in the liver and kidneys, and is thought to involve CYP3A4 and CYP24A1. There is little potential for an interaction with bictegravir via modulation of, or competition for, metabolic pathways. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Bictegravir does not inhibit or induce CYP450 or UGTs enzymes; emtricitabine and tenofovir alafenamide do not interact with buprenorphine’s metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as pregabalin is cleared mainly by glomerular filtration.