Liverpool HIV Interactions

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Potential Interaction

Dolutegravir (DTG)

Metformin

Quality of Evidence: Low

Summary:

Coadministration of metformin (500 mg twice daily) was studied with dolutegravir (50 mg once or twice daily) in 15 subjects. Coadministration with once daily dolutegravir increased metformin Cmax and AUC by 66% and 79%, whereas coadministration with twice daily dolutegravir increased metformin Cmax and AUC by 111% and 145%. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin in order to maintain glycaemic control. The US Prescribing Information suggests limiting the total daily dose of metformin to 1000 mg when starting metformin or dolutegravir. However, limiting metformin to 1000 mg daily may result in subtherapeutic exposures in obese people living with HIV as administration of metformin (1000 mg) and dolutegravir (50 mg daily) to obese women living with HIV (n=15; mean BMI of 45.6 kg/m2 (range 35.6-56.7)) resulted in metformin and dolutegravir concentrations which were approximately half of that in historical non-obese healthy volunteers. Monitoring renal function during coadministration and monitoring blood glucose when starting and stopping coadministration is recommended. As metformin is eliminated renally, patients with moderate renal impairment may be at increased risk for lactic acidosis due to increased metformin concentrations.

Description:

Coadministration of metformin with once daily dolutegravir (50 mg once daily) increase metformin AUC and Cmin by 79% and 66%. Coadministration with twice daily dolutegravir (50 mg twice daily) increased metformin AUC and Cmax by 145% and 111%. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control. Metformin is eliminated renally and therefore it is of importance to monitor renal function when co-treated with dolutegravir. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45– 59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.
Tivicay Summary of Product Characteristics, ViiV Healthcare, March 2019.

Coadministration of metformin (500 mg twice daily) was studied with dolutegravir (50 mg once or twice daily) in 15 subjects. Coadministration with once daily dolutegravir increased metformin Cmax and AUC by 66% and 79%, whereas coadministration with twice daily dolutegravir increased metformin Cmax and AUC by 111% and 145%. With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or dolutegravir. When stopping dolutegravir, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of dolutegravir is recommended.
Tivicay US Prescribing Information, ViiV Healthcare, July 2019.

Co-administration of metformin (500 mg twice daily) was studied with dolutegravir alone (50 mg once or twice daily) in 15 subjects. Co-administration of dolutegravir 50 mg once daily increased metformin AUC and Cmax by 79% and 66%, respectively, whereas dolutegravir 50 mg twice daily increased metformin area AUC and Cmax by 145% and 111%, respectively. Co-administration of dolutegravir and metformin was well tolerated. In vitro, dolutegravir was not a clinically relevant inhibitor of OCT1, OCT3, multidrug and toxin extrusion protein 1, multidrug and toxin extrusion protein 2-K, or plasma membrane monoamine transporter. Increased metformin plasma exposure can be partially explained by OCT2 inhibition by dolutegravir. It is recommended that dose adjustments of metformin be considered to maintain optimal glycemic control when patients are starting/stopping dolutegravir while taking metformin.

Song IH, Zong J, Borland J, et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Acquir Immune Defic Syndr. 2016 Aug 1;72(4):400-7.

Dolutegravir has been shown previously to increase metformin plasma exposure by 79% (historical data) however the magnitude of this interaction has not been evaluated in obese individuals. Obesity has been shown to lower metformin exposure therefore the magnitude of the interaction between dolutegravir and metformin could be more pronounced in obese individuals. A pharmacokinetic study was conducted in 15 women with HIV virologically suppressed receiving metformin 1000 mg and dolutegravir 50 mg daily. The participants had a mean BMI of 45.6 kg/m2 (range 35.6-56.7). Metformin and dolutegravir concentrations were approximately half of that in the historical non-obese healthy volunteers with metformin AUC decreasing by 40.9% and dolutegravir AUC decreasing by 54.4%. Metformin and dolutegravir clearance were 1.7 and 2.2-fold higher, respectively. The authors conclude that limiting metformin to 1000 mg daily is likely to result in subtherapeutic exposures in obese women with HIV on dolutegravir. Lower metformin exposure could be due to the reduced dolutegravir exposure and the related reduced dolutegravir inhibitory effect on drug transporters (i.e., OCT2, MATE1). Increased volume of distribution due to obesity may also contribute to the lower exposures.

Reduced metformin concentrations in obese women with HIV treated with dolutegravir. Van Rensburg R, Kellermann T, Pillay-Fuentes Lorente V, et al. J Infect Dis. 2025, 232(6):e1012-1021.

Potential Interaction

Bictegravir/ Emtricitabine/Tenofovir alafenamide (BIC/FTC/TAF)

Metformin

Quality of Evidence: Moderate

Summary:

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.

Description:

Coadministration of metformin (500 mg twice daily) and bictegravir/emtricitabine/tenofovir alafenamide increased metformin AUC and Cmin by 39% and 36% (due to inhibition of OCT1/MATE1), but had no significant effect on Cmax. No dose adjustment is required upon co-administration in patients with normal renal function. In patients with moderate renal impairment, close monitoring should be considered when starting coadministration of bictegravir with metformin, due to the increased risk for lactic acidosis in these patients. A dose adjustment of metformin should be considered if required.

Biktarvy Summary of Product Characteristics, Gilead Sciences Ltd, June 2019.

Coadministration may increase metformin concentrations. Refer to the prescribing information of metformin for assessing the benefit and risk of concomitant use of Biktarvy and metformin. Coadministration of metformin (500 mg twice daily) and bictegravir/tenofovir alafenamide (50/25 mg once daily) increased metformin Cmax, AUC and Cmin by 28%, 39% and 36%.

Biktarvy Prescribing Information, Gilead Sciences Inc, August 2019.

Glycemic control under metformin treatment before and after the initiation of a bictegravir containing regimen was evaluated retrospectively in 20 people living with HIV. The mean metformin dose was 1455 + 726 mg daily (ranging from 500 to 3000 mg daily). No clinically significant differences were observed in the glucose fasting values when comparing values pre- versus post- bictegravir initiation (fasting blood glucose 134+33 versus 128+24 mg/dL, mean difference -2.2%; P=0.311). Similarly, no differences were observed for HbA1c (48+11 versus 50+10 mmol/mol, mean difference +2%; P=0.907). The same observation applied when comparing fasted glucose or HbA1c values before and after initiation of bictegravir in individuals receiving metformin daily doses >1000 mg (fasting blood glucose 130+33 versus 124+24 mg/L; P=0.504 and HbA1c 49+12 versus 52+10 mmol/mol; P=0.863). No individuals experienced episodes of hypoglycaemia or lactic acidosis after initiating bictegravir. All individuals included in the study had a normal renal function or mild renal dysfunction. In conclusion, this study provides evidence from a real-life setting that coadministration of bictegravir and metformin did not result in statistically and/or clinically relevant effects on glycaemic control. This was confirmed also for daily doses of metformin >1000 mg.

Lack of clinically relevant interactions between bictegravir and metformin in persons with diabetes and HIV. Cattaneo D, Fromenti T, Minisci D, et al. J Antimicrob Chemother 2021;76(7):1945-1946.

Coadministration of bictegravir/emtricitabine/tenofovir alafenamide and metformin (850 mg followed by 500 mg twice daily) was studied in healthy subjects. Inhibition of renal transporters OCT2 and/or MATE1 by bictegravir led to a modest increase (~39%) of metformin plasma exposure following coadministration with bictegravir/emtricitabine/tenofovir alafenamide. The pharmacodynamics responses for metformin (such as glucose reduction, and active GLP-1 and lactate increases after OGTT) were not significantly affected by bictegravir/emtricitabine/tenofovir alafenamide relative to placebo.

Lack of clinically relevant effect of bictegravir on metformin pharmacokinetics and pharmacodynamics. Zhang H, West S, Vu A, et al. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, Chicago, June 2017, abstract P_50.