Metformin dose needs adjusting in patients taking dolutegravir

By Marilynn Larkin

NEW YORK (Reuters Health) - Dose adjustments should be considered to maintain optimal glycemic control in patients who are starting or stopping dolutegravir while taking metformin, according to new research.

Dolutegravir belongs to a class of antiretroviral drugs known as integrase strand transfer inhibitors (INSTIs), and is an inhibitor of the renal uptake transporter OCT2.

Metformin, an OCT2 substrate, is an antihyperglycemic agent that improves glucose tolerance in subjects with type 2 diabetes and has been used for a number of the metabolic comorbidities that are associated with HIV.

The research team sought to determine the effect of dolutegravir on the pharmacokinetics of metformin to guide coadministration of the two drugs.

In an open-label, parallel-group, three-period crossover study, healthy men were enrolled into one of two treatment groups (15 per group). One group received 500 mg metformin twice daily for five days in study period one, and 500 mg of metformin twice daily plus 50 mg dolutegravir once daily for seven days in study period two.

The second group received 500 mg metformin twice daily plus 50 mg dolutegravir twice daily for seven days in study period two, and 500 mg metformin twice daily for 10 days in study period three. There were no washout periods between treatments, and the effects of dolutegravir on metformin transport and paracellular permeability were evaluated in vitro.

Coadministration of 50 mg dolutegravir daily increased metformin area under the curve by 79% and maximum serum concentration by 66%. Coadministration of 50 mg dolutegravir twice daily increased metformin AUC and Cmax by 145% and 111%, respectively. Increased metformin exposure during dolutegravir coadministration returned to study period one levels after dolutegravir was discontinued in period three.

In an article online March 11 in the Journal of Acquired Immune Deficiency Syndromes, the authors said that coadministration of dolutegravir and metformin was well tolerated, and that dolutegravir was not a clinically relevant inhibitor of OCT2-related transporters and did not affect metformin paracellular permeability or uptake into an intestinal cell line.

Nonetheless, dolutegravir "significantly increased metformin exposure," and the researchers recommend that metformin dose adjustments be considered for patients who start or stop taking the drug.

On behalf of the study authors, Dr. Michael Aboud, global medical lead, dolutegravir, at GlaxoSmithKline, told Reuters Health by email, "Plasma exposures of metformin were increased when coadministered with dolutegravir. PK (pharmacokinetic) effects were dolutegravir dose-dependent. When coadministered with dolutegravir, a dose adjustment of metformin may be considered."

"When starting metformin while on dolutegravir, start at a low metformin dose and gradually increase the dose to achieve glycemic control and minimize gastrointestinal symptoms," Dr. Aboud advised. "When starting/stopping dolutegravir while on metformin, a dose adjustment of metformin may be necessary to maintain optimal glycemic control and/or minimize GI symptoms."

Commenting by email, Dr. Paul Sax, of Brigham and Women's Hospital in Boston, told Reuters Health, "These data have been in the public domain for some time, having been presented previously at a scientific meeting. They led to a label change for dolutegravir, indicating that the maximum daily dose of metformin should not exceed 1,000 mg. Clinicians should be aware that dose reductions in metformin may be necessary if their patients start dolutegravir, and that stopping dolutegravir could lead to alterations in glucose control if metformin is part of the diabetes treatment regimen."

Eight coauthors are employees and shareholders of GlaxoSmithKline and one is a contract worker for the company. ViiV Healthcare funded the study and employed one coauthor.

SOURCE: http://bit.ly/1Uvm5Vf

J Acquir Immun Defic Syndr 2016.

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