Reduced Metformin Concentrations in Obese Women With Human Immunodeficiency Virus Treated With Dolutegravir

Obesity among women with human immunodeficiency virus (WWH) is nearly 2-fold higher than in men. Obesity is closely associated with dysglycemia, and frequently necessitates the coadministration of dolutegravir and metformin. A pharmacokinetic study in 15 nonobese healthy volunteers determined that dolutegravir increased metformin plasma exposure by 79%, prompting regulatory and guideline recommendations to limit metformin to 1000 mg/day when coadministered with dolutegravir. Obesity has been linked to lower metformin exposures, and our study aimed to verify the metformin pharmacokinetic exposure in the increasing population of obese WWH.

We conducted intensive plasma sampling in virally suppressed WWH receiving metformin extended-release 1000 mg once daily with concomitant dolutegravir 50 mg once daily. Dual-energy X-ray absorptiometry was performed to quantify body fat composition. Noncompartmental analysis of metformin and dolutegravir concentrations was performed, and our findings were compared to the reference study.

We enrolled 15 participants with a mean body mass index of 45.6 kg/m2. Metformin area under the concentration-time curve over the 24-hour dosing interval (AUC0-24) was 40.9% lower and dolutegravir AUC0-24 was 54.4% lower in obese WWH compared to the reference study. Metformin and dolutegravir clearance were 1.7- and 2.2-fold higher, respectively. Linear regression did not show associations between body fat composition and metformin or dolutegravir exposures.

Limiting metformin to 1000 mg daily is likely to lead to underdosing in obese WWH on dolutegravir. Lower metformin exposure appears to be due to the reduced inhibitory effect of lower dolutegravir concentrations on metformin clearance and increased volume of distribution due to obesity. Our data support the revision of the current maximum dose restriction of metformin in the target population of obese WWH.