Dolutegravir versus Metformin
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Study Design
This was an open-label, parallel-group, 3-period crossover study in healthy adult subjects. Subjects were enrolled into 1 of 2 treatment cohorts (15 subjects/cohort) receiving metformin 500 mg q12h for 5 days in period 1; metformin 500 mg q12h plus dolutegravir 50 mg q24h (cohort 1) or 50 mg q12h (cohort 2) for 7 days in period 2; and metformin 500 mg q12h for 10 days in period 3. There were no washout periods between treatments. Effects of dolutegravir on metformin transport and paracellular permeability were evaluated in vitro.
Study Results
Co-administration of dolutegravir 50 mg q24h increased metformin area under the curve(0–τ) by 79% and Cmax by 66%, whereas dolutegravir 50 mg q12h increased metformin area under the curve(0–τ) and Cmax by 145% and 111%, respectively. Metformin t(1/2) remained unchanged. Increased metformin exposure during dolutegravir co-administration returned to period 1 levels after dolutegravir discontinuation in period 3. 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, and it did not affect metformin paracellular permeability or uptake into an intestinal cell line.
Study Conclusions
Dolutegravir significantly increased metformin plasma exposure, which can be partially explained by OCT2 inhibition. It is recommended that dose adjustments of metformin be considered to maintain optimal glycemic control when patients are starting/stopping dolutegravir while taking metformin.
Other authors have provided evidence from real-life setting that, even if pharmacokinetic DDIs may take place between dolutegravir and metformin ultimately resulting in increased drug exposure, its clinical relevance may be limited. Therefore, instead of proposing a priori adjustments in metformin dose1—with unnecessary potential reduction of drug efficacy—we suggest just to monitor, as per clinical practice, glycemic control in HIV-infected patients on metformin who start or stop dolutegravir. We would like to reassure physicians that, in most cases, it is likely that nothing happens and no dose adjustment may be required.
References
Song IH, Zong J, Borland J, Jerva F, Wynne B, Zamek-Gliszczynski MJ, Choukour M. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. Journal Of Acquired Immunodeficiency Syndromes. 2016; 4: 400.
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