Background
Metformin exposures have been reported to be 79% higher when co-administered with dolutegravir in healthy volunteers (1). A previous non-compartmental analysis (NCA) revealed 41% lower exposure in obese South African people living with HIV (PLWH) on a dolutegravir-based antiretroviral regimen (2). A drug-drug interaction (DDI) between dolutegravir and metformin at the level of renal clearance is a proposed mechanism for reduced metformin exposures. We aimed to evaluate the metformin-dolutegravir DDI using a pharmacometric modelling approach in obese South African PLWH (3,4).
Methods
Intensive pharmacokinetic sampling (n=120 observations) was collected from 15 obese South African PLWH receiving 1000mg slow-release metformin and 50mg dolutegravir daily. Blood samples were taken at 0, 1, 3, 4, 6, 8, 10, and 12 hours at steady state. A metformin population pharmacokinetic model was developed in Monolix 2024R1 using stochastic approximation expectation maximization (SAEM). Covariates of interest included body weight, BMI, lean body weight, transporter genotypes, and dolutegravir AUC. Dolutegravir AUC from NCA was evaluated as a continuous covariate on clearance. Allometric scaling used lean body mass with fixed exponents on clearance (0.75) and volume (1.0). Residual error was modeled using combined proportional-additive error.
Results
A one-compartment model with transit compartments and linear elimination best described the metformin data. Absorption parameter estimates were Ktr=0.307h⁻¹ (RSE 15.8%), Mtt=3.16 (RSE 13.7%), ka=0.175h⁻¹ (RSE 10.3%). Apparent clearance and volume were 71L/h (RSE 6.6%) and 98.2L (RSE 22%), respectively. Inter-individual variability (IIV) was successfully estimated on ka (CV 23.3%), volume (CV 32.8%), and clearance (CV 25.0%). Combined error model: proportional 7.1%, additive 0.053mg/L. Dolutegravir was not found to have a significant influence on metformin clearance.
Conclusion
A one-compartment model successfully characterized metformin kinetics using transit compartment absorption. Future work will utilize the model for dose optimization simulations in obese PLWH and re-evaluate published guidelines restricting metformin dosing to 1g when co-administered with dolutegravir.
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