Metformin-Cimetidine Drug Interaction and Risk of Lactic Acidosis in Renal Failure: A Pharmacovigilance-Pharmacokinetic Appraisal.

ABSTRACT

OBJECTIVE: This study aimed to evaluate lactic acidosis (LA) risk when using metformin combined with histamine H2 receptor inhibitors (H2RI) in patients with renal failure (RF). RESEARCH DESIGN AND METHODS: This study analyzed FDA Adverse Event Reporting System data (2012Q4 to 2022Q4) to characterize reports of LA associated with metformin alone or combined with H2RI. Using a disproportionality approach, LA risk signal in the overall population and in patients with RF was assessed. A physiologically based pharmacokinetic (PBPK) model was developed to predict metformin and cimetidine pharmacokinetic changes following conventional doses of the combinations in patients with various degrees of RF. To explore its correlation with LA risk, a peak plasma metformin concentration of 3 mg/L was considered the threshold. RESULTS: Following the 2016 U.S. Food and Drug Administration metformin approval for mild-to-moderate RF, the percentage of patients with RF reporting LA associated with metformin combined with H2RI increased. Disproportionality analysis showed reported LA risk signal associated with metformin and cimetidine in the overall population within the study timeframe only. Furthermore, with PBPK simulations, for metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d.) in stage 1 of chronic kidney disease, metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d. or 800 mg q.d.) in stage 2, and most combinations in stage 3, the peak plasma metformin concentrations exceeded the 3 mg/L threshold. CONCLUSIONS: Metformin combined with cimetidine at conventional doses may cause LA in patients with mild-to-moderate RF.