Pharmacokinetics of metformin in patients with chronic kidney disease stage 4 and metformin-naïve type 2 diabetes
Abstract
The pharmacokinetics of metformin therapy in patients with chronic kidney disease stage 4 (CKD-4) were studied using data from the largest Phase I consecutive cohort trial yet performed in this population. Eighteen metformin-naïve men and women with Type 2 Diabetes and creatinine clearance (CrCl) in the range 18-49 mL/min (eGFR 15-29 mL/min/1.73 m2) were allocated to daily immediate-release metformin of 250 mg, 500 mg, or 1000 mg. A first-dose profile and trough concentrations for 4 weeks were taken on all patients. Pharmacokinetic (PK) parameters were estimated by fitting a first-order compartment model with absorption in a peripheral compartment to concentrations measured 24 hours post-first dose. Single-dose PK parameters time to maximum concentration (tmax) and maximum concentration (Cmax) were consistent with previous observations in patients with normal renal function (healthy and diabetic), as was the association between CrCl and apparent total oral clearance (Cl/F). However, patients with a CrCl below 32 mL/min had trough concentrations that were consistently above the steady-state minimum implied by the population PK model. This suggests the model may not apply to patients with CrCl below 32 mL/min. Metformin in doses of 500-1000 mg/day could be taken by CKD-4 patients. However, the single-compartment model breaks down as CrCl declines below 32 mL/min suggesting that metformin levels should be monitored regularly in progressive stage 4 CKD.
How strong is the evidence?
Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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