Abstract
Metformin, a biguanide, is widely accepted to be the preferred first-line oral antihyperglycaemic agent to manage type 2 diabetes. There is considerable concern that patients receiving metformin therapy may be at an increased risk of developing lactic acidosis. The risk has traditionally been assumed to be increased in patients with chronic renal impairment, resulting in many patients being denied access to an effective first-line treatment agent. The overarching aims of this thesis were to explore the safe use of metformin and to create a renal dosing guideline that will mitigate the risk of lactic acidosis.
The safe use of metformin was explored by formally evaluating the association between metformin therapy and lactic acidosis in published case reports of metformin associated lactic acidosis (MALA) using two causality assessments. Metformin was found to play only a possible role in the development of lactic acidosis based on the results from the causality assessments. Almost all cases presented with other risk factors that could on their own have caused lactic acidosis.
A subgroup analysis was performed in MALA cases with a history of chronic renal impairment to explore the relationship between metformin dose, plasma concentration and lactic acidosis. Most cases presented with acute renal failure, confounding the relationship between metformin dose and plasma concentrations. The prescribed metformin dose exceeded the dosing recommendations in over 60% of cases with an estimated glomerular filtration rate of <60 mL/min by a median of 1000 mg/day. Despite this, based on simulations, the pre-admission plasma metformin concentrations measured pre-dose did not exceed the proposed upper limit of the therapeutic range of 5 mg/L.
A quantitative analysis was performed to explore the relationship between plasma metformin and lactate concentrations. Plasma metformin concentrations greater than 4.5 mg/L were found to be associated with severe hyperlactatemia. These findings suggest that metformin doses should be adjusted to maintain plasma concentrations below 4.5 mg/L to mitigate the risk of lactic acidosis.
A noncompartmental pharmacokinetic analysis was performed to explore the pharmacokinetics of metformin in renal impairment, from which an empirical renal dosing guideline for metformin was developed. Patients with poorer renal function were found to have lower apparent and renal clearance for metformin. These findings support the notion that metformin can be used safely for the treatment of type 2 diabetes mellitus in patients with chronic renal impairment provided plasma metformin concentrations are maintained within a safe therapeutic range.
A population pharmacokinetic model for metformin was developed and evaluated. A covariate analysis found that renal function and total body weight could describe patient variability in the apparent clearance and central compartment volume for metformin, respectively. The developed population pharmacokinetic model was used to assess the safety of the empirical renal dosing guidelines and the current published renal dosing guidelines in the New Zealand Formulary. Based on the simulations, plasma metformin concentrations are not expected to exceed the upper limit of safety of 4.5 mg/L under either of the dosing guidelines.
The influence of flip-flop pharmacokinetics in population pharmacokinetic models was explored using metformin as a motivating example. Approaches to address problems arising due to flip-flop in population pharmacokinetic models are presented in this thesis.
In conclusion, the findings in this thesis support the notion that metformin can be used safely for the treatment of type 2 diabetes mellitus provided plasma metformin concentrations are maintained within a safe range. In addition, an empirical renal dosing equation for metformin was developed and assessed for safety.