Population pharmacokinetics of milrinone in patients undergoing cardiovascular surgery with cardiopulmonary bypass

Abstract Background Milrinone, a selective phosphodiesterase III inhibitor with both positive inotropic and vasodilatory effects, is widely used during cardiovascular surgery. However, limited information is available on the pharmacokinetics (PK) of milrinone in patients undergoing cardiovascular surgery with cardiopulmonary bypass (CPB). CPB may alter the PK of many drugs through hemodilution, altered protein binding, hypothermia, and changes in organ perfusion. This study aimed to develop a population pharmacokinetic (PPK) model of milrinone and evaluate the influence of renal function on PK parameters in patients undergoing cardiovascular surgery with CPB. Methods This prospective observational single-center study included adult patients who received intravenous milrinone during cardiovascular surgery with CPB between October 2021 and March 2022. Plasma milrinone concentrations were measured at 0.5, 2, 12–24, and 24–36 h after the initiation of administration and quantified using liquid chromatography-tandem mass spectrometry. PPK analysis was performed using nonlinear mixed-effects modeling. Candidate covariates included age, sex, body weight, creatinine clearance (Ccr), serum albumin, CPB priming volume, and cell saver volume. Their effects on the clearance (CL) and volume of distribution (V) were evaluated. Model performance and stability were assessed using goodness-of-fit diagnostics and bootstrap validation. Results A total of 61 patients and 229 plasma samples were included in the analysis. The one-compartment structural model with a proportional error model provided the best fit to the observed data. Covariate analysis identified Ccr as a significant covariate influencing CL. Bootstrap validation generally supported model stability, although uncertainty remained in the estimation of some parameters. The final model was described as follows: CL (L/h) = 2.26×Ccr 0.48 , V (L) = 13.32. Conclusions This study developed a PPK model of milrinone use in patients undergoing cardiovascular surgery with CPB, and identified renal function as a factor influencing CL. These findings suggest that renal function may be important when determining milrinone dosing in this population, although further external validation is required.