Population Pharmacokinetics Of Caspofungin In Heart Transplant Recipients

Objective: Heart transplantation is an effective approach to improve survival in patients with end-stage heart failure.Invasive fungal infection is a rare but severe complication after heart transplantation.Caspofungin is the first-line medication for invasive candidiasis.However,there is a lack of studies on the pharmacokinetics of caspofungin in heart transplant recipients.The aim of the study was to establish a population pharmacokinetics(PPK)model of caspofungin in heart transplant recipients and provide recommendations for individualized dosing in heart transplant recipients.Methods: Blood samples were collected from the patients receiving caspofungin in the surgical intensive care unit.The plasma concentrations of caspofungin were determined by liquid chromatography-tandem mass spectrometry.The demographic information,physiological conditions and medication regimens of patients were recorded.The PPK model of caspofungin in heart transplant recipients was established by the nonlinear mixed effects model method and the potential covariates on the pharmacokinetics of caspofungin were screened.The models were internally validated using goodness-of-fit plots,bootstrap,visual prediction test plots,and normalized prediction distribution errors.The final model was used for simulations to further investigate the probability of target attainment(PTA)under different minimum inhibitory concentration(MIC),different albumin(ALB)levels,and different dosing regimens in heart transplant recipients.Results: A total of 58 patients(27 heart transplant recipients,31 non-heart transplant patients)with 414 drug concentrations were included for PPK analysis.A two-compartment model fitted the pharmacokinetic profiles of caspofungin in the patients.The typical values for clearance(CL)of the central compartment,the volume of the central compartment,the intercompartment clearance and the volume of the peripheral compartment were 0.385 L/h,4.27 L,2.85 L/h,and 6.01 L,respectively.Covariates analysis indicated that heart transplantation did not significantly affect the pharmacokinetics of caspofungin,while the ALB levels had significant effects on CL of caspofungin.The adjustment factor of ALB level for caspofungin CL was-1.01.The final PPK model had good accuracy,stability and predictive ability based on the internal validation.The simulations showed that for the patients with ALB levels of 37g/L,at the dose of 50 mg caspofungin(1-h infusion once daily)for the treatment of Candida albicans(MIC ≤0.06 mg/L),Candida glabrata(MIC ≤ 0.125 mg/L)and Candida parapsilosis(MIC ≤ 0.06 mg/L),the PTA values were 100%,100%,and 97%,respectively.For the treatment of Candida albicans(MIC = 0.125 mg/L),the dose of caspofungin should be increased to at least 70 mg.Conclusion: This is the study to establish a PPK model of caspofungin in heart transplant recipients.The ALB level had a significant effect on the CL of caspofungin,and the dose of caspofungin should be increased as the ALB level decreased.The results provided a foundation for rational administration of caspofungin in heart transplant recipients.