Population pharmacokinetics and pharmacodynamics of caspofungin in renal allograft recipients during perioperative period
OBJECTIVE To establish a population pharmacokinetics(PPK)model of caspofungin and explore appropriate dosing optimization against Candida spp.in renal allograft recipients during perioperative period.METHODS Totally 134 blood concentration monitoring data were prospectively collected from 51 renal transplant recipients receiving caspofungin intravenously.The relevant covariates included age,gender,body weight,body mass index,alanine aminotransferase,aspartate aminotransfer-ase,total bilirubin,albumin,serum creatinine,serum cystatin C and other biochemical parameters.PPK model was established by nonlinear mixed effect method.Bootstrap method and normal prediction distribution error(NPDE)were adopted for internal validation of model.Monte Carlo simulations were performed using Crystal Ball software and likely success of treatment examined with the probability of target attainment(PTA)by comparing the pharmacodynamic exposure against minimum inhibitory concen-tration(MIC)distribution.The regimens had an optimal success of fungistatic effect if PTA＞90％.RESULTS The pharmaco-kinetics of caspofungin was best described by one-compartment model with first-order elimination.Body weight(WT)and serum cystatin C(CysC)had significant effects on caspofungin clearance from covariate analysis.Final model was CL(L·h-1)=0.411×(CysC/3.17)-0.277X(WT/57)0.519,V(L)=10.7.PPK model was validated as reliable and stable by Bootstrap method.And NPDEs indicated a good fit of the model to individual data.The results of simulations predicted that various drug regimens(50-150 mg·d-1)may have a high probability of successful outcome against Candida albicans(MIC90=0.06 mg·L-1)and Can-dida glabrata(MIC90=0.125 mg·L-1)with a broad range of WT(40-80 kg)and CysC(1-10 mg·L-1).However,none of dosage regimens of caspofungin achieved an expected fungicidal target for Candida parapsilosis(MIC90=1 mg·L-1).CONCLUSION This study has established a PPK model of caspofungin in renal transplant population.It may be applied for sup-porting individualized caspofungin dosing based upon body mass,renal function status,specific species and MIC level of Candida spp.for achieving the goals of improving clinical outcomes and minimizing adverse reactions.
renal transplantationcaspofunginpopulation pharmacokineticsMonte Carlo simulations
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