Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS• A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMSTo characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODSData were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16-28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTSA one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h CONCLUSIONSThe range of estimated CL/F in the study population was 0.67-7.38 l h -1. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

Potassium canrenoate treatment in paediatric patients

“…Inclusion of weight and PMA as covariates on CL/F explained 67% of the variability in CL/F and inclusion of weight and gestational age on V/F explained more than 99% of variability in V/F. More covariates explaining canrenone disposition than a plasma model described earlier by our group were identified [10], that is in the latter study, canrenone disposition was affected only by weight that was included on both CL/F and V/F. As canrenone does not distribute into erythrocytes [22], hematocrit is expected to influence the measured DBS concentrations and, hence, the estimated V/F of canrenone in the 'DBS Model'.…”

“…Recently, our group published a population pharmacokinetic model for canrenone based on measured canrenone plasma concentrations in 23 paediatric patients who received the drug as part of their routine management [10]. The current study is unique in being the first to report the pharmacokinetic data for canrenone based on dried blood spot (DBS) measurements.…”

“…In addition, a whole blood sample was collected from full-term infants and children in EDTA tubes, at the time of each blood spot collection; the plasma fraction was stored at À208C until analysis. DBS and plasma concentrations of canrenone, the active metabolite of K-canrenoate, were also measured in matched samples from another group of 16 patients recruited in a previous study [10] using developed and validated bioanalytical methods [11,12]. Accurate data regarding time of sampling and timing of K-canrenoate doses were recorded for each sample.…”

“…Potential models considered using the DBS dataset were classical linear 1-compartment and 2-compartment models. Pharmacokinetic parameters estimated were apparent clearance (CL/F) and apparent volume of distribution (V/F) for canrenone and the metabolic transformation rate constant (K f ) of K-canrenoate into canrenone, as described earlier [10]. CL/F and V/F were scaled, as follows, to 70 kg to facilitate comparison between the different models [14,15].…”

Potassium canrenoate in brain-dead organ donors: a randomised controlled clinical trial protocol (CANREO-PMO)

“…Very few studies are available on the impact of their administration in ICU patients. Suyagh et al investigated the pharmacokinetics of potassium canrenoate in resuscitated children but did not address the question of tolerance 43. The administration of MRAs in addition to mannitol to 56 brain-injured patients by Bilotta et al showed better potassium retention and a decrease in cardiac arrhythmias 19.…”