Search

BackgroundThe inotropic drug levosimendan is often used as an individualized therapeutic approach perioperatively in cardiac surgery patients with cardiopulmonary bypass (CPB). Data regarding serum concentrations of levosimendan and its metabolites within this context is lacking.MethodsIn this retrospective descriptive proof-of-concept study, total serum concentrations (TSC) and unbound fractions (UF) of levosimendan and its metabolites OR-1896 and OR-1855 in cardiac surgery patients with CPB were measured using LC-ESI-MS/MS. Simulation of expected levosimendan TSC was performed using Pharkin 4.0. Serum NT-proBNP was assessed with ELISA.ResultsAfter levosimendan infusion (1.25 mg or 2.5 mg, respectively) after anaesthesia induction, a median TSC of 1.9 ng/ml and 10.4 ng/ml was determined in samples taken directly after surgery (T1). Median TSC of 7.6 ng/ml and 22.0 ng/ml, respectively, were simulated at T1. Whereas 1.1 ng/ml and 1.6 ng/ml TSC of OR-1896, respectively, was quantified the day after surgery (T2), TSC of the intermediate metabolite OR-1855 was mostly below the lower limit of quantification (LLOQ). The UF was 0.5% and 1.1% for levosimendan and 64.1% and 52.1% for OR-1896, respectively, with over half the samples being below LLOQ. NT-proBNP concentrations before surgery and T2 did not differ.DiscussionThe low TSC, UF and unchanged NT-proBNP levels in combination with high variation of serum levels between patients suggest a need for optimized dosing regimen of levosimendan combined with therapeutic drug monitoring for such an individualized approach. In addition, the differences between the measured and estimated concentrations may suggest a possible influence of CPB on levosimendan serum concentrations.

IntroductionHemoadsorption shows promising signals in organ preservation and post lung transplantation. However, its potential impact on the pharmacokinetics of immunosuppressant drugs (ID) is still unknown.MethodsIn this interventional study, CytoSorb® hemoperfusion was tested in healthy sheep (n = 5) against a sham extracorporeal circuit (n = 3). Seven different ID (tacrolimus (TAC), cyclosporin A (CYA), mycophenolate mofetil (MMF), everolimus (EVER), basiliximab (BAS), methylprednisolone (MP) and prednisolone (PRED)) were administered in clinically relevant doses and combinations. Their levels were measured repeatedly in blood samples from the extracorporeal circulation over 6 h following administration. Population pharmacokinetic modeling analysis (NONMEM® 7.5) was performed.ResultsNegligible clearance was observed for PRED and BAS. For all other substances, a saturable adsorption sub-model with linear decrease of the adsorption effect over the adsorbed amount best described the measured concentrations. The maximum absolute adsorbed amounts (95% CI) for TAC, CYA, MMF, EVER, and MP were 0.040 (0.028–0.053), 1.15 (0.39–1.91), 4.17 (2.00–6.35), 0.0163 (0.007–0.026), and 53.4 mg (20.9–85.9), respectively, indicating an adsorption of less than 5% of the daily administered dosages for all investigated substances.DiscussionIn this large animal model, CytoSorb® hemoperfusion appears to have a limited effect on the clearance of tested ID.