Background and aims LEVO is a novel inodilator developed to treat heart failure. Biotransformation of LEVO in the intestinal tract gives rise to intermediate metabolites with prolonged beneficial haemodynamic effects. There are no data on LEVO PKs in neonates. We aim to investigate LEVO and intermediate metabolites PKs in newborns undergoing CPB.
Methods Eleven infants received step-wise dose increase of LEVO (0.10, 0.15, 0.20 mg/k/min) delivered as i.v. continuous infusion, starting before CPB up to 48h post-surgery. Eleven blood samples per subject were collected up to day 14 post-infusion started. Samples were quantified by HPLC-MS/MS. Non-compartmental methods were used for PK parameters. Median (IQR) values are reported.
Results Area under the curve (AUC, ng*h/mL) OR-1855 plasma concentration [1717.10 (930.38–3756.41)] was 2.3- and 8.2-fold higher than LEVO [742.10 (527.23–1046)] and OR-1896 [209.78 (99.54–275.36)], respectively. LEVO clearance (CL, L/h/k) was 0.67 (0.44–1.0). OR-1855 maximum concentration (Cmax, ng/ml) was 5.2-fold higher than OR-1896 [18.5 (10.44–33.25) vs. 3.58 (2.94–4.38)]. OR-1896 and OR-1855 Cmax were respectively achieved 2h before and 120h after LEVO infusion stopped. LEVO CL increased and AUC decreased with postnatal age, explaining 66.23% (p=0.023) and 34.51% (p=0.047) of their respective variance. LEVO AUC and pre-surgery antibiotics explained 38.89% (p=0.016) and 26.68% (p=0.035) of OR-1855 AUC variance, respectively. Use of additional diuretics to furosemide explained 27.21% (p=0.025) of OR-1896 AUC. No other covariates influenced LEVO or metabolites PKs.
Conclusions This study describes the pharmacokinetic profile of LEVO and intermediate metabolites in newborns as well as covariates explaining a significant part of their variance.