ABSTRACT 347: DISEASE SEVERITY DETERMINES PHARMACOKINETICS OF PHENOBARBITAL IN CRITICALLY ILL NEONATES WITH OR WITHOUT WHOLE BODY HYPOTHERMIA.

Background and aims: Induction of whole body hypothermia (HT) in neonates results potential changes in absorption, distribution and elimination (ADME) of phenobarbital (PHE). Aims: to evaluate individual pharmacokinetics (PK) of PHE and determine the impact of comorbidities on PK parameters. Methods: Prospective evaluation of neonates treated for seizures and/or hypoxic-ischemic encephalopathy (HIE) undergoing HT (target temperature range 33°C-34°C). Open label PHE loading dose of 10 - 40 mg/kg, maintenance dose of 2 - 5 mg/kg every 12 h intravenously. Plasma profile of PHE was determined using a validated HPLC method. Clearance (Cl), volume of distribution (Vd) of PHE were estimated using a non-compartment analysis. Results: are reported as mean (SD) and Student´s t test analysis, Pearson chi-square test, and multiple regression analysis. Results: Fifty eight neonates were treated: group1 (14/58) PHE and HT; group2 (12/58,) PHE + phenytoin and HT, group3 (18/58) PHE or with PHE + phenytoin for seizures without HT, group4 (14/58) PHE for seizures control without HT. In group1 the mean (SD) predicted total CL1 was 0.0054 (0.0016) L/kg.h1; Vd1 0.529 (0.163) L/kg. In group2 CL2 was 0.0016 (0.0013) L/kg.h-1; Vd2 0.517 (0.083) L/kg; in group3 CL3 was 0.0011 (0.0010) L/kg.h-1; Vd3 0.097 (0.095) L/kg; in group4 CL4 was 0.0027 (0.0017) L/kg.h-1; Vd4 0.409 (0.228) L/kg. CL was significantly reduced (gr2 vs gr1, p=0.043; gr3 vs gr4; p=0.013). Vd was significantly reduced (gr3 vs gr4; p=0.013). Conclusions: In neonates with comorbidities treated with or without HT PK of PHE should be evaluated to optimize the therapeutic effect.