480 - Pharmacokinetics of Oral N-acetylcysteine (NAC) in Infants of Diabetic Mothers Treated with Transcutaneous Auricular Vagus Stimulation (taVNS) for Failing Oral Feeds

Poster Number: 480
Publication Number: 480.343

Sandra S. Garner, Medical University of South Carolina, Charleston, SC, United States; Dorothea D. Jenkins, Medical University of South Carolina College of Medicine, Charleston, SC, United States; Bashar W. Badran, Medical University of South Carolina College of Medicine, Charleston, SC, United States; Mark S. George, Medical University of South Carolina College of Medicine, Charleston, SC, United States; Don Wiest, Medical University of South Carolina College of Medicine, Charleston, SC, United States

Background: Infants of diabetic mothers (IDM) are at risk of poor oral feeding potentially related to exposure to hyperglycemia, CNS oxidative stress, and subsequent impairment of developing motor skills. Prior work suggests taVNS improves oral feeding in newborns; however, this novel therapy was ineffective in poorly controlled IDM with lower CNS glutathione levels. This current pilot study aims to address this gap in efficacy by adding NAC to taVNS therapy. Intravenous (IV) NAC has been safely used in infants; however, nasogastric (NG) administration is more feasible. Given the lack of available data for NG NAC in infants, evaluation of NAC serum concentrations and pharmacokinetic (PK) parameters are needed.

Objective: To determine the disposition of oral NAC following NG administration in infants receiving taVNS for failing oral feeding.

Design/Methods: Following informed consent, six IDM with failed oral feeding being considered for G-tube placement were enrolled in a pilot study of taVNS plus NAC. The first 4 infants received NAC 75 mg/kg/dose q6 hours NG as a 1:3 dilution (650 mOsm/L) with sterile water (SWI) 1 hour prior to feeds. NAC was increased to 100 mg/kg/dose q6 hours as a 1:2 dilution with SWI (870 mOsm/L) for the last 2 infants. NAC was dosed for 4 days then combined with taVNS for 10-14 days. Total NAC serum concentrations were determined by HPLC at baseline (pre-NAC dosing), steady-state trough, and at 1, 2, and 4-hours post dose on day 3-4 of therapy. PK parameter estimates were calculated using a non-compartmental modeling program.

Results: At the start of NAC dosing, mean ± SD postmenstrual age= 41 ± 1.3 weeks, postnatal age= 47 ± 9.2 days and weight= 4.146 ± 0.466 kg. Observed Cmaxss and Cminss NAC concentrations (mean ± SD) were 26.1 ± 12.2 and 7.71 ± 1.74 mcg/mL. PK parameters included t½ = 1.78 ± 0.44 hours, AUC= 58.7 ± 26.3 mcg-hr/mL, and CL= 1106.7 ± 257.4 mL/hr/kg. NAC 75 mg/kg/dose q6 hours was well tolerated without adverse effects.  Daily emesis events increased with NAC 100mg/kg/dose. No other adverse effects were observed. Conclusion(s): This is the first oral NAC PK study in infants following NG administration.  Preliminary PK estimates demonstrate a shorter t½ and more rapid CL than previously reported in neonates receiving IV NAC. NG NAC appeared to be well tolerated at the 75mg/kg dose using a 1:3 dilution. NAC serum concentrations reflected low bioavailability of oral NAC similar to previous reports in adults (4-10%). This study provides preliminary evidence for the possible use of oral NAC as an antioxidant in future controlled trials in infants.