Background Current dosage regimen of aminophylline is similar in both Appropriate for Gestational Age (AGA) and Small for Gestational Age (SGA) preterm neonates.¹ In contrast with AGA babies, SGA babies handle drugs in different way. However, developing countries like India has significant proportion of Growth Restricted/SGA babies. Hence, there is a need to develop appropriate dosage regimen in this population. Objective of the current study was set to develop and qualify the Population-Pharmacokinetic (PPK) model for aminophylline in premature neonates in Indian population.²

Methods Aminophylline-treated neonates with IV loading dose of 5 mg/kg followed by maintenance dose of 1.5 or 2 mg/kg 8th hourly for Apnoea of Prematurity (AOP) were included. Any other conditions for secondary causes were excluded. Blood samples were collected by adopting sparse sample scheme and estimated by LCMS-MS. PPK model was developed with appropriate covariates.³ Data was analysed by NONMEM vesion 7.3. Non-parametric bootstrap procedure and Visual Predictive Check (VPC) was used to qualify the developed model.

Results One compartment, first-order structured model was fitted to the dataset containing 454 observations from 107 neonates. PPK parameters were represented as model estimated values and variability was depicted as% Co-efficient of variation (%CV). Typical population value of CL was 0.011 L/hour with inter-individual variability (IIV) of 59% and V was 0.332 (L/kg) with 31% IIV. Residual error was found to be 19%. Only postnatal age (PNA) had significant effect on V which was assessed by forward addition and backword elimination regression model.

Conclusion AGA and SGA had no influence on PK parameters. However, PNA showed to have significant influence on V. Developed nomogram based on the qualified model may be effective and safe for aminophylline therapy in preterm neonates with apnoea.

References

1. Shivakumar M, Jayashree P, Najih M, Lewis LES, Bhat Y R, Kamath A, et al. Comparative Efficacy and Safety of Caffeine and Aminophylline for Apnea of Prematurity in Preterm (≤34 weeks) Neonates: A Randomized Controlled Trial. Indian Pediatr 2017 Apr 15;54(4):279–83.

2. U S Department of Health and Human Services, FDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER): Guidance for Industry Population pharmacokinetics; 1991; Feb CP1, 35 pages.

3. Ette EI, Sun H, Ludden TM, Balanced designs in longitudinal Population Pharmacokinetic studies. Journal of Clinical Pharmacology 1998 May; 38(5):417–423.

Disclosure(s) Nothing to disclose