Learn and Apply Paradigm to Optimize Pharmacotherapy in Neonatal Abstinence Syndrome Using Pharmacometrics

Abstract

Every one hour a baby with neonatal abstinence syndrome (NAS) is born in the United States. NAS is a clinical syndrome of opiate withdrawal in infants exposed to drugs either prenatally in the form of maternal use (non-iatrogenic), or postnatally in the form of medical therapy (iatrogenic). The syndrome is comprised of a combination of central nervous system, digestive system and autonomic system abnormalities that result from uninhibited excitatory neurotransmitter release from the neurons. Between 2000 and 2009, a 3-fold increase in the use of opiate drugs among pregnant women led to an increase in NAS and associated higher health care costs. Currently, morphine is the first line pharmacotherapy for NAS. Pharmaceutical companies have no incentive to invest in therapy optimization for NAS, and the current dosing strategies vary from hospital to hospital. This research is based on a virtual consortium between the Center for Translational Medicine at the University of Maryland Baltimore, Johns Hopkins Medical Institute and Thomas Jefferson University Hospital. The purpose of this research is to optimize the morphine dosing strategy in NAS patients who require pharmacotherapy by using a pharmacometrics approach with the "learn and apply" philosophy. First, a comprehensive morphine pharmacokinetic model that accounts for prognostic factors, such as body size and age, was developed in neonates. The results suggested a uridine diphosphate glucuronic acid dependent morphine clearance during the first week of life. Second, an exposure-response (ER) relationship between morphine plasma concentrations and modified Finnegan scores was built, and the model prediction was evaluated for the primary and secondary clinical outcomes, such time-on-treatment and total morphine dose. Lastly, different morphine dosing strategies were simulated based on the ER relationship and then optimized dosing strategies were proposed. The proposed dosing strategies will minimize suffering due to the withdrawal symptoms and ultimately lead to an earlier hospital discharge.