Pharmacokinetic assessment of alprazolam-induced neonatal abstinence syndrome using physiologically based pharmacokinetic model
2019
Abstract Sustained benzodiazepine use during pregnancy can induce neonatal abstinence syndrome (NAS). In this study, the association between NAS and plasma
alprazolamconcentration was examined using the measured neonatal concentrations in the time series as well as simulated plasma concentrations of pregnant woman and neonate by physiologically based pharmacokinetic (PBPK) modeling. A neonate born to a mother taking
alprazolamdaily throughout pregnancy exhibited symptoms such as
apneaand vomiting from 9 h to 4 days after birth. Finnegan score was 7 at birth and decreased to 0 by day 4.
Apneaimproved by 24 h post-delivery and gastrointestinal symptoms disappeared by day 4. The plasma
alprazolamconcentration in the neonate was 15.2 ng/mL immediately after birth and gradually decreased over 3 days. Measured neonate and estimated maternal plasma
alprazolamconcentrations were within the 90%
prediction intervalsof each concentration by PBPK simulation using “pregnancy” and “pediatrics” population parameters including Simcyp population-based ADME simulator. In conclusion, NAS such as
apneaand digestive symptoms disappeared in parallel with the decrease of the neonate’s plasma
alprazolamconcentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data.
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