The Pharmacokinetics and Pharmacodynamics of Buprenorphine in Neonatal Abstinence Syndrome

Abstract

Neonatal abstinence syndrome (NAS) is a condition affecting newborns that are exposed to an opioid in utero. In a randomized, controlled trial assessing the efficacy of buprenorphine and morphine in NAS, blood samples were analyzed from a subset of patients receiving buprenorphine along with NAS scores. The data were used to validate and adapt an existing model of buprenorphine in neonates and to identify relationships between buprenorphine or norbuprenorphine pharmacokinetics (PK) and efficacy or safety. The time to NAS stabilization was found to decrease with increasing buprenorphine exposure. This pharmacokinetic-pharmacodynamic (PK-PD) relationship was able to be quantified and adequately described with a mathematical model. The findings confirm a previous PK model of buprenorphine and extend the model to describe the PK of norbuprenorphine and to identify a novel PK-PD relationship of buprenorphine in NAS. This model will allow optimization of dosing strategies in future clinical trials.

Conflict of interest statement

Conflict of Interest Statement

Dr. Kraft is an unpaid consultant to Chiesi. The authors have no other conflicts of interest to disclose.

© 2018 American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1

Serum Buprenorphine PK Model Goodness-of-Fit Plots. A) Individual predictions (IPRED) vs observed values (DV). B) Population predictions (PRED) vs DV. C) Conditional weighted residuals (CWRES) vs PRED. D) CWRES vs TIME (hr).

Figure 2

Serum Norbuprenorphine PK Model Goodness-of-Fit Plots. A) IPRED vs DV. B) PRED vs DV. C) CWRES vs PRED. D) CWRES vs TIME(hr).

Figure 3

Buprenorphine-NAS PK-PD Relationship. A) Relationship of Average Buprenorphine Clearance and Time to NAS Stabilization (TNS). The size of each dot represents each neonate’s maximum NAS Score. B) Relationship between Buprenorphine AUC and NAS Severity. Each neonate included is represented by a point, which represents the maximum NAS score and AUC of buprenorphine until that time. C) Relationship between TNS and Average Buprenorphine Concentration. Each neonate included is represented by a point, which represents the TNS and average concentration of buprenorphine until that time. D) NAS Survival Analysis. This graph represents the predicted stabilization of NAS over time for a theoretical neonate at one of the 4 quartiles of buprenorphine concentration and a max NAS score of 11.

Figure 4

Buprenorphine-NAS PK-PD Model Goodness-of-Fit Plots. A) IPRED vs DV. B) PRED vs DV. C) CWRES vs PRED. D) CWRES vs time.

Figure 5

NAS Dose Simulation. A) This is a frequency polygon plot representing the prediction of when each neonate would have stabilized if given a different dose relative to the original based on simulations from the PK-PD model. B) This point range plot shows the median and 95% confidence interval of time to stabilization by dose based on the PK-PD simulation. Here, “Original” refers to the dosing performed in the study.