Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome

Rena Eudy-Byrne, Nicole Zane, Susan C Adeniyi-Jones, Marc R Gastonguay, Ana Ruiz-Garcia, Gagan Kaushal, Walter K Kraft, Rena Eudy-Byrne, Nicole Zane, Susan C Adeniyi-Jones, Marc R Gastonguay, Ana Ruiz-Garcia, Gagan Kaushal, Walter K Kraft

Abstract

Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up-titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up-titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half-maximal effective concentration (EC50 ) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model-based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.

Conflict of interest statement

The authors declared no competing interests for this work.

© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1
FIGURE 1
Dosing algorithm used in Blinded Buprenorphine OR Neonatal morphine solution (BBORN) and Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE) trials
FIGURE 2
FIGURE 2
Clinical data used in model‐based analysis for BBORN (Blinded Buprenorphine OR Neonatal morphine solution) and BPHORE (Buprenorphine Pharmacometric Open Label Research study of Drug Exposure) studies
FIGURE 3
FIGURE 3
Graphical depiction of endpoints investigated in adaptive dose simulations. Time to stabilization (TTS) is the time from first dose until maximum dose was reached. Time to wean (TTW) is the time from first dose until weaning (weaning was defined as down titration as a result of the sum of the 3 previous MOTHER neonatal abstinence syndrome (NAS) scores being less than 18 and no up‐titrations within 48 h) and can only be reached if stabilization is reached, first. Time to cessation (TTC) is the time from start of weaning until dose was within 10% of initial dose and can only be reached if time to wean ()TTW is reached, first
FIGURE 4
FIGURE 4
Kaplan‐Meir plots for simulated time to event time to stabilization (TTS) are shown at different initial dose levels and at a 25% up‐titration rate. + denotes censoring. The table below the plot summarizes the estimated percentage of patients who have not reached stabilization stratified by starting dose
FIGURE 5
FIGURE 5
Kaplan‐Meir plots for the simulated time to event time to wean (TTW) are shown at different initial dose levels and at a 25% up‐titration rate. “+” denotes censoring. The table below the plot summarizes the estimated percentage of patients who have not reached weaning stratified by starting dose
FIGURE 6
FIGURE 6
Kaplan‐Meir plots for the simulated time to event time to cessation (TTC) are shown at different dose levels and at a 10% weaning rate. “+” denotes censoring. The table below the plot summarizes the estimated percentage of patients who have not reached cessation stratified by starting dose

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