Dose-adjusted plasma concentrations of sublingual buprenorphine are lower during than after pregnancy

Jaime R Bastian, Huijun Chen, Hongfei Zhang, Scott Rothenberger, Ralph Tarter, Dennis English, Raman Venkataramanan, Steve N Caritis, Jaime R Bastian, Huijun Chen, Hongfei Zhang, Scott Rothenberger, Ralph Tarter, Dennis English, Raman Venkataramanan, Steve N Caritis

Abstract

Background: Buprenorphine is a Food and Drug Administration-approved maintenance therapy for opioid use disorders and is increasingly being used in pregnant women with opioid use disorders as an alternative to methadone. Dosing of buprenorphine in pregnant women is based on the regimen recommended for nonpregnant females and males. Limited data are available defining the pharmacokinetic properties of sublingual buprenorphine administered during pregnancy.

Objective: This study evaluated the impact of physiological changes associated with pregnancy on the pharmacokinetics of sublingual buprenorphine during and after pregnancy.

Study design: Pregnant women (n = 13), between 180/7 and 376/7 weeks' singleton gestation, receiving sublingual buprenorphine twice daily for opioid use disorders were studied. Pharmacokinetic-2 studies were performed between 18 and 25 weeks (n = 7), pharmacokinetic-3 studies were performed between 31 and 37 weeks (n = 11), and pharmacokinetic-P was performed 4-18 weeks postpartum (n = 10). On the day of the study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after the dose. Buprenorphine plasma concentrations were analyzed by liquid chromatography tandem mass spectrometric detection. All pharmacokinetic parameters were observed or estimated using Microsoft Excel. Statistical analyses were performed to identify significant changes in study participants' buprenorphine pharmacokinetic parameter estimates over the duration of the study. Univariate linear and generalized linear mixed models were used to investigate changes in these measures over time, some of which were log transformed for normality.

Results: Dose-normalized (plasma concentration per dose) buprenorphine plasma concentrations were significantly lower during pregnancy (pharmacokinetic-2 plus pharmacokinetic-3) than during the postpartum period (pharmacokinetic-P). Specific pharmacokinetic parameters (and level of significance) were as follows: the area under the buprenorphine plasma concentration-time curves (P < .003), maximum buprenorphine concentrations (P < .018), buprenorphine concentrations at 0 hour (P < .002), and buprenorphine concentrations at 12 hours (P < .001). None of these parameters differed significantly during pregnancy (ie, pharmacokinetic-2 vs pharmacokinetic-3). The time to maximum buprenorphine concentrations did not differ significantly between groups.

Conclusion: The dose-normalized plasma concentrations during a dosing interval and the overall exposure of buprenorphine (area under the buprenorphine plasma concentration-time curves) are lower throughout pregnancy compared with the postpartum period. This indicates an increase in apparent clearance of buprenorphine during pregnancy. These data suggest that pregnant women may need a higher dose of sublingual buprenorphine compared with postpartum individuals. The dose of buprenorphine should be assessed after delivery to maintain similar buprenorphine exposure during the postpartum period.

Keywords: buprenorphine; exposure; pharmacokinetics; plasma concentration; pregnancy.

Conflict of interest statement

Drs Bastian, Rothenberger, Tarter, English, Venkataramanan and Caritis have no conflicts to report. Ms. Chen and Zhang also report no conflicts of interest.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Figure 1. Dose-Normalized Buprenorphine Plasma Concentrations during…
Figure 1. Dose-Normalized Buprenorphine Plasma Concentrations during Pregnancy and Postpartum
The mean dose-normalized buprenorphine plasma concentration-time curves (±SD) during the 12h pharmacokinetic study visits: PK1a (n=7), PK1b (n=11) and PK2 (n=10). X axis = time in hours; Y axis = mean dosenormalized buprenorphine plasma concentrations in ng/mL per mg of buprenorphine.
Figure 2. Relationship between Trough Buprenorphine Plasma…
Figure 2. Relationship between Trough Buprenorphine Plasma Concentrations (C0) and Area Under the Plasma Concentration-Time Curve (AUC0→12)
The relationship between trough buprenorphine plasma concentrations at time 0h (C0) and area under the plasma concentration-time curve (AUC0→12) during the 12h pharmacokinetic study visits (n=28). X axis = trough buprenorphine plasma concentrations at time 0h in ng/mL; Y axis = area under the buprenorphine plasma concentration-time curve during the 12h pharmacokinetic study visits in ng*h/mL

Source: PubMed

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