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


METHODS
Pregnant women (n = 13), between 180/7and 376/7weeks' 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 On the day of the study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after the dose.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.


CONCLUSIONS
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.
Divisions of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. Electronic address: jbas22@gmail.com.
Jaime R
JR
Bastian
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
Huijun
H
Chen
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
Hongfei
H
Zhang
Center for Research on Healthcare Data Center, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
Scott
S
Rothenberger
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
Ralph
R
Tarter
Divisions of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
Dennis
D
English
Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
Raman
R
Venkataramanan
Divisions of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
Steve N
SN
Caritis
D000286:Administration, Sublingual; D000328:Adult; D002047:Buprenorphine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D009292:Narcotic Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D058850:Opiate Substitution Treatment / Q000379:methods*; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D049590:Postpartum Period / Q000378:metabolism*; D011247:Pregnancy / Q000378:metabolism*; D011248:Pregnancy Complications / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D009292:Narcotic Antagonists; D002047:Buprenorphine
buprenorphine; exposure; pharmacokinetics; plasma concentration; pregnancy
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