Background Buprenorphine is an FDA-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 non-pregnant females and males. Limited data are available defining the pharmacokinetic (PK) properties of sublingual (SL) buprenorphine administered during pregnancy. Objective This study evaluated the impact of physiological changes associated with pregnancy on the PK of sublingual buprenorphine during and after pregnancy. Study Design Pregnant women (N=13), between 18 0/7 and 37 6/7 weeks’ singleton gestation, receiving sublingual buprenorphine twice daily for opioid use disorders were studied. PK-2 studies were performed between 18–25 weeks (N=7), PK-3 studies were performed between 31–37 weeks (N=11), and PK-P was performed 4–18 weeks postpartum (N=10). On the day of study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8 and 12h post-dose. Buprenorphine plasma concentrations were analyzed by LCMS-MS. All PK 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 employed to investigate changes in these measures over time, some of which were log transformed for normality. Results Dose-normalized (plasma concentration/dose) buprenorphine plasma concentrations were significantly lower during pregnancy (PK-2 + PK-3) than during the postpartum period (PK-P). Specific PK parameters (and level of significance) were as follows: the area under the BUP plasma concentration-time curves (AUC0→12, p<0.003), maximum BUP concentrations (Cmax, p<0.018), average BUP concentrations (Cavg, p<0.003), BUP concentrations at 0h (C0, p<0.002) and BUP concentrations at 12h (C12, p<0.001). None of these parameters differed significantly during pregnancy (ie PK-2 vs PK-3). The time to maximum BUP concentrations (Tmax) did not differ significantly between groups. Conclusion The dose-normalized plasma concentrations during a dosing interval and the overall exposure of BUP (AUC0→12) are lower throughout pregnancy compared to the postpartum period. This indicates an increase in apparent clearance of BUP during pregnancy. These data suggest that pregnant women may need a higher dose of sublingual buprenorphine compared to postpartum individuals. The dose of buprenorphine should be assessed after delivery to maintain similar buprenorphine exposure during the postpartum period.

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Background Dose-adjusted plasma concentrations of buprenorphine are significantly decreased during pregnancy compared to the non-pregnant state. This observation suggests that pregnant women may need a higher dose of buprenorphine than non-pregnant individuals in order to maintain similar drug exposure (plasma concentrations over time after a dose). The current dosing recommendations for buprenorphine during pregnancy address the total daily dose of buprenorphine to be administered but the frequency of dosing is not clearly addressed. Based on buprenorphine’s long terminal half-life, once daily or twice daily dosing has generally been suggested. Objective To assess the impact of dosing frequency on buprenorphine plasma concentration time course during pregnancy. Study Design We have utilized three data sources to determine an optimal frequency for dosing of buprenorphine during pregnancy: data from a pharmacokinetic study of 14 pregnant and post-partum women on maintenance buprenorphine in a supervised clinical setting; data from pregnant women attending a buprenorphine clinic; and data from a physiologically based pharmacokinetic (PBPK) modeling of buprenorphine pharmacokinetics in non-pregnant subjects. Results Among the fourteen women participating in the pharmacokinetic study during and after pregnancy, plasma concentrations of buprenorphine were < 1ng/ml (the theoretical concentration required to prevent withdrawal symptoms) for 50–80% of the 12 hour dosing interval while at steady state. Among 62 women followed in a opioid agonist treatment program, where dosing frequency is determined in part by patient preference, 10 (16 %) were on once daily dosing, 10 (16%) were on twice daily dosing, 28 (45%) were on thrice daily dosing and 14 (23%) were on four times daily dosing. A physiologic based pharmacokinetic (PBPK) model in non- pregnant subjects demonstrated that dosing frequency impacts the duration over which the plasma concentrations are below a specified plasma concentration threshold. Conclusion(s) A more frequent dosing interval i.e. TID or QID dosing may be required in pregnant women to sustain plasma concentrations above the threshold of 1ng/ml to prevent withdrawal symptoms and to improve adherence.

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