Pharmacokinetics of buprenorphine in pregnant sheep after intravenous injection

Abstract

Buprenorphine is a semi‐synthetic opioid, widely used in the maintenance treatment for opioid‐dependent pregnant women. Limited data exist on the pharmacokinetics of buprenorphine in pregnancy. We conducted a pharmacokinetic study to determine the pharmacokinetics of intravenous buprenorphine in pregnant sheep. Fourteen pregnant sheep in late gestation received 10 µg/kg of buprenorphine as an intravenous bolus injection. Plasma samples were collected up to 48 h after administration. Buprenorphine and its metabolite, norbuprenorphine, were quantified from plasma using a LC/MS/MS method, with lower limits of quantification of 0.01 µg/L and 0.04 µg/L for buprenorphine and norbuprenorphine, respectively. The pharmacokinetic parameters were calculated using noncompartmental analysis. The pharmacokinetic parameters, median (minimum−maximum), were C max 4.31 µg/L (1.93–15.5), AUC inf 2.89 h*µg/L (1.72–40.2), CL 3.39 L/h/kg (0.25–6.02), terminal t½ 1.75 h (1.07–31.0), V ss 8.04 L/kg (1.05–49.3). Norbuprenorphine was undetected in all plasma samples. The median clearance in pregnant sheep was higher than previously reported for nonpregnant sheep and human (male) subjects. Our sensitive analytical method was able to detect long terminal half‐lives for six subjects, and a wide between‐subject variability in the study population. Significance statement: Buprenorphine is widely used for the treatment of opioid use disorder in pregnancy. However, limited data exist on the pharmacokinetics of buprenorphine during pregnancy. As this type of study cannot be done in humans due to ethical reasons, we conducted a study in pregnant sheep. This study provides pharmacokinetic data on buprenorphine in pregnant sheep and helps us to understand the pharmacokinetics of the drug in humans.

Supporting Prospective Pregnancy Trials via Modeling and Simulation: Lessons From the Past and Recommendations for the Future

“…Another example is understanding the PK of buprenorphine in pregnant sheep after intravenous administration, which could be extrapolated to supplement the limited PK data available in pregnant women. 23 Non-compartmental analysis is often employed across different therapeutic areas. [24][25][26][27][28][29][30][31][32] This type of analysis requires rich (intensive) sampling and is not often feasible beyond Phase 1 and certainly not in populations such as pediatrics and pregnant.…”

“…For example, human and mouse trophoblast stem cell signaling pathways are different. Another example is understanding the PK of buprenorphine in pregnant sheep after intravenous administration, which could be extrapolated to supplement the limited PK data available in pregnant women 23 …”