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Optimization of buprenorphine dosing in pregnant women

Zhang, Hongfei (2019) Optimization of buprenorphine dosing in pregnant women. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The primary objective of this work was to optimize buprenorphine (BUP) dosing based on
exposure in treating opioid addiction in pregnant women. A combination of clinical
pharmacokinetic study and modeling and simulation was used to accomplish this.
The clinical study evaluated BUP pharmacokinetics (PK) during pregnancy and postpartum. Up to 3 studies were performed in each participant during 1st-, 2nd -half of pregnancy, and postpartum.
At each study visit, multiple blood samples and specific pharmacodynamics measurements were
collected. Plasma concentrations of BUP were quantified using UPLC-MS/MS. In this study BUP
exposure was lower during pregnancy compared to postpartum.
A physiologically-based pharmacokinetic (PBPK) model of intravenous and sublingual BUP was
developed and verified using 14 independent BUP PK studies. This PBPK model predicted
decreased BUP exposure during pregnancy compared to postpartum, consistent with the
observations from the clinical study.
Non-linear mixed effects modeling using a first-order conditional estimation with interaction to
analyze changes in BUP PK in pregnant women was conducted. Buprenorphine PK data were
well-characterized by a two-compartment model with first-order absorption with enterohepatic
recirculation and first-order elimination. The model estimated population apparent clearance
(CL/F) of BUP in a typical pregnant woman was 469 L/h. Pregnancy was associated with a 1.64
folds increase in CL/F of BUP compared to postpartum period. A pharmacodynamic (PD) analysis
showed that the average area under curves of COWS scores during pregnancy were significantly
greater than postpartum period following administration of BUP, which is consistent with the
observed lower buprenorphine exposure during pregnancy. The relationship between pupillary
diameters and BUP concentration was described by a sigmoidal Emax model with a hypothetical
effect compartment. The calculated IC50 of BUP concentration for pupillary diameter changes was
not significantly different during pregnant and postpartum, suggesting that there may not be any
significant change in the sensitivity and /or number of µ-opioid receptors in the brain in pregnant
women compared to non-pregnant women.
Overall, the clinical observations and the two different modeling approaches demonstrated that
BUP exposure is decreased during pregnancy and this alteration in BUP exposure is associated a
decreased response to BUP in pregnancy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zhang, Hongfeihoz24@pitt.eduhoz240000-0003-1087-8186
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVenkataramanan, Ramanrv@pitt.edurv
Committee MemberCaritis,
Committee MemberPoloyac, Samuelpoloyac@pitt.edupoloyac
Committee MemberBeumer, Janbeumerjh@upmc.edujhb11
Committee MemberWang,
Date: 8 August 2019
Date Type: Publication
Defense Date: 18 April 2019
Approval Date: 8 August 2019
Submission Date: 8 August 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 294
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Buprenorphine, opioids, pregnant women, pharmacokinetics, PBPK, population pharmacokinetic modeling
Date Deposited: 08 Aug 2019 19:11
Last Modified: 08 Aug 2020 05:15


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