Impact of Pregnancy on Buprenorphine Pharmacokinetics and Pharmacodynamics

Currently, the standard of care for an opioid-dependent pregnant woman in most institutions
is methadone, however, buprenorphine (BUP) is also used for this indication, as it is
FDA-approved for opioid addiction although not specifically for pregnant women. There has
been increasing evidence that BUP may have comparable efficacy to methadone, and may have
fewer severe neonatal complications especially neonatal abstinence syndrome (NAS) and
decreased severity of adverse reactions. The dosing of BUP currently is based on studies in
men and non-pregnant women (adjusted to the patient's symptomatology using the Clinical
Opiate Withdrawal (COW) score, some of which is subjective and some based on objective
physiological parameters) and limited animal data that related plasma concentrations of BUP
to the degree of saturation of the µ receptor in the brain.

The study team will define the pharmacokinetics and limited pharmacodynamics of BUP in early
and late pregnancy and the postpartum period and determine what contributes to the variation
in plasma concentrations and response and will also relate plasma concentrations of BUP and
its major metabolites to physiologic parameters that can be used to gauge the amount of drug
in mother's plasma. It is expected to demonstrate that higher doses of BUP are needed
throughout pregnancy and that the dosing regimen can be adjusted using patient covariates and
biophysical measurements in addition to the COW scores.

Inclusion Criteria:

- Age between 18 - 45 years

- Currently on a stable two, three, four, or five times daily dose of sublingual BUP

- Willingness to participate in at least one pharmacokinetic(PK)/pharmacodynamics study
either during pregnancy or in postpartum*

- Gestational age < 19 6/7 weeks *

- Singleton gestation

- Able to give informed consent and undergo study procedures

- Willing to have urine samples screened for the presence of alcohol, barbiturates,
opiates, cocaine (or metabolites), benzodiazepines, synthetic opioids and
phencyclidine

- Requirement applies only to those subjects in the PK study

Exclusion Criteria:

- Major fetal anomalies or malformations

- HIV or AIDS

- Comorbid dependence on benzodiazepines or other central nervous system depressants
(including anti-seizure medications)

- Taking medication known to interfere with buprenorphine metabolism

- Active or chronic suicidal or homicidal ideation or attempts

- Elevated liver enzymes (AST, alanine aminotransferase (ALT) > 2 times normal) *

- Creatinine > 1.5 mg/dl *

- Delivery at other institution where outcome data or samples cannot be obtained on
mother and baby

- Active use of non- prescribed opiates/opioids detected during the urine drug screen
performed within 1 week prior to each PK visit *

- Hematocrit <28 *

- Requirement applies only to those subjects in the PK study

There are several parts to this study and subjects may participate in the PK study and/or
one or more procedures other than the PK study. All parts of the study (Parts A-E) are
described in the attached protocol.