Buprenorphine Pharmacometric Open Label Research Study of Drug Exposure

The overall rationale for this study is to explore new dose regimens in a small number of
patients. There is evidence from pharmacometric models with dose simulation that suggest
there is room for improvement in buprenorphine dosing. This study will explore these doses.
While the endpoint will be primarily pharmacokinetic, it is likely that the revised dose
regimen will be more effective and thus holds the potential for benefit for those infants
participating. This information will be used to feed back to the model and generate
rationally derived, optimal doses to be tested in subsequent efficacy trials.

The neonatal abstinence syndrome (NAS) is a set of signs of withdrawal in an infant with in
utero exposure to opioids. Cardinal manifestations include increased muscle tone, autonomic
instability, irritability, poor sucking reflex, gastrointestinal symptoms, and impaired
weight gain. All infants are treated with non-pharmacologic methods such as swaddling,
rooming in with mother and minimization of stimuli. Despite these measures, ~50% of infants
require pharmacologic treatment to ensure proper growth and development. While the optimal
pharmacologic treatment for NAS has not been identified, expert review identifies an opioid
as the primary therapy. In the US 80% of infants are treated with morphine and 20% with
methadone. Sublingual buprenorphine has been demonstrated to be safe and effective in an open
label phase 1 clinical trial conducted by the Thomas Jefferson University Team [NCT00521248].
These data were used to plan the BBORN (Blinded Buprenorphine OR Neonatal morphine solution)
clinical trial [NCT01452789] comparing buprenorphine to morphine for NAS. BBORN demonstrated
a 40% reduction in length of treatment compared to morphine in a double blind fashion (New
England Journal of Medicine, June 2017). The external validity of this finding has been
supported by retrospective examination of buprenorphine used in a treatment paradigm at the
University of Cincinnati Medical Center, with a reduction in length of treatment of ~30% in
>200 infants.

Dose selection for both the phase 1 trial and the efficacy trial (BBORN) were empirically
derived. A population pharmacokinetic model for buprenorphine in NAS has been published by
our group. In addition a pre-specified endpoint for the BBORN trial was a pharmacokinetic
analysis of buprenorphine. A pharmacokinetic/pharmacodynamic model from the BBORN study has
been published (Clinical Pharmacology and Therapeutics, March 2018). The time to control of
symptoms was directly tied to buprenorphine exposure, which itself appeared to be driven
primarily by clearance. Among the strengths of pharmacometric models is the ability to
simulate in silico many potential dose regimens. In this manner, a dose regimen can be chosen
that is more likely to be in the desired range of concentrations. This approach also allows
for incorporation of covariates of drug exposure or response to treatment. This is much safer
and efficient than the traditional approach of choosing an empiric dose that would need to be
tested in clinical trial. An ideal dose would quickly reach this exposure while maintaining a
good safety margin. There was no evidence of decline in respiratory rate in infants treated
with higher doses of buprenorphine compared to lower doses, or those treated with
buprenorphine compared to those treated with morphine. This may allow a higher initial dose
to more quickly reach therapeutic buprenorphine concentrations. This ultimately could lead to
shorter lengths of treatment and stay, though achieving this goal is outside of the scope of
the current proposed project.

In summary, buprenorphine at the dose and schedule used in prior clinical trials has been
demonstrated to be safe and effective. The goal of the proposed study is to simulate a dose
of sublingual buprenorphine for NAS using pharmacometric modelling techniques. This dose will
be tested in infants requiring treatment for NAS. Pharmacokinetic samples would be collected
and used to confirm and refine the pharmacokinetic model. The proposed study would allow
broad examination and refinement of the exposure/response relationship. This optimized dose
could later be used in an efficacy trial.

Inclusion Criteria:

1. ≥ 36 weeks gestation

2. Exposure to opioids in utero

3. Demonstration of signs and symptoms of neonatal abstinence syndrome requiring
pharmacologic treatment

Exclusion Criteria:

1. Major congenital malformations and/or intrauterine growth retardation, defined as
birth weight <2000 gm

2. Medical illness requiring intensification of medical therapy. This includes but is not
limited to suspected sepsis requiring antibiotic therapy.

3. Hypoglycemia requiring treatment with intravenous dextrose

4. Bilirubin >20 mg/dL (The need for phototherapy is not exclusionary)

5. Inability of mother to give informed consent due to co-morbid psychiatric diagnosis