Safety, Tolerability and Pharmacokinetics of Single Doses of Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-blind, Phase 1 Study

Abstract

Background: The utility of intramuscular (IM) oxytocin for the prevention of postpartum hemorrhage in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. We evaluated the safety, tolerability and pharmacokinetics (PK) of a heat-stable, inhaled (IH) oxytocin formulation.

Methods: This phase 1, randomized, single-center, single-blind, dose-escalation, fixed-sequence study (NCT02542813) was conducted in healthy, premenopausal, non-pregnant, non-lactating women aged 18-45years. Subjects initially received IM oxytocin 10 international units (IU) on day 1, IH placebo on day 2, and IH oxytocin 50μg on day 3. Subjects were then randomized 4:1 using validated GSK internal software to IH placebo or ascending doses of IH oxytocin (200, 400, 600μg). PK was assessed by comparing systemic exposure (maximum observed plasma concentration, area under the concentration-time curve, and plasma concentrations at 10 and 30min post dose) for IH versus IM oxytocin. Adverse events (AEs), spirometry, laboratory tests, vital signs, electrocardiograms, physical examinations, and cardiac telemetry were assessed.

Findings: Subjects were recruited between September 14, 2015 and October 12, 2015. Of the 16 subjects randomized following initial dosing, 15 (IH placebo n=3; IH oxytocin n=12) completed the study. IH (all doses) and IM oxytocin PK profiles were comparable in shape. However, systemic exposure with IH oxytocin 400μg most closely matched IM oxytocin 10IU. Systemic exposure was approximately dose proportional for IH oxytocin. No serious AEs were reported. No clinically significant findings were observed for any safety parameters.

Interpretation: These data suggest that similar oxytocin systemic exposure can be achieved with IM and IH administration routes, and no safety concerns were identified with either route. The inhalation route may offer the opportunity to increase access to oxytocin for women giving birth in resource-poor settings.

Keywords: Inhaled oxytocin; Phase 1; Placebo; Postpartum hemorrhage.

Copyright © 2017. Published by Elsevier B.V.

Figures

Fig. 1

Study design. IH = inhaled; IM = intramuscular; IU = international units.

Fig. 2

Trial profile. *Ineligible subjects: did not meet inclusion/met exclusion criteria (n = 5); subject withdrew consent (n = 2); reserve, not used (n = 2); investigator discretion (n = 1). †One subject was withdrawn at the investigator's discretion due to inability to cannulate. She received IM oxytocin only. This subject was replaced and assigned the same randomization sequence, thus, a total of 16 subjects were randomized; ‡subjects had received IM oxytocin and IH oxytocin (50 μg) in the initial dosing session. IH = inhaled; PK = pharmacokinetics.

Fig. 3

Median oxytocin plasma concentration-time profile on A) non-logarithmic and B) logarithmic scales (PK population). IH = inhaled; IM = intramuscular; IU = international units; LLQ = lower limit of quantification; PK = pharmacokinetic.