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 18–45 years. Subjects initially received IM oxytocin 10 international units (IU) on day 1, IH placebo on day 2, and IH oxytocin 50 μg 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, 600 μg). PK was assessed by comparing systemic exposure (maximum observed plasma concentration, area under the concentration-time curve, and plasma concentrations at 10 and 30 min 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 400 μg most closely matched IM oxytocin 10 IU. 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.

Highlights

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  First-in-human study of a heat-stable, dry powder oxytocin formulation for oral inhalation using a simple inhaler device

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  Data suggest that similar oxytocin systemic exposure can be achieved with intramuscular and inhaled administration routes.

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  This could provide an effective delivery system for prevention of postpartum hemorrhage in women in resource-poor settings.

Intramuscular or intravenous oxytocin is the gold standard preventative therapy for postpartum hemorrhage (PPH). However, the utility of intramuscular oxytocin in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. The Innovation Countdown 2030 Initiative has estimated that the introduction of alternative, heat-stable formulations of oxytocin could prevent 146,000 maternal deaths over a period of 8 years. This study provides encouraging preliminary evidence that inhaled oxytocin can be delivered using a heat-stable dried powder for inhalation with no safety concerns. Establishing the clinical utility of this potential medicine will require further studies.