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Pharmacokinetics and Safety of Inhaled Oxytocin Compared with Intramuscular Oxytocin: The First Randomised Open-Label Study in Women in the Third Stage of Labour

25 Pages Posted: 5 Mar 2021

See all articles by Katarzyna Gajewska-Knapik

Katarzyna Gajewska-Knapik

Cambridge University Hospitals - Department of Obstetrics and Gynaecology

Subramanya Kumar

GSK

Amy Sutton-Cole

Cambridge University Hospitals - Department of Obstetrics and Gynaecology

Kirsten R. Palmer

Monash University - Monash Institute of Pharmaceutical Sciences

Anthony Cahn

GSK

Rachel A. Gibson

GSK

Simon Parry

GSK

Ian Schneider

Massachusetts Institute of Technology (MIT)

Annie Stylianou

GSK

Kimberley Hacquoil

GSK

Marcy Powell

GSK

Melissa Ellis

GSK

Michelle P. McIntosh

Monash University - Monash Institute of Pharmaceutical Sciences

Pete Lambert

Monash University - Monash Institute of Pharmaceutical Sciences

Tri-Hung Nguyen

Monash University - Monash Institute of Pharmaceutical Sciences

Jack Murray

Monash University - Drug Delivery, Disposition and Dynamics

Cleo Goodall

Monash University - Monash Institute of Pharmaceutical Sciences

Carl Kirkpatrick

Monash University - Monash Institute of Pharmaceutical Sciences

Sarah Siederer

GSK

Victoria L. Oliver

Monash University - Monash Institute of Pharmaceutical Sciences

More...

Abstract

Background: Intramuscular (IM) oxytocin for postpartum haemorrhage (PPH) prevention in resource-poor settings is limited by the need for cold-chain storage and skilled staff for safe injection. We compared the pharmacokinetics (PK) and safety of heat-stable oxytocin inhaled (IH) versus IM administration in women during third stage of labour (TSL). 

Methods: The phase 1, randomised, open-label clinical study (NCT02999100) was conducted across three centres in the UK and Australia. Participants (Group 1, women in TSL; Group 2, non-pregnant women of childbearing potential) were randomised 1:1 via validated GSK internal software: Group 1, oxytocin 240 IU (400 μg) IH or oxytocin 10 IU (17 μg) IM immediately after delivery; Group 2, intravenous (IV) oxytocin 5 IU (8·5 μg) and oxytocin 240 IU (400 μg) IH at two separate dosing sessions in a cross-over design. Primary endpoints included characterising oxytocin IH PK. The safety population included patients who received ≥1 dose; any PK sample obtained and analysed was included in the PK population. Additional investigations explored the validity of the PK concentration data. 

Findings: Participants were recruited between November 2016 and March 2019. In Group 1, 29 participants were randomised; 17 received IH (n=9) or IM (n=8) oxytocin. After IH and IM administration most plasma oxytocin concentrations were below quantification limits (2 pg/ml). In Group 2 (n=14), oxytocin IH concentrations remained quantifiable up to 3 hrs post dose. Adverse events were reported for: Group 1, IH n=3 (33%) and IM n=2 (25%); Group 2, n=14 (100%). No deaths were reported. 

Interpretation: Safety profiles of oxytocin IH and IM were similar; PK profiles could not be defined for oxytocin IH or IM in women in TSL, despite using a highly sensitive assay. Ex vivo investigations suggested oxytocin metabolism occurred in vivo and not during sample collection and processing. 

Trial Registration: Trial Registration Number, (ClinicalTrials.gov: NCT02999100). The study protocol can be found online (https://clinicaltrials.gov/ProvidedDocs/00/NCT02999100/Prot_000.pdf).

Funding: GlaxoSmithKline (GSK 205920; NCT02999100)

Declaration of Interest: KG-K, AS-C, KRP, PL, TN, JM, CG, CK and VLO have no conflicts to declare. SK, AC, RAG, SP, IS, AS, KH, MP, ME and SS are employees of and hold stocks in GSK.
MPM is an inventor on the patent method and formulation for oxytocin inhalation (WO2013/016754 A1 [PCT/AU2011001430]).

Ethical Approval: The study protocol was reviewed and approved by the Office for
Research Ethics Committees of Northern Ireland (UK) and the Monash Health Human Research Ethics Committee (Australia) in accordance with Good Clinical Practice (GCP) guidelines.

Suggested Citation

Gajewska-Knapik, Katarzyna and Kumar, Subramanya and Sutton-Cole, Amy and Palmer, Kirsten R. and Cahn, Anthony and Gibson, Rachel A. and Parry, Simon and Schneider, Ian and Stylianou, Annie and Hacquoil, Kimberley and Powell, Marcy and Ellis, Melissa and McIntosh, Michelle P. and Lambert, Pete and Nguyen, Tri-Hung and Murray, Jack and Goodall, Cleo and Kirkpatrick, Carl and Siederer, Sarah and Oliver, Victoria L., Pharmacokinetics and Safety of Inhaled Oxytocin Compared with Intramuscular Oxytocin: The First Randomised Open-Label Study in Women in the Third Stage of Labour. Available at SSRN: https://ssrn.com/abstract=3798543 or http://dx.doi.org/10.2139/ssrn.3798543

Katarzyna Gajewska-Knapik

Cambridge University Hospitals - Department of Obstetrics and Gynaecology ( email )

Hills Road
Cambridge, CB2 0QQ
United Kingdom

Subramanya Kumar

GSK

United Kingdom

Amy Sutton-Cole

Cambridge University Hospitals - Department of Obstetrics and Gynaecology ( email )

Hills Road
Cambridge, CB2 0QQ
United Kingdom

Kirsten R. Palmer

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Anthony Cahn

GSK

United Kingdom

Ian Schneider

Massachusetts Institute of Technology (MIT) ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Annie Stylianou

GSK

United Kingdom

Kimberley Hacquoil

GSK

United Kingdom

Marcy Powell

GSK

United Kingdom

Melissa Ellis

GSK

United Kingdom

Michelle P. McIntosh

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Pete Lambert

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Tri-Hung Nguyen

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Jack Murray

Monash University - Drug Delivery, Disposition and Dynamics

23 Innovation Walk
Wellington Road
Clayton, Victoria 3800
Australia

Cleo Goodall

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Carl Kirkpatrick

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Sarah Siederer

GSK

United Kingdom

Victoria L. Oliver

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

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