Since IM oxytocin reaches its site of action the uterus
Since IM oxytocin reaches its site of action, the uterus, via the plasma it is proposed that demonstrating a comparable plasma drug profile following IH and IM routes of administration allows for extrapolation from the extensive clinical safety and efficacy data for the approved IM oxytocin product for the prevention of PPH to the IH product. Overall, the shape of the plasma PK profile following IH administration was similar to that following IM administration. Both administration routes demonstrated rapid resperidone cost of oxytocin into plasma (median tmax 8–20min), followed by rapid elimination, with an apparent t1/2 consistent across administration routes. Oxytocin exposure with IH oxytocin was approximately linear over the 200–600μg dose range, while dose normalized exposure at 50μg was lower. Lower exposure (AUC) following 50μg may in part reflect censoring of the PK profile; since concentrations of oxytocin fell below the lower limit of quantification in at least half the subjects by 1h post-dose. The dose range of IH oxytocin assessed in this study was predicted to cover the therapeutic range and the 400μg dose of IH oxytocin was found to result in systemic exposure most similar to that of IM oxytocin 10IU; with the rate and extent of absorption of oxytocin into plasma most consistent with that observed following IM oxytocin 10IU (as reflected by the geometric mean ratio for IH versus IM for the PK parameters Cp10, Cp30, and AUC[0–3h]). However, between subject variability tended to be higher following IH compared with IM dosing.
This study provides important preliminary evidence in humans that a heat-stable, dry powder IH formulation has the potential to deliver a systemic profile of oxytocin comparable with parenteral (IM) administration, although important questions remain. This study was conducted in healthy non-pregnant women. The physiological changes associated with pregnancy, including higher levels of circulating oxytocin, increased renal/hepatic blood flow, increased blood/plasma volume and cardiac output, increased total body water, and decreased plasma proteins have the potential to alter the PK of oxytocin (Sheffield et al., 2014; Prevost et al., 2014). However, unless affecting lung absorption, these factors would be expected to affect IH and IM administration equally. To determine whether there are differences in PK between pregnant and non-pregnant women, investigations are ongoing to study women in third stage of labor. We conducted an enabling study in women in the third stage of labor and observed that their inspiratory profile using the ROTAHALER™ inhaler device was not materially different from non-pregnant volunteers (Wong et al., 2016). However, any effect of altered inspiratory profile during labor on the PK of IH oxytocin will need to be determined in future investigations in women in the third stage of labor. In this study IH oxytocin was not associated with evidence of respiratory tract irritancy, but the information is preliminary; an evaluation of tolerability in smokers and people with asthma would form part of future investigations.
The device for delivery was selected on the basis of its simplicity. The capsule is pushed into the device, the device twisted once to break open the capsule and the powder IH. There has been over 20years of experience with this type of device, which has optimized and simplified the design to support practical use. Effective delivery in the field will depend on appropriate educational materials and training; in use studies are planned as part of the development program.
Role of the Funding Source GSK, the funder of this study (NCT02542813), was involved in the study design, data collection, data analysis, data interpretation, and writing of the study report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit. The McCall MacBain Foundation and Grand Challenges Canada (funded by the Government of Canada) provided funding support to the project team at Monash University and had no role in the design, conduct, interpretation, or reporting of this study.