A phase 1 evaluation of inhaled oxytocin: Physiologically-based pharmacokinetic model informed dosing of a novel heat-stable oxytocin delivery system.

AIM: To develop and validate a physiologically-based pharmacokinetic (PBPK) model enabling inhaled oxytocin dose selection for clinical evaluation. Subsequently, to conduct a phase 1 study investigating the pharmacokinetics and safety of selected doses of an optimized inhaled oxytocin product in healthy, non-pregnant female participants.

METHOD: A general PBPK model for inhaled oxytocin in non-pregnant female participants was developed with the ability to estimate clinical exposure for new devices and deposition characteristics. This was used to select the oxytocin dose range for a randomized, single-centre, partially single-blind, placebo-controlled, fixed-sequence phase 1 study in comparison to standard of care injectable doses in a part cross-over design. Participants received increasing inhaled oxytocin doses (150 μg, 300 μg, 600 μg and 900 μg) in single and/or repeat dose regimens. The primary endpoints were pharmacokinetic characteristics and local tolerability following inhaled dosing.

RESULTS

Fifteen of 20 randomized participants completed the study. The pharmacokinetics following inhaled oxytocin administration were consistent with intramuscular dosing with the 150 μg (Cmax = 77 pg/mL, AUC0-inf = 2488 min.pg/mL) and 600 μg (Cmax = 398 pg/mL, AUC0-inf = 14 792 min.pg/mL) inhaled oxytocin doses bracketing the 10 IU intramuscular doses (Cmax = 197 pg/mL, AUC0-inf = 8560 min.pg/mL). Repeat dosing of inhaled oxytocin was well-tolerated, and no significant treatment-related adverse events or clinical findings were reported. The PBPK model accurately predicted key PK parameters within two-fold of the observed values.

CONCLUSION

Further development of inhaled oxytocin as an innovative product to address preventable postpartum haemorrhage in low-resource settings is warranted.

TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry (ACTRN12622001077752p) registered 04/08/2022.