Abstract

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

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

Results: Fifteen of 20 randomized participants completed the study. The pharmacoki-netics following inhaled oxytocin administration were consistent with intramusculardosing with the 150 μg (C max = 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 bracket-ing 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 accuratelypredicted key PK parameters within two-fold of the observed values.

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

By Pete Lambert, Carl M. J. Kirkpatrick, Rory Marriott, Siladitya Ray Chaudhuri, David Polidori, Bart Remmerie, Michelle P. McIntosh