Plasma pharmacokinetics of intravenous and intranasal oxytocin in nonpregnant adults.

BACKGROUND

The development of oxytocin as a therapeutic agent outside of obstetrics has been hampered by antibody-based assays that lack specificity, leading to inconsistent and incompletely reported pharmacokinetic models to guide drug dosing. This study describes the population plasma pharmacokinetics of intravenous and intranasal oxytocin using a sensitive and specific liquid chromatography-tandem mass spectroscopy (LC/MS) assay.

METHODS

Two studies in healthy adult men and nonpregnant women were performed, the first with intravenous oxytocin 16.7 μg over 1 or 10 min and the second with intravenous oxytocin 13.7 μg over 30 min and, on a separate day, intranasal oxytocin 100 μg (n=24). Venous plasma oxytocin concentration was measured using LC/MS and enzyme-linked immunosorbent assay. Pharmacokinetic parameters were estimated using NONMEM.

RESULTS

The pharmacokinetics of intravenous oxytocin were well described by a two-compartment model (0% bias, 18% median inaccuracy). The two-compartment model for intranasal oxytocin was characterised by substantial subject-to-subject variability (9% median bias, 47% median inaccuracy). Nasal oxytocin bioavailability was 0.7%. Oxytocin samples assayed with LC/MS were systematically higher than simultaneous samples assayed with enzyme-linked immunosorbent assay.

CONCLUSIONS

The pharmacokinetics of intravenous oxytocin are well described by a two-compartment model. The low bioavailability (<1%) and large intersubject variability in plasma oxytocin after intranasal dosing could partially explain the inconsistent reports of oxytocin efficacy in the clinical literature with this delivery method. A publicly available simulator was created to guide oxytocin dosing in future studies.

CLINICAL TRIAL REGISTRATION

NCT03929367 (Study 1) and NCT05672667 (Study 2).