A multiscale PBPK-PD model of oxytocin-induced uterine excitation and contraction.

Coordinated excitation of uterine smooth muscle cells (USMCs) is the physiological basis of labour, and several mathematical models have been developed to understand the function of USMCs. However although the key role of oxytocin in parturition has been established, most existing USMC models still rely on external electrical stimulation to initiate action potentials rather than including oxytocin as a stimulus. This study developed a multiscale dynamic model. First a pregnancy physiologically based pharmacokinetic (PBPK) model was built to describe pulsatile oxytocin release, systemic transport and clearance. This PBPK model was coupled to a cell-level model via local myometrial oxytocin exposure. This model explicitly captures oxytocin binding to and dissociation from the oxytocin receptor (OXTR), as well as downstream OXTR signalling. The cell-level model incorporates excitation-contraction coupling, enabling the simulation of USMC excitation and contractile responses without external electrical stimulation. The model aligns with published data across multiple key endpoints, including oxytocin pharmacokinetic parameters, maternal venous and umbilical arterial and umbilical venous concentrations, and the duration and amplitude of cellular excitation and contraction. The results also show that an increased oxytocin association rate constant