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 $k_{\mathrm{on}}$ lowers the half-maximal effective concentration (EC₅₀) and is a key determinant of USMC sensitivity to oxytocin. This model provides a quantitative framework to explain oxytocin's role in uterine excitability during pregnancy and to investigate pathological conditions such as preterm labour and uterine atony. KEY POINTS: Oxytocin is a major physiological regulator of labour contractions, but most existing uterine smooth muscle cell models still require external electrical stimulation to trigger excitation, rather than recapitulating oxytocin-induced myometrial activity. We developed a multiscale physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model that links pulsatile endogenous oxytocin release, maternal-fetal distribution, oxytocin receptor binding, IP₃-mediated Ca²⁺ signalling and excitation-contraction coupling in uterine smooth muscle cells. The model reproduced published ranges for key pharmacokinetic and pharmacodynamic endpoints, including oxytocin half-life and clearance, maternal and fetal oxytocin concentrations, intracellular Ca²⁺ responses, membrane potential, contraction duration and active stress. Simulations showed that the oxytocin association rate constant and oxytocin receptor abundance strongly influence the oxytocin dose-response relationship, shifting EC50 and modulating uterine excitability. This work provides a quantitative framework for studying how endogenous oxytocin can induce uterine excitation and contraction, and offers a basis for investigating abnormal uterine activity such as preterm labour and uterine atony.