Unravelling sources of variability on rocuronium pharmacokinetics: Implications for prolonged recovery in older patients

Residual neuromuscular blockade (RNB) commonly occurs when using neuromuscular blockers and increases the risk for pulmonary complications, such as airway obstruction and severe hypoxemia, in extubated patients. Rocuronium exhibits a high variability in recovery time, contributing to an increased risk for RNB. This study aimed to identify and characterize the sources of variability in rocuronium exposure and response via a population pharmacokinetic/pharmacodynamic (PK/PD) analysis and to apply the developed PK/PD model to investigate clinical implications. A nonlinear mixed-effect model was developed for rocuronium in patients undergoing general anaesthesia, using doses of 0.3-1.2 mg/kg. Plasma concentrations and the neuromuscular block (train of four ratio) were assessed up to 6 h after dosing. The influence of age, body mass index, renal function and sex on PK and PD was explored. Simulations were performed to predict the recovery time. A two-compartment model with linear elimination and an indirect sigmoid I-max model was used to describe PK and PD. The transfer rate into the periphery increases with age. The predicted recovery time was significantly longer in older subjects aged 85 years (median: 2.8 h; interquartile range [IQR]: 2.18-4.0) compared to young adults aged 25 years (median: 2.5 h; IQR: 2.0-3.1) following single bolus administrations of doses ≥ 0.7 mg/kg. Our findings suggest that older patients take slightly longer to recover than younger adults due to an age-dependent increase in tissue uptake. However, a priori dose adjustments for rocuronium in older patients are not feasible, since age contribution is overshadowed by the overall variability in the recovery time.