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 compared to young adults following single bolus administrations of doses ≥ 0.7 mg/kg. Our findings suggest that geriatric 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 elderly patients are not feasible, since age contribution is overshadowed by the overall variability in the recovery time.

Aim: A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. Methods: PopPK models were developed utilizing data from 52 subjects, including non-obese, obese, and post-RYGB patients who received rac-carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug-metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)-carvedilol to simulate the changes in exercise-induced heart rate. Results: A two-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to non-operated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour beta-blocker response. Simulation results suggested that a 50 mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25 mg dose in non-operated subjects. Conclusion: Integrated PK/PD modeling indicated that standard dosage regimens for non-operated subjects do not provide equivalent beta-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.