Population pharmacokinetics-pharmacodynamics-based dose optimization of carvedilol in patients following a gastric bypass surgery
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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.