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