(T0930-10-69) Optimizing Carvedilol Dosing Following Gastric Bypass Surgery Using Population-Based PK/PD Modeling

Purpose: Gastric bypass surgery can potentially alter drug pharmacokinetics (PK) and response. Several factors contribute to these changes, including weight loss, changes in stomach pH, gastric volume and emptying time, decreased absorptive surface area and expression of drug-metabolizing enzymes and transporters in the small intestine. Carvedilol, a third-generation beta-blocker, is a weak base with low and pH-dependent solubility and dissolution. We aimed to assess the impact of gastric bypass on the PK of (S)-carvedilol using population-based modeling approach (PopPK). By identifying differences in the PK parameters, our aim was to optimize the dosing regimen for carvedilol in patients submitted to a gastric bypass surgery by means of a pharmacokinetic/pharmacodynamic (PK/PD) link model.

Methods: The PopPK model for (S)-carvedilol was developed using a nonlinear mixed-effect modeling approach with data obtained from 52 subjects receiving 25 mg rac-carvedilol orally based on a case-controlled study [1]. Model building and verification were performed in Monolix™ 2023R1 and R Studio (Rsmlx package). Covariate analysis was performed with anthropometric and laboratory data, gastric bypass surgery, phenotype and relative intestinal abundance of major drug metabolizing enzymes and transporters. A direct effect inhibitory E_max PD model was linked to the final PK model of (S)-carvedilol [2]. Finally, the PK/PD link model was used to simulate the beta-blocking activity as the change in exercise-induced heart rate using Simulx 2023R1. Simulations were performed to assess the covariate effects on the exposure and response of (S)-carvedilol and for dose optimization after gastric bypass.

Results: The pharmacokinetics of (S)-carvedilol was best described by a two-compartmental model with linear elimination and parallel first-order absorptions, characterized by slow (ka1, F1) and fast (ka2, 1-F1, Tlag) rates (Figure 1). The covariate model incorporated gastric bypass surgery, which increases the fraction absorbed (F1) and apparent total clearance. Additionally, the intestinal ABCC2 mRNA expression showed a positive correlation with the Tlag and was included as a covariate. The exposure (AUC) of (S)-carvedilol in the post-gastric bypass subjects was approximately 2-fold lower compared to the non-obese. This reduced exposure translated into a 30% decrease in the predicted response, represented by the area under the response curve (AUEC) for the 24-h beta-blocking effect (Figure 2). In post-gastric bypass subjects, a 50% increase in the dose had equivalent predicted exposure and 24-h beta-blocking activity compared with non-obese subjects receiving carvedilol once daily (Figure 3).

Conclusion: Gastric bypass surgery resulted in a 2-fold reduction in the exposure for the beta-blocker (S)-carvedilol. The increased contribution of slow absorption of (S)-carvedilol in the gastric bypass group can be attributed to reduced dissolution in the higher gastric pH. Our integrated PK/PD modeling demonstrated that standard daily dose in non-obese do not provide optimal beta-blocking activity in patients submitted to a gastric bypass. This study highlights the importance of personalized dosing strategies to achieve desired therapeutic outcomes in this specific patient population.<

References: [1] Yamamoto et al., J Clin Pharmacol. 2023. DOI: 10.1002/jcph.2221.
[2] Tenero et al., Am J Cardiol. 2006; 98(7A):27L-31L.

Acknowledgements: This work was supported by the Sao Paulo Research Foundation (FAPESP 2018/06569-9). The study protocol was approved by the Ethics Committee of the Clinical Hospital of the Ribeirao Preto Medical School, CAAE: 94756418.0.3001.5440) and the University of Florida institutional review board (IRB202103000).

Figure 1. Population pharmacokinetic model of (S)-carvedilol. The covariate effects are displayed in red. RYGB: Roux-en-Y gastric bypass; ABCC2: gene encoding MRP2 transporter.

Figure 2. Covariate effects on (S)-carvedilol exposure and response based on the PK/PD link model.

Figure 3. Simulation of (S)-carvedilol doses in post-gastric bypass subjects.