Author: Yamamoto, Priscila Akemi ; Vozmediano, Valvanera ; de Moraes, Natalia Valadares ; de Gaitani, Cristiane Masetto ; Salgado Junior, Wilson ; dos Santos, Jose Sebastião ; Schmittgen, Thomas D. ; Kemp, Rafael ; Sankarankutty, Ajith Kumar ; Jiang, Jinmai ; Cristofoletti, Rodrigo

AimsA 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.MethodsPopPK models were developed utilizing data from 52 subjects, including nonobese, 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.ResultsA 2‐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 nonoperated 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 β‐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 nonoperated subjects.ConclusionIntegrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent β‐blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

01 Oct 2023·Chirality

Enantioselective binding of carvedilol to human serum albumin and alpha-1-acid glycoprotein.

Article

Author: Imre, Silvia ; Marc, Gabriel ; Farczadi, Lenard ; Toma, Camelia-Maria ; Ion, Valentin

Carvedilol, a highly protein-bound beta-blocker, is used in therapy as a racemic mixture of its two enantiomers that exhibit different pharmacological activity. The aim of this study was to evaluate the stereoselective nature of its binding to the two major plasma proteins: albumin and alpha-1-acid glycoprotein. The determination of the plasma protein-binding degree for carvedilol and its enantiomers was achieved using ultrafiltration for the separation of the free fraction, followed by LC-MS/MS quantification, using two different developed and validated methods in terms of stationary phase: achiral C18 type and chiral ovomucoid type. Furthermore, molecular docking methods were applied in order to investigate and to better understand the mechanism of protein-binding for S-(-)- and R-(+)-carvedilol. A difference in the binding behavior of the two enantiomers to the plasma proteins was observed when taken individually, with R-(+)-carvedilol having a higher affinity for albumin and S-(-)-carvedilol for alpha-1-acid glycoprotein. However, in the case of the racemic mixture, the binding of the S enantiomer to alpha-1-acid glycoprotein seemed to be influenced by the presence of its antipode, although no such influence was observed in the case of albumin. The results raise the question of a binding competition between the two enantiomers for alpha-1-acid glycoprotein.

01 Jul 2023·The Journal of Clinical Pharmacology

Effect of Roux‐En‐Y Gastric Bypass in the Pharmacokinetics of (R)‐Carvedilol and (S)‐Carvedilol

Article

Author: Santos, Jose Sebastião Dos ; Sankarankutty, Ajith Kumar ; Yamamoto, Priscila Akemi ; Cristofoletti, Rodrigo ; Salgado Junior, Wilson ; Kemp, Rafael ; da Silva, Rodrigo Moreira ; Vozmediano, Valvanera ; de Moraes, Natalia Valadares ; de Gaitani, Cristiane Masetto

AbstractRoux‐en‐Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long‐term weight loss and remission of associated comorbidities. Carvedilol, a third‐generation β‐blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH‐dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux‐en‐Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux‐en‐Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n = 15, body mass index < 25 kg/m2), obese (n = 19, body mass index ≥ 30), and post‐roux‐en‐Y gastric bypass subjects submitted to surgery for at least 6 months (n = 19) were investigated. All subjects were administered a single oral dose of 25‐mg racemic carvedilol, and blood was sampled for up to 24 hours. Plasma concentrations of (R)‐ and (S)‐carvedilol were determined by liquid chromatography–tandem mass spectrometry. The maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve (AUC) of (R)‐carvedilol were 2‐ to 3‐fold higher than (S)‐carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)‐ and (S)‐carvedilol without changing the AUC. Post‐roux‐en‐Y gastric bypass subjects presented a 3.5‐fold reduction in the Cmax of the active (S)‐carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)‐carvedilol increased 2.5‐fold in post‐roux‐en‐Y gastric bypass subjects compared to obese or nonobese. Although the β‐blockade response was not assessed, the reduced exposure to carvedilol in subjects post‐roux‐en‐Y gastric bypass may be clinically relevant and require dose adjustment.

100 Deals associated with S-carvedilol(AHN-GOOK PHARMACEUTICAL Co., Ltd.)

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Indication	Country/Location	Organization	Date
Essential Hypertension	KR	AHN-GOOK PHARMACEUTICAL Co., Ltd.	14 Apr 2018

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