Development of a Pharmacokinetic/Pharmacodynamic Model for Carvedilol to Predict β1-Blockade in Patients with Congestive Heart Failure

Tenero, David M.; Henderson, Linda S.; Campanile, Andrea M.; Baidoo, Charlotte A.; Boyle, Duane

doi:10.1016/j.amjcard.2006.07.016

Cited by 11 publications

(21 citation statements)

References 6 publications

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“…A good correlation was found between S-carvedilol plasma concentrations and the chronotropic response using a direct effect inhibitory E max model [48]. The PK/PD model defined in healthy subjects was able to predict heart rate effects of carvedilol in patients with mild-to-severe heart failure or asymptomatic patients with post myocardial infarction treated with immediate and controlled release formulations [48]. The area under the effect curve after controlled release carvedilol was equivalent to immediate release formulation, suggesting a 24-h β-blocking coverage for the controlled release formulation of carvedilol given once daily in patients with heart failure [48].…”

Section: Preclinical Pk/pd Modelingmentioning

confidence: 99%

Section: Preclinical Pk/pd Modelingmentioning

confidence: 99%

“…For instance, Tenero and coworkers [48] compared the PD properties the PK/PD properties of immediate release and controlled release formulations of carvedilol on change in exercise-induced heart rate in patients with cardiac dysfunction or post myocardial infarction. A good correlation was found between S-carvedilol plasma concentrations and the chronotropic response using a direct effect inhibitory E max model [48]. The PK/PD model defined in healthy subjects was able to predict heart rate effects of carvedilol in patients with mild-to-severe heart failure or asymptomatic patients with post myocardial infarction treated with immediate and controlled release formulations [48].…”

Section: Preclinical Pk/pd Modelingmentioning

confidence: 99%

“…Comparison of PK/PD properties of immediate release and controlled release formulations of carvedilol and metipranolol Impact of gender on stereoselective pharmacokinetics and pharmacodynamics of metoprolol Impact of aging on blood pressure lowering response to acebutolol and dilevalol Quantification of delay in antihypertensive response to atenolol and carvedilol Effect of pregnancy on PK/PD properties of labetalol Impact of genetic polymorphism on PK/PD properties of metoprolol [48,49] [50]…”

Section: Preclinical Pk/pd Modelingmentioning

confidence: 99%

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PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

Höcht

Bertera

Mauro

et al. 2016

Int. J. Pharmacokinet.

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Review β-blockers play a central role in the treatment of the various main cardiovascular diseases, including hypertension, coronary artery disease and systolic heart failure. As a therapeutic class, β-blockers form a heterogeneous family that differs in their pharmacokinetic (PK) and pharmacodynamic (PD) properties, highlighting the relevance of the extensive evaluation of PK/PD properties of these agents in order to optimize the outcomes of the treatment of cardiovascular diseases. Preclinical and clinical studies using PK/PD models have been able to identify different factors associated with cardiovascular response of β-blockers, including age, pharmaceutical formulation and genetic polymorphism, among others. PK/PD modeling of β-blockers can also be attractive for the early detection of poor responders and the optimization of dose regimen in their different indications.

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Section: Preclinical Pk/pd Modelingmentioning

confidence: 99%

Section: Preclinical Pk/pd Modelingmentioning

confidence: 99%

Section: Preclinical Pk/pd Modelingmentioning

confidence: 99%

Section: Preclinical Pk/pd Modelingmentioning

confidence: 99%

See 2 more Smart Citations

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

Höcht

Bertera

Mauro

et al. 2016

Int. J. Pharmacokinet.

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“…It has also been reported that the PK/PD analyses of the relationship between early virological response and the plasma concentration of enfuvirtide in HIV patients was investigated using a model (de Requena et al, 2008). Likewise, for cardiovascular drugs such as ␤-adrenoreceptor antagonists, many PK/PD analyses using modeling and simulation were conducted during the nonclinical and clinical stages (Tenero et al, 2006). Many findings and trials suggest that PK/PD analyses play an important role in furthering effective drug development.…”

mentioning

confidence: 99%

Relationship between Exposure of (–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a “Funny” If Current Channel Inhibitor, and Heart Rate Reduction in Tachycardia-Induced Beagle Dogs

Umehara

Wada²,

Noguchi³

et al. 2009

Drug Metab Dispos

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ABSTRACT:(؊)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel (If channel) inhibitor, is developed as a treatment for stable angina and atrial fibrillation. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) relationship after intravenous administration of YM758 to tachycardia-induced dogs was investigated and described based on the simplified compartment model. The PK of YM758 in dogs did not differ between the nontreated and tachycardia-induced groups. A drug-induced reduction in heart rate (HR) was clearly observed, and the half-life of the duration of the effect (approximately 4.0 h) was longer than that of the plasma concentration of the unchanged drug. The fitting and simulation procedure from the PK/PD relationship between the time profiles for YM758 plasma concentration and HR reduction had an ECe 50 value (YM758 concentration in the effective compartment resulting in a 50% decrease of the maximum effect) of 6.0 ng/ml, which did not agree with the results of the in vitro experiment using right atria isolated from guinea pigs (EC 30 , 70.4 ng/ml). In addition, in the in vitro experiments, YM758 metabolites had a weak inhibitory effect, if any, on the spontaneous beat rate of the right atria from guinea pigs. These data, along with the previous finding that YM758 and its metabolites are eliminated rapidly from rat hearts, indicate that the duration of the pharmacological effect of YM758 (compared with the rapid elimination of the plasma drug concentration) may be the result of strong binding and/or slower dissociation of YM758 in the If channel. Such PK/PD analyses allow the pharmacological profiles of many drugs, especially cardiovascular drugs, to be more readily understood and better predicted during the clinical stages.

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

Yamamoto

Cristofoletti

Vozmediano

et al. 2023

The Journal of Clinical Pharma

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Roux‐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.

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Development of a Pharmacokinetic/Pharmacodynamic Model for Carvedilol to Predict β1-Blockade in Patients with Congestive Heart Failure

Cited by 11 publications

References 6 publications

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

Relationship between Exposure of (–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a “Funny” If Current Channel Inhibitor, and Heart Rate Reduction in Tachycardia-Induced Beagle Dogs

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

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