Steady‐State Pharmacokinetics of Carvedilol and Its Enantiomers in Patients with Congestive Heart Failure

Tenero, David M.; Boike, Steven C.; Boyle, Duane; Ilson, Bernard E.; Fesniak, Henry; Brozena, Susan C.; Jorkasky, Diane K.

doi:10.1177/00912700022009576

Cited by 74 publications

(70 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The population means of the CL/F for R-and S-carvedilol were similar to those reported in pharmacokinetic studies of patients with CHF. 5,18) Carvedilol clearance in CHF patients is about half that in healthy subjects. This is likely because of decreased hepatic blood flow in a background of impaired cardiac function.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of R- and S-Carvedilol in Japanese Patients with Chronic Heart Failure

Saitō

Kawana

Ohno

et al. 2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Carvedilol is an b 1 , b 2 and a 1 adrenergic receptor antagonist, clinically administered as a racemic mixture of the R(ϩ)-and S(Ϫ)-enantiomers. Beta-blockers have been reported to prolong life and reduce the risk of disease progression in patients with chronic heart failure (CHF).1-3) However, these drugs have a risk of causing symptomatic hypotension and/or worsening heart failure during the dose titration step. As tolerance to treatment with carvedilol varies widely among individuals, careful titration and treatment initiation are necessary in daily practice. The pharmacokinetics of carvedilol and its covariates in patients with CHF have been investigated, 4,5) but the relationship between pharmacokinetics and tolerability, and the cause of this wide inter-individual variability, are still unclear.The R-and the S-enantiomers of carvedilol exhibit different pharmacological effects, i.e., the b-receptor blocking activity of S-carvedilol is about 200 times higher than that of R-carvedilol, whereas both enantiomers are equipotent ablockers.6) Also, the enantiomers exhibit differences in pharmacokinetic behavior in humans. 7,8) Carvedilol is metabolized to various derivatives by both oxidation and conjugation in the liver, and the main oxidative isoenzyme is cytochrome P450 (CYP) 2D6. 9) Absolute bioavailability upon oral administration is 31.1% and 15.1% for the R-and Senantiomers, respectively, and the difference in metabolic stability is attributed mainly to CYP2D6.10,11) Carvedilol shows high plasma protein binding (98-99%), 12) and is known to bind to a 1 -acid glycoprotein with high affinity. 13)The COMMET study reported that serious adverse and CHF-related events in patients switching from metoprolol (a b 1 -selective agent) to carvedilol (a nonselective agent) were lower than in patients switching from carvedilol to metoprolol.14) It is considered that the vasodilation effect through a 1 blockade and its potency might be a key factor in b-blocker tolerability. Therefore, it is very important to assess the characteristics of enantioselective pharmacokinetics, and clarify the factors that influence clinical response.In this study, we investigated the population pharmacokinetic parameters of R-and S-carvedilol and its covariates in Japanese patients with CHF, and evaluated the effect of CYP2D6 genotypes on individual oral clearance (CL/F) values. Relationships between adverse events and drug exposure level were also assessed by exploratory analysis. Research." These protocols were approved by the institutional review board of Sakakibara Heart Institute. Written informed consent for participation in the study was obtained from all patients. Studies I and II had the same inclusion and exclusion criteria. The main demographic characteristics are presented in Table 1. The patients ranged in age from 31 to 87 years (mean: 65 years), with a body weight of between 33.8 and 94.0 kg (mean: 58.5 kg). Carvedilol is a b-adrenoceptor antagonist used for treating chronic heart failure (CHF). Two clinical studies were cond...

show abstract

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of R- and S-Carvedilol in Japanese Patients with Chronic Heart Failure

Saitō

Kawana

Ohno

et al. 2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…MEDLINE database was searched for screening and identification of PK studies of R-and S-carvedilol in healthy adults and CHF patients with known demographic information and reported systemic drug concentration-time profiles. As a result of the search, systemic drug concentration-time data from five different clinical studies in healthy adults (4 studies and 36 subjects) and CHF patients (one study, 10 patients with NYHA III and 10 patients with NYHA IV, 4 PK data sets) were used in the adult model development and evaluation (Neugebauer et al, 1990;Spahn et al, 1990;Zhou and Wood, 1995;Tenero et al, 2000;Behn, 2001). These studies provided a total of 11 data sets (7 data sets in healthy and 4 data sets in CHF patients) ( Table 2).…”

Section: Pk/clinical Datamentioning

confidence: 99%

“…or oral doses of R-and S-carvedilol. Among the data sets used, one was provided by the author (Behn, 2001) and the rest were scanned from the publications' figures (Neugebauer et al, 1990;Spahn et al, 1990;Zhou and Wood, 1995;Tenero et al, 2000) using the "digitizer" tool in software OriginPro version 9.0 (OriginLab, Northampton, MA). CYP2D6-specific genotype data were available in two clinical studies (Zhou and Wood, 1995;Behn, 2001).…”

Section: Pk/clinical Datamentioning

confidence: 99%

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

Rasool

Khalil

Läer

2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.

show abstract

“…The C max and T max appeared to be around 100 ng/ml and 1 h, respectively. In Figure 2, the mean plasma curves of two formulations were apparently similar and shown typical pattern for carvedilol plasma concentration curves after the oral administration to healthy humans [21]. The relevant pharmacokinetic parameters of carvedilol are listed in Table 4.…”

Section: Application To Bioequivalence Studymentioning

confidence: 69%

Rapid and Sensitive Carvedilol Assay in Human Plasma Using a High-Performance Liquid Chromatography with Mass/Mass Spectrometer Detection Employed for a Bioequivalence Study

Kim¹,

Lee²

2010

AJAC

View full text Add to dashboard Cite

A method for the determination of carvedilol in human plasma was developed using a high-performance liquid chromatography with tandem mass spectrometer (HPLC-MS/MS). Plasma samples were deproteinized using acetonitrile and the supernatant was directly injected onto the HPLC column without any preparative steps. Chromatography was performed on a reversed-phase (C 18 ) column with isocratic mobile phase for 2 min. The calibration curve was linear over the range of 2 to100 ng/ml (R 2 > 0.9998) and the lower limit of quantitation (LLOQ) was 2 ng/ml. This method showed acceptable precision and accuracy, good recovery from the plasma matrix, and stability during the analytical procedures. When its application to the bioequivalence test of two carvedilol 25 mg tablet formulations in male healthy 28 volunteers, this validated analysis method was appropriate resulting in the bioequivalence of two formulations: no statistically significant difference was observed between the logarithmic transformed area under curve (AUC) and maximum plasma concentration (C max ) values of the two formulations. The 90% confidence interval for the ratio of the above mentioned two parameters were within the bioequivalence limit of 0.80-1.25. These results suggested that the HPLC-MS/MS analysis method developed was suitable for the carvedilol analysis in human plasma.

show abstract

Steady‐State Pharmacokinetics of Carvedilol and Its Enantiomers in Patients with Congestive Heart Failure

Cited by 74 publications

References 16 publications

Population Pharmacokinetics of R- and S-Carvedilol in Japanese Patients with Chronic Heart Failure

Population Pharmacokinetics of R- and S-Carvedilol in Japanese Patients with Chronic Heart Failure

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

Rapid and Sensitive Carvedilol Assay in Human Plasma Using a High-Performance Liquid Chromatography with Mass/Mass Spectrometer Detection Employed for a Bioequivalence Study

Contact Info

Product

Resources

About