Optimizing the Clinical Use of Carvedilol in Liver Cirrhosis Using a Physiologically Based Pharmacokinetic Modeling Approach

Rasool, Muhammad Fawad; Khalil, Feras; Läer, Stephanie

doi:10.1007/s13318-016-0353-2

Cited by 29 publications

(31 citation statements)

References 46 publications

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“…(25,29) Furthermore, carvedilol is a highly protein-bound drug, and as liver dysfunction progresses and hypoalbuminemia worsens, unbound concentrations of carvedilol increase, theoretically needing lower doses to achieve the same pharmacodynamic effect. (30) Because of its anti-a-1-adrenergic activity, carvedilol induces a greater decrease in arterial pressure than traditional NSBBs, (31) and in studies using high doses (25 mg/ day), it was associated with fluid retention and worsening ascites. (25) The maximum dose used in RCT with clinical endpoints has been 12.5 mg/day, and therefore, this is the maximum recommended dose in cirrhosis.…”

Section: Clinical Pharmacology Of Nsbbs In Portal Hypertension Relatementioning

confidence: 99%

Beta‐blockers in patients with advanced liver disease: Has the dust settled?

2017

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Nonselective beta-blockers (NSBBs) have been the backbone for the treatment of portal hypertension in cirrhosis for the last 3 decades. A publication in 2010 of a prospective observational study suggested that NSBBs could increase mortality in patients with refractory ascites. This opened a controversy about the safety and efficacy of NSBBs in patients with advanced liver disease and led to the publication of a large corpus of observational data assessing the safety of NSBBs in patients with advanced cirrhosis. In this article, we briefly review the clinical pharmacology of NSBBs, the pathophysiological basis for the underlying benefits and harms of NSBBs in advanced cirrhosis, and the evidence in favor and against the use of NSBBs in specific scenarios. Finally, we summarize the current recommendations and propose areas of opportunity for future research. Liver Transplantation 23 1058-1069 2017 AASLD.

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Section: Clinical Pharmacology Of Nsbbs In Portal Hypertension Relatementioning

confidence: 99%

Beta‐blockers in patients with advanced liver disease: Has the dust settled?

2017

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“…The pharmacokinetics (PK) of numerous drugs is altered in patients with liver cirrhosis, especially when the drugs are cleared predominately by hepatic metabolism. These changes are known to be caused by dysregulation of protein expression of drug-metabolizing enzymes (DMEs) and transporters, altered hepatic blood flow, and decreased plasma protein binding (Johnson et al, 2010;Wang et al, 2016;Rasool et al, 2017). Therefore, the Food and Drug Administration has recommended that clinical studies be conducted in patients with various degrees of hepatic impairment for all narrow therapeutic index drugs predominately cleared by the liver, as well as wide therapeutic index drugs if more than 20% of the drug is cleared by the liver (http://www.…”

Section: Introductionmentioning

confidence: 99%

Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study

Prasad¹,

Bhatt²,

Johnson³

et al. 2018

Drug Metab Dispos

119

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To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic ( = 27) or hepatitis C (HCV, = 30) cirrhotic versus noncirrhotic (control) livers ( = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.

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“…Drug-disease modeling is another recognizable advantage to PBPK modeling as drug-and patient-specific parameters may be investigated to better understand altered pharmacokinetics for agents in distinct disease states. Rasool developed a PBPK model that incorporated hepatic and renal hemodynamic changes in patients using carvedilol for chronic heart failure [43]. Vogt developed a PBPK drug-disease model for milrinone in pediatric patients with and without low cardiac output syndrome (LCOS) after open heart surgery in order to provide guidance on optimal dosing [44].…”

Section: Application For Cardiovascular Medicationsmentioning

confidence: 99%

Utilization of Physiologically Based Pharmacokinetic Modeling in Clinical Pharmacology and Therapeutics: an Overview

et al. 2020

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The purpose of this review was to assess the advancement of applications for physiologically based pharmacokinetic (PBPK) modeling in various therapeutic areas. We conducted a PubMed search, and 166 articles published between 2012 and 2018 on FDA-approved drug products were selected for further review. Qualifying publications were summarized according to therapeutic area, medication(s) studied, pharmacokinetic model type utilized, simulator program used, and the applications of that modeling. The results showed a 13-fold increase in the number of papers published from 2012 to 2018, with the largest proportion of articles dedicated to the areas of infectious diseases, oncology, and neurology, and application extensions including prediction of drug-drug interactions due to metabolism and/or transporter-mediated effects and understanding drug kinetics in special populations. In addition, we profiled several high-impact studies whose results were used to guide package insert information and formulate dose recommendations. These results show that while utilization of PBPK modeling has drastically increased over the past several years, regulatory support, lack of easy-to-use systems for clinicians, and challenges with model validation remain major challenges for the widespread adoption of this practice in institutional and ambulatory settings. However, PBPK modeling will continue to be a useful tool in the future to assess therapeutic drug monitoring and the growing field of personalized medicine.Keywords Physiologically based pharmacokinetic modeling . PBPK modeling applications . Modeling and simulation . In vitro in vivo extrapolation . Personalized medicine

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Optimizing the Clinical Use of Carvedilol in Liver Cirrhosis Using a Physiologically Based Pharmacokinetic Modeling Approach

Abstract: The presented model-generated data can guide the optimization of carvedilol therapy on the basis of differences in unbound and total drug exposures with respect to disease severity and can help improve the design of some necessary clinical studies in the drug development process.

Cited by 29 publications

References 46 publications

Beta‐blockers in patients with advanced liver disease: Has the dust settled?

Beta‐blockers in patients with advanced liver disease: Has the dust settled?

Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study

Utilization of Physiologically Based Pharmacokinetic Modeling in Clinical Pharmacology and Therapeutics: an Overview

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