Modeling Ribavirin‐Induced Anemia in Patients with Chronic Hepatitis C Virus

Modeling Ribavirin‐Induced Anemia in Patients with Chronic Hepatitis C Virus

Ribavirin remains an important component of hepatitis C treatment in certain clinical scenarios, but it causes hemolytic anemia. A quantitative understanding of the ribavirin exposure‐anemia relationship is important in dose individualization/optimization. We developed a model relating ribavirin tri...

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Bibliographic Details
Published in:CPT: pharmacometrics and systems pharmacology Vol. 5; no. 2; pp. 65 - 73
Main Authors: Wu, LS, Jimmerson, LC, MacBrayne, CE, Kiser, JJ, D'Argenio, DZ
Format: Journal Article
Language:English
Published: United States John Wiley & Sons, Inc 01-02-2016
John Wiley and Sons Inc
Subjects:
Adenosine triphosphate
Algorithms
Anemia
Anemia - chemically induced
Antiviral Agents - administration & dosage
Antiviral Agents - adverse effects
Bone marrow
Clinical trials
Computer Simulation
Dose-Response Relationship, Drug
Erythrocytes - drug effects
Feedback
Genotype & phenotype
Hemoglobin
Hepatitis
Hepatitis C
Hepatitis C, Chronic - drug therapy
Humans
Interferons
Interleukins - genetics
Models, Biological
Ordinary differential equations
Original
Partial differential equations
Patients
Phosphorylation
Plasma
Polymorphism
Pyrophosphatases - genetics
Regulatory approval
Ribavirin - administration & dosage
Ribavirin - adverse effects
Simulation
Studies
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Summary:Ribavirin remains an important component of hepatitis C treatment in certain clinical scenarios, but it causes hemolytic anemia. A quantitative understanding of the ribavirin exposure‐anemia relationship is important in dose individualization/optimization. We developed a model relating ribavirin triphosphate (RTP) exposure in red blood cells (RBCs), RBC lifespan, feedback regulation of RBC production when anemia occurs, and the resulting hemoglobin decline. Inosine triphosphatase (ITPA) and interleukin 28B (IL28B) genetics were found to be significant covariates. Clinical trial simulations predicted that anemia is least severe in IL28B non‐CC (rs12979860, CT or TT), ITPA variant subjects, followed by IL28B non‐CC, ITPA wild‐type, IL28B CC, ITPA variant, and IL28B CC, ITPA wild‐type subjects (most severe). Reducing the ribavirin dose from 1,200/1,000 mg to 800/600 mg could reduce the proportions of grade 2 anemia by about half. The resulting model framework will aid the development of dosing strategies that minimize the incidence of anemia in treatment regimens that include ribavirin.
ISSN:2163-8306
2163-8306
DOI:10.1002/psp4.12058