An additional complication is that the half-life of the elimination phase increases from 79 h following a single dose to — h following multiple dosing [48] , suggesting that parameters that describe single dose pharmacokinetics may not apply to multiple dose pharmacokinetics. In the absence of rigorous models of ribavirin pharmacokinetics, one may have to rely on empirical relationships between the dosage and the resulting steady state plasma concentration following multiple dosing e.
Second, our model suggests guidelines for the usage of hormone supplements, such as erythropoietin, which enhance RBC production and improve the tolerability of ribavirin.
This response, however, is inadequate to suppress ribavirin-induced anemia adequately and renders ribavirin intolerable. We estimate then that growth hormone supplements must increase RBC production rate by an additional 0.
This compensation that hormone supplements must provide increases with ribavirin accumulation. Identifying the dosage of the growth hormones that induces the necessary RBC production requires knowledge of the dose-response relationships and of the pharmacokinetics of the growth hormones, which are yet to be fully elucidated [26] — [31]. Third, genetic variations that resulted in a deficiency in the enzyme inosine triphosphatase ITPA were recently found to protect HCV patients against ribavirin-induced anemia [51].
Because deficiency in ITPA is a clinically benign condition, therapeutic intervention to suppress ITPA presents a promising new strategy to curtail ribavirin-induced anemia without compromising the antiviral activity of ribavirin [51]. Our model may be adapted to inform the development of such an intervention strategy. In our model, the dependence of the death rate of RBCs on ribavirin accumulation, determined by Eq. Thus, experiments that determine how variations in the ITPA level both in the absence and in the presence of ribavirin influence RBC lifespan would provide the necessary inputs for our model to account explicitly for the role of ITPA in ribavirin-induced anemia.
The resulting model would enable determination of the minimal inhibition of ITPA necessary to maintain ribavirin-induced anemia within tolerable limits. Conversely, using information of the ITPA level intrinsic to a patient, the model can be applied to predict the maximum ribavirin dosage that the patient can tolerate, thus presenting an avenue for personalizing the treatment of HCV infection.
RBCs produced at different times in the interval from 0 to t will have been exposed to ribavirin for different durations and accordingly have different intracellular levels of ribavirin. The time evolution of is governed by the following equation Text S1 1.
The first term on the right-hand-side in Eq. We assume therefore that , the concentration of ribavirin in plasma. With twice daily oral administration of ribavirin, rises from zero at and reaches an asymptotic maximum, , so that , where is the characteristic timescale of the accumulation of ribavirin in plasma [6] , [38]. The second term on the right-hand side of Eq. We assume that the death rate, D , of RBCs increases with as follows 2 where is the death rate of RBCs in the absence of ribavirin, is that value of at which the death rate doubles or the lifespan halves compared to that in the absence of ribavirin, and , analogous to the Hill coefficient, determines the sensitivity of to changes in.
A second constraint on Eq. The production of RBCs by the bone marrow is regulated by a negative feedback mechanism involving the hormone erythropoietin [58]. Recent studies on modeling erythropoiesis elucidate the complexities involved in a quantitative description of this feedback mechanism [59] — [65]. Here, we employ Eq. Equations 1 — 3 present a model of the population dynamics of RBCs in individuals undergoing treatment with ribavirin. We solve the equations see below and obtain the population density, , and the corresponding cumulative population, , using which we predict the time-evolution of the hemoglobin level in blood, where is the volume of a single erythrocyte ; the average concentration of ribavirin in RBCs, ; and the average RBC lifespan, , where is the average death rate of RBCs.
Equation 1 along with the initial and boundary conditions is equivalent to the following set of differential equations obtained using the method of characteristics Text S4 4 where S i t is the subpopulation of cells born within an interval of that survive at time t. C i t is the concentration of RXP in the latter cells at time t. We solve Eq. We validate our solution methodology against an analytical solution that can be obtained in the limiting case when the RBC death rate is independent of RXP accumulation Text S6 , Fig.
We also ensure that d allows accurate integration of Eq. From the solution, we calculate the quantities of interest, viz. We employ the following values of the model parameters unless stated otherwise. We fix and [67]. Using [47] , we get.
We obtain from the initial steady state. The remaining parameter values , , , and are obtained from best-fits of our model predictions to experimental data Fig. We summarize model parameters and their values in Table 1.
We fit model predictions to experimental data Fig. Hemoglobin reduction as a function of the intracellular ribavirin concentration. Performed the experiments: SMK. Introduction — million people worldwide are currently infected with hepatitis C virus HCV [1].
Download: PPT. Figure 1. Model predictions Population dynamics of RBCs during treatment with ribavirin. Figure 2. Model predictions of the dynamics of ribavirin-induced anemia. Factors that influence the severity of ribavirin-induced anemia. Figure 3. Factors influencing the dynamics of ribavirin-induced anemia. Inter-patient variations. Figure 4. Model predictions of the variations in the severity of ribavirin-induced anemia.
Comparisons of model predictions with patient data We consider a recent study of the time-evolution of and in 19 Japanese patients following the onset of combination therapy [47]. Clinical implications Our model has several clinical implications. Figure 6. Model predictions of threshold ribavirin exposure and requisite RBC production. Discussion The ability to enhance treatment response rates renders ribavirin central to the treatment of HCV infection. The time evolution of is governed by the following equation Text S1 1 The first term on the right-hand-side in Eq.
Solution of model equations using the method of characteristics Equation 1 along with the initial and boundary conditions is equivalent to the following set of differential equations obtained using the method of characteristics Text S4 4 where S i t is the subpopulation of cells born within an interval of that survive at time t. Model parameters We employ the following values of the model parameters unless stated otherwise. Table 1. Summary of model parameters and their values employed.
Fits of model predictions to patient data We fit model predictions to experimental data Fig. Supporting Information. Figure S1. Figure S2. Analysis of RBC recovery following phlebotomy. Figure S3. Validation of the solution methodology.
Figure S4. Sensitivity of the numerical solution to the integration time step. Text S1. Derivation of equation 1 and its boundary condition.
Text S2. Dependence of RBC death rate on intracellular ribavirin concentration. Text S3. Analysis of phlebotomy experiments. Text S4. Solution of model equations using the method of characteristics. Text S5. Text S6. Acknowledgments We thank Alan S.
Perelson and Ruy M. Ribeiro for helpful comments. References 1. Lavanchy D The global burden of hepatitis C. Liver Int 74— View Article Google Scholar 2. Recent studies suggest that erythrocyte oxidative defense mechanisms may play an important role in RBV-induced anemia.
Clinical risk factors for severe RBV-induced anemia include impaired renal function, high age, high dose per body weight and female gender. Determination of RBV concentrations has little value in the management of anemia. The only proven effective prevention of RBV-induced anemia is the concomitant administration of erythropoietin. Other side effects of ribavirin are teratogenicity, cough, dyspnea, and rash. The adverse effects of pegylated interferon alfa plus ribavirin are the same as those of standard interferon alfa plus ribavirin.
Pseudo-flu symptoms are more frequent when pegylated interferon alfa is administered in high doses, probably because the dose of interferon is greater.
As with pegylated interferon alfa monotherapy, pegylated interferon alfa plus ribavirin results in a higher incidence of localized erythema, which is generally light and does not require discontinuation of treatment. The occurrence of anemia, an adverse effect of ribavirin, is similar when ribavirin is given in combination with pegylated interferon alfa or regular interferon alfa. Neutropenia is an exclusion criterion for treatment protocols and is reversible after discontinuation of treatment.
However, a recent study failed to detect a higher incidence of infection in hepatitis C patients with neutropenia, except in cirrhotic, immunosuppressed, or transplanted patients. Granulocyte colony-stimulating factor Neupogen is often used at a dose of mg three times weekly, but there is no solid evidence to support this practice. Ribavirin is an analogue of guanosine.
Ribavirin causes anemia by inducing hemolysis and bone marrow dysfunction. The decrease in hemoglobin concentration begins after the first week of treatment, reaches a nadir of 2. Anemia is fully reversible upon discontinuation of treatment. Ribavirin treatment should be discontinued if, after administration of a reduced the dose of ribavirin for 4 weeks, hemoglobin levels are less than 8.
It has been suggested that simultaneous administration of erythropoietin should be considered for these patients to enable the dose of ribavirin to be maintained. The usual dose of erythropoietin is 40,, IU per week. However, some studies have recommended lower doses. Variation in the reported incidence of depression is attributable to variations in criteria for the detection and diagnosis of depression. Depression is associated with patients who experienced alcoholism, drug addiction, or had a history of comorbidity prior to treatment.
Some studies reported that treatment with antidepressives before commencement of antiviral therapy significantly reduced the incidence of psychiatric symptoms. Therefore, it is advisable to establish whether the patient has a history of depression and, if so, to initiate prophylactic treatment with antidepressives such as selective serotonin recapture inhibitors, which have few adverse effects, are not hepatotoxic, and have no effect on cytochrome P Should antidepressant treatment be used during treatment for HCV infection?
Evaluations before and during treatment are recommended in order to detect possible neuropsychological changes. The use of antidepressants before or during treatment is recommended when necessary. Should drug doses be adjusted according to changes in biochemical or hematological parameters during treatment?
What is the most frequent cause of dosage modification during antiviral treatment? Inicio Annals of Hepatology Management of adverse reactions to chronic hepatitis C treatment. ISSN: Previous article Next article.
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