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Population pharmacokinetic and pharmacodynamic analyses of ribavirin in patients with chronic hepatitis C
HEPATOLOGYVoL 34, No. 4, Pt. 2, 2001
AASLD ABSTRACTS
599A
1707
1708
SAFETY AND EFFICACY OF AMANTADINE AS RESCUE THERAPY FOR PATIENTS FAILING TO CLEAR HCV RNA IN SERUM AFTER SIX MONTHS OF TREATMENT W I T H INTERFERON AND RIBAVIRIN.
W H A T HAPPENS TO THE USED MATERIAL (NEEDLES, VIALS, SYRINGES, PENS ) AFTER HOME INTERFERON THERAPY FOR CHRONIC HEPATITIS C ?. Denis Ouzan Dr, Arnault Tzank Institute, Saint Laurent du
Gerond V Lake-Bakaar, Jericho Turnpike, Syosset, NY
Var France; Remy Collomp, Aline Mousnier, pharmacie CHU nice, Nice France
The combination of interferon and ribavirin is currently first line treatment in patients with chronic hepatitis C liver disease. However, a significant number of patients, especially those infected with genotype la or lb do not achieve complete virological clearance, defined as absence of HCV RNA in serum by PCR or TMA assay, after six months of continuous treatment. Therapy is usually terminated at this point since the probability of a sustained virological response after full 48-week treatment is low in these patients. There have been a number of reports suggesting that Amantadine, a synthetic antiviral agent with activity against influenza A and C viruses, may have some activity in chronic HCV liver disease, as triple therapy in Rebetron failures. We therefore evaluated the safety and efficacy of adding amantadine to concomitant interferon plus ribavirin, in chronic HCV liver disease patients who have failed to clear HCV after six months of treatment with interferon and ribavirin. We included 24 patients (six females, aged between 32 to 56 years) in the study, on an intention to treat basis. All but one was known to be infected with genotype 1. Six had histological evidence of established cirrhosis. All had failed at least six months of treatment with interferon and ribavirin. Interferon and ribavirin were given at standard or slightly reduced doses, Amantadine was given orally at a dose of 100 mg twice daily. Results: Twenty one of 24 patients completed at least six months of treatment. One discontinued after 2 weeks because of increased malaise; another after one month because of increased weight loss; and a third because of lack of efficacy after three months. One initially stopped treatment for one week because of a rash; however, the rash did not recur on restarting treatment. In the group of patients who completed six months of treatment, the mean WBC did not differ significantly before and after treatment • Hemoglobin levels also did not change significantly before and after. Two of the 24 (8 percent) had a sustained virological response. Conclusion: Triple therapy appears to be safe in patients with chronic HCV liver disease, However, treatment efficacy is low, since only eight percent achieved a sustained virological response.
The current treatment of reference for chronic hepatitis C is a combination of recombinant alfa interferon and ribavirin. The interferon therapy is administered entirely at the patient's home (3 injections a week for 6 to 12 months). This study was designed to determine the outcome of the material used for home interferon therapy and to assess the information given to patients concerning interferon administration and waste disposal. For this purpose, a prospective survey was conducted from Septembre to December 1999 on 108 patients who had been on interferon therapy for chtonic hepatitis C for at least 1 month. In more than 50% of cases, the interferon was self-injected by the patient (patient 58%, nurse 32%, family member 10%). Only 32% of the patients received special containers for disposal of used needles. In 41% of cases, the needles were merely put into the trash ; in 23%, the needles were thrown away without having been recapped. Uncapped needles thrown away directly into the trash, which involve a maximum risk of exposure, represented 5% of cases. Seven needlestick injuries were reported (6.5%), including one involving a family member ; most of these accidents occured while recapping the used needle. Whereas instructions for interferon administration appeared to be correctly explained to patients (83% of cases, either verbally or with the help of a written instruction sheet), only 51% of patients had been given instructions on proper disposal of the used material. In conclusion, although this French study cannot be extrapolated to all settings, findings suggest that the disposal of materials used for home treatment of chronic hepatitis C is less than optimum and should be improved. The potential risk of viral contamination is increased for co-infectd patients (hepatitis C and HIV). Improvement of waste disposal requires better patient information and the establishment of specific procedures for infectious waste disposal, which should be extended to include all types of material used for home care. The purpose of this study is to make all health care professionals involved in such treatments aware of their responsibility in this domain.
1709
1710
POPULATION PHARMACOKINETIC A N D PItAILMACODYNAMIC ANALYSES OF RIBAVIRIN IN PATIENTS W I T H CHRONIC HEPATITIS
SYMPTOM DEVELOPMENT AND MANAGEMENT IN PATIENTS WITH CHRONIC HEPATITIS C ON PEGYLATED INTERFERON AND RIBAVIRIN THERAPY. Reem H Ghalib, Cheryl Levine, Rise Stribling, Thikra Kadhim,
C. Juif F Jen, Mark Laughlin, Carol Chung, Samuel Heft, Melton B Affrime, Gerald Hajian, Schering-Plongh Research Institute, Kenilworth, NJ Background: There is a positive association between ribavirin concentration and sustained virologic response and hematological toxicity in the patients treated with interferon alfa-2b (Intron A) + ribavirin (Jen, Glue, Gupta, et.al. Ther Drug Monit. 2000). Objective: To quantify the dose-concentration-response/toxicity relationships for ribavirin in the patients with chronic hepatitis C including the possible influences of covariates on these relationships in the patients treated with PEG-Intron/Intron A + ribavirin. Method: Population pharmacokinetics (PPK) of ribavirin was assessed on 2911 sparsely sampled serum concentrations obtained from 1367 patients. Ribavirin doses ranged 800-1200 rag/day BID. Covariates included body weight, age, gender, serum creatinine, and estimated creatinine clearance. Ribavirin apparent clearance (CLapp) was the primary pharmacokinetic parameter, and was determined by steady-state infusion model. Mixed-effects modeling was used to analyze the data. The model building and parameter estimation were carried out using NONMEM. The virologic response and toxicity (hemoglobin level at treatment week 4 < 10.5 g/dL as an event) were analyzed using logistic regression. The PPK-model based estimates of ribavirin concentrations together with other important factors including demography, virus genotype, baseline viral load, and baseline hemoglobin level were included in the analyses. Results: CLapp was an increasing function of body weight which was the mo~- i-~uential covariate. Other covariates in the clearance model included age, gender, and SelT~m creatinine, Mean ribavirin clearance estimates were 18.3 L/hr for a typical male patient, and 13.5 L/hr for a typical female patient. The intersubject variability was 24%. The residual variability was 17% at the ribavirin concentration level of 2500 ng/mL. Higher ribavirin concentrations were associated with a higher chance of response. Hepatitis C virus (HCV) genotype and baseline viral load had substantial impact on response, with HCV genotype one and high baseline virus count having the lowest chance of response. Age was less influential but statistically significant. Ribavirin concentration and baseline hemoglobin level were the most important toxicity factors; patients with high ribavirin concentration and low baseline hemoglobin had the highest risk of experiencing toxicity, Body weight and age were also included in the toxicity model for their significant effects. Conclusion: The concentration-response relationship was consistent with that from previous Intron A + ribavirin studies. In order to achieve similar systemic exposure and better clinical response, ribavirin should be administered (in combination with PEG-Intron) according to body weight.
Baylor Coll of Medicine, Houston, Tx, Houston, TX; Paul Gaglio, Andrea Duchini, Tricia McClelland, Baylor Colt of Medicine, Houston, TX This study includes a sample of 11 patients (6 males, 5 females) who are either non-responders (n= 6) or relapsers (n= 5) to a prior treatment of combination or monotherapy for chronic hepatitis C. When beginning Pegylated interferon and Ribavirin therapy, at week 2 and 4 and every 4 weeks during treatment; these patients are being monitored for severity of side effects using the Symptom Score Sheet ($3) and for depression using the Beck Depression Index (BDI). Duration of therapy in these patients ranges from 2 to 20 weeks (mean 8.9 --_ 6.2). Severity of side effects increased from baseline (mean 9.2 -+ 7.0) to 2 weeks of treatment (mean 16.2 + 15.0) and increased further at 4 weeks of treatment (mean 18.9 ± 18.0). Of the 7 subjects who have completed more than 8 weeks of treatment, 4 have continued to demonstrate increased severity of side effects at the 8 week time point. A similar pattern was present in the depression scores (baseline mean 7.3 -+ 7.0; 2 week mean 11.2 ± 10.0; 4 week mean 15.0 + 9.5) and number of medications needed during treatment for side effect management (baseline mean 0.7 ± 0; 2 week mean 1.7 + 1.0; 4 week mean 2.5 + 1.5; 8 week mean 3.0 + 3.0). Regression analysis revealed that 56% of the variance in the severity of side effects during treatment was explained by the average BDI score during treatment (F = 11.69, p = .008). Compared to the 7 patients not on antidepressants at the beginning of treatment, the 4 subjects who were on antidepressants had more severe average side effects ($3 mean 14.0 ± 10.4 vs mean 6.4 + 6.3) and more depression (BDI mean 10.8 ± 7.1 vs 5.4 - 4.9) prior to treatment. This difference continued during treatment with the patients on antidepressants prior to treatment having higher average $3 (mean 27.6 --- 2.6 vs 11.8 ± 6.2) and average BDI (mean 21.4 + 9.5 vs mean 8.7 + 6.1 ) scores during treatment. Conclusions: This interim analysis of patients on Pegylated interferon and Ribavirin therapy reveals that the side effects tend to be cumulative during the first 4 to 8 weeks of medication. Patients who will suffer the most severe side effects and require the most support during treatment are those with increased depression, especiafly those who show signs of depression or are on treatment for depression prior to initiation of treatment.
AASLD ABSTRACTS
599A
1707
1708
SAFETY AND EFFICACY OF AMANTADINE AS RESCUE THERAPY FOR PATIENTS FAILING TO CLEAR HCV RNA IN SERUM AFTER SIX MONTHS OF TREATMENT W I T H INTERFERON AND RIBAVIRIN.
W H A T HAPPENS TO THE USED MATERIAL (NEEDLES, VIALS, SYRINGES, PENS ) AFTER HOME INTERFERON THERAPY FOR CHRONIC HEPATITIS C ?. Denis Ouzan Dr, Arnault Tzank Institute, Saint Laurent du
Gerond V Lake-Bakaar, Jericho Turnpike, Syosset, NY
Var France; Remy Collomp, Aline Mousnier, pharmacie CHU nice, Nice France
The combination of interferon and ribavirin is currently first line treatment in patients with chronic hepatitis C liver disease. However, a significant number of patients, especially those infected with genotype la or lb do not achieve complete virological clearance, defined as absence of HCV RNA in serum by PCR or TMA assay, after six months of continuous treatment. Therapy is usually terminated at this point since the probability of a sustained virological response after full 48-week treatment is low in these patients. There have been a number of reports suggesting that Amantadine, a synthetic antiviral agent with activity against influenza A and C viruses, may have some activity in chronic HCV liver disease, as triple therapy in Rebetron failures. We therefore evaluated the safety and efficacy of adding amantadine to concomitant interferon plus ribavirin, in chronic HCV liver disease patients who have failed to clear HCV after six months of treatment with interferon and ribavirin. We included 24 patients (six females, aged between 32 to 56 years) in the study, on an intention to treat basis. All but one was known to be infected with genotype 1. Six had histological evidence of established cirrhosis. All had failed at least six months of treatment with interferon and ribavirin. Interferon and ribavirin were given at standard or slightly reduced doses, Amantadine was given orally at a dose of 100 mg twice daily. Results: Twenty one of 24 patients completed at least six months of treatment. One discontinued after 2 weeks because of increased malaise; another after one month because of increased weight loss; and a third because of lack of efficacy after three months. One initially stopped treatment for one week because of a rash; however, the rash did not recur on restarting treatment. In the group of patients who completed six months of treatment, the mean WBC did not differ significantly before and after treatment • Hemoglobin levels also did not change significantly before and after. Two of the 24 (8 percent) had a sustained virological response. Conclusion: Triple therapy appears to be safe in patients with chronic HCV liver disease, However, treatment efficacy is low, since only eight percent achieved a sustained virological response.
The current treatment of reference for chronic hepatitis C is a combination of recombinant alfa interferon and ribavirin. The interferon therapy is administered entirely at the patient's home (3 injections a week for 6 to 12 months). This study was designed to determine the outcome of the material used for home interferon therapy and to assess the information given to patients concerning interferon administration and waste disposal. For this purpose, a prospective survey was conducted from Septembre to December 1999 on 108 patients who had been on interferon therapy for chtonic hepatitis C for at least 1 month. In more than 50% of cases, the interferon was self-injected by the patient (patient 58%, nurse 32%, family member 10%). Only 32% of the patients received special containers for disposal of used needles. In 41% of cases, the needles were merely put into the trash ; in 23%, the needles were thrown away without having been recapped. Uncapped needles thrown away directly into the trash, which involve a maximum risk of exposure, represented 5% of cases. Seven needlestick injuries were reported (6.5%), including one involving a family member ; most of these accidents occured while recapping the used needle. Whereas instructions for interferon administration appeared to be correctly explained to patients (83% of cases, either verbally or with the help of a written instruction sheet), only 51% of patients had been given instructions on proper disposal of the used material. In conclusion, although this French study cannot be extrapolated to all settings, findings suggest that the disposal of materials used for home treatment of chronic hepatitis C is less than optimum and should be improved. The potential risk of viral contamination is increased for co-infectd patients (hepatitis C and HIV). Improvement of waste disposal requires better patient information and the establishment of specific procedures for infectious waste disposal, which should be extended to include all types of material used for home care. The purpose of this study is to make all health care professionals involved in such treatments aware of their responsibility in this domain.
1709
1710
POPULATION PHARMACOKINETIC A N D PItAILMACODYNAMIC ANALYSES OF RIBAVIRIN IN PATIENTS W I T H CHRONIC HEPATITIS
SYMPTOM DEVELOPMENT AND MANAGEMENT IN PATIENTS WITH CHRONIC HEPATITIS C ON PEGYLATED INTERFERON AND RIBAVIRIN THERAPY. Reem H Ghalib, Cheryl Levine, Rise Stribling, Thikra Kadhim,
C. Juif F Jen, Mark Laughlin, Carol Chung, Samuel Heft, Melton B Affrime, Gerald Hajian, Schering-Plongh Research Institute, Kenilworth, NJ Background: There is a positive association between ribavirin concentration and sustained virologic response and hematological toxicity in the patients treated with interferon alfa-2b (Intron A) + ribavirin (Jen, Glue, Gupta, et.al. Ther Drug Monit. 2000). Objective: To quantify the dose-concentration-response/toxicity relationships for ribavirin in the patients with chronic hepatitis C including the possible influences of covariates on these relationships in the patients treated with PEG-Intron/Intron A + ribavirin. Method: Population pharmacokinetics (PPK) of ribavirin was assessed on 2911 sparsely sampled serum concentrations obtained from 1367 patients. Ribavirin doses ranged 800-1200 rag/day BID. Covariates included body weight, age, gender, serum creatinine, and estimated creatinine clearance. Ribavirin apparent clearance (CLapp) was the primary pharmacokinetic parameter, and was determined by steady-state infusion model. Mixed-effects modeling was used to analyze the data. The model building and parameter estimation were carried out using NONMEM. The virologic response and toxicity (hemoglobin level at treatment week 4 < 10.5 g/dL as an event) were analyzed using logistic regression. The PPK-model based estimates of ribavirin concentrations together with other important factors including demography, virus genotype, baseline viral load, and baseline hemoglobin level were included in the analyses. Results: CLapp was an increasing function of body weight which was the mo~- i-~uential covariate. Other covariates in the clearance model included age, gender, and SelT~m creatinine, Mean ribavirin clearance estimates were 18.3 L/hr for a typical male patient, and 13.5 L/hr for a typical female patient. The intersubject variability was 24%. The residual variability was 17% at the ribavirin concentration level of 2500 ng/mL. Higher ribavirin concentrations were associated with a higher chance of response. Hepatitis C virus (HCV) genotype and baseline viral load had substantial impact on response, with HCV genotype one and high baseline virus count having the lowest chance of response. Age was less influential but statistically significant. Ribavirin concentration and baseline hemoglobin level were the most important toxicity factors; patients with high ribavirin concentration and low baseline hemoglobin had the highest risk of experiencing toxicity, Body weight and age were also included in the toxicity model for their significant effects. Conclusion: The concentration-response relationship was consistent with that from previous Intron A + ribavirin studies. In order to achieve similar systemic exposure and better clinical response, ribavirin should be administered (in combination with PEG-Intron) according to body weight.
Baylor Coll of Medicine, Houston, Tx, Houston, TX; Paul Gaglio, Andrea Duchini, Tricia McClelland, Baylor Colt of Medicine, Houston, TX This study includes a sample of 11 patients (6 males, 5 females) who are either non-responders (n= 6) or relapsers (n= 5) to a prior treatment of combination or monotherapy for chronic hepatitis C. When beginning Pegylated interferon and Ribavirin therapy, at week 2 and 4 and every 4 weeks during treatment; these patients are being monitored for severity of side effects using the Symptom Score Sheet ($3) and for depression using the Beck Depression Index (BDI). Duration of therapy in these patients ranges from 2 to 20 weeks (mean 8.9 --_ 6.2). Severity of side effects increased from baseline (mean 9.2 -+ 7.0) to 2 weeks of treatment (mean 16.2 + 15.0) and increased further at 4 weeks of treatment (mean 18.9 ± 18.0). Of the 7 subjects who have completed more than 8 weeks of treatment, 4 have continued to demonstrate increased severity of side effects at the 8 week time point. A similar pattern was present in the depression scores (baseline mean 7.3 -+ 7.0; 2 week mean 11.2 ± 10.0; 4 week mean 15.0 + 9.5) and number of medications needed during treatment for side effect management (baseline mean 0.7 ± 0; 2 week mean 1.7 + 1.0; 4 week mean 2.5 + 1.5; 8 week mean 3.0 + 3.0). Regression analysis revealed that 56% of the variance in the severity of side effects during treatment was explained by the average BDI score during treatment (F = 11.69, p = .008). Compared to the 7 patients not on antidepressants at the beginning of treatment, the 4 subjects who were on antidepressants had more severe average side effects ($3 mean 14.0 ± 10.4 vs mean 6.4 + 6.3) and more depression (BDI mean 10.8 ± 7.1 vs 5.4 - 4.9) prior to treatment. This difference continued during treatment with the patients on antidepressants prior to treatment having higher average $3 (mean 27.6 --- 2.6 vs 11.8 ± 6.2) and average BDI (mean 21.4 + 9.5 vs mean 8.7 + 6.1 ) scores during treatment. Conclusions: This interim analysis of patients on Pegylated interferon and Ribavirin therapy reveals that the side effects tend to be cumulative during the first 4 to 8 weeks of medication. Patients who will suffer the most severe side effects and require the most support during treatment are those with increased depression, especiafly those who show signs of depression or are on treatment for depression prior to initiation of treatment.