Peginterferon Pharmacokinetics in African American and Caucasian American Patients With Hepatitis C Virus Genotype 1 Infection
2008; Elsevier BV; Volume: 6; Issue: 5 Linguagem: Inglês
10.1016/j.cgh.2008.02.035
ISSN1542-7714
AutoresCharles D. Howell, Thomas C. Dowling, M.Ch. Saint Paul, Abdus S. Wahed, Norah A. Terrault, Milton W. Taylor, Lennox J. Jeffers, Jay H. Hoofnagle,
Tópico(s)Systemic Lupus Erythematosus Research
ResumoBackground & Aims: The relationship between serum peginterferon pharmacokinetics and pharmacodynamics and the early virologic response (EVR) to peginterferon and ribavirin therapy was assessed in patients with chronic hepatitis C virus (HCV) genotype 1 infection. Methods: A total of 333 patients (160 African Americans [AA] and 173 Caucasian Americans [CA]) who received peginterferon alfa-2a (180 μg/wk) without a dose modification during the initial 4 weeks of therapy were analyzed. Peginterferon and 2,5-oligoadenylate synthetase (2,5-OAS) serum levels were measured on days 0, 1, 2, 3, 7, 14, 28, 56, 84, and 168 of treatment. The EVR (≥2-log10 decline in HCV RNA levels by week 12 of therapy) was the primary virologic end point. Results: Peginterferon pharmacokinetics after the first dose were similar in AA and CA, but AA had greater peginterferon concentrations at days 1, 3, 14, and 28 (P < .05). AA had higher absolute serum 2,5-OAS levels on days 0, 1, 2, 3, 7, 14, 28, and 56 (P < .05), but the magnitude of 2,5-OAS induction during treatment were similar. AA patients showed a smaller decline in serum HCV RNA during the first 28 days of treatment (P < .001) and a lower EVR (65% vs 83%). AA and CA with EVR had significantly higher serum peginterferon concentrations and serum 2,5-OAS induction during the first 12 weeks than patients without an EVR. Conclusions: Peginterferon alfa-2a pharmacokinetic and pharmacodynamic variability is associated with EVR in both AA and CA with HCV infection, but do not explain the racial disparity in combination treatment efficacy. Background & Aims: The relationship between serum peginterferon pharmacokinetics and pharmacodynamics and the early virologic response (EVR) to peginterferon and ribavirin therapy was assessed in patients with chronic hepatitis C virus (HCV) genotype 1 infection. Methods: A total of 333 patients (160 African Americans [AA] and 173 Caucasian Americans [CA]) who received peginterferon alfa-2a (180 μg/wk) without a dose modification during the initial 4 weeks of therapy were analyzed. Peginterferon and 2,5-oligoadenylate synthetase (2,5-OAS) serum levels were measured on days 0, 1, 2, 3, 7, 14, 28, 56, 84, and 168 of treatment. The EVR (≥2-log10 decline in HCV RNA levels by week 12 of therapy) was the primary virologic end point. Results: Peginterferon pharmacokinetics after the first dose were similar in AA and CA, but AA had greater peginterferon concentrations at days 1, 3, 14, and 28 (P < .05). AA had higher absolute serum 2,5-OAS levels on days 0, 1, 2, 3, 7, 14, 28, and 56 (P < .05), but the magnitude of 2,5-OAS induction during treatment were similar. AA patients showed a smaller decline in serum HCV RNA during the first 28 days of treatment (P < .001) and a lower EVR (65% vs 83%). AA and CA with EVR had significantly higher serum peginterferon concentrations and serum 2,5-OAS induction during the first 12 weeks than patients without an EVR. Conclusions: Peginterferon alfa-2a pharmacokinetic and pharmacodynamic variability is associated with EVR in both AA and CA with HCV infection, but do not explain the racial disparity in combination treatment efficacy. The efficacy of peginterferon alfa and ribavirin treatment for chronic hepatitis C virus (HCV) infection varies by several viral and host factors including HCV genotype, pretreatment HCV RNA serum concentrations, amount of liver fibrosis, patient sex, age, and race. African Americans (AA) have the highest prevalence of anti-HCV (3.0%) in the United States, followed by Mexican Americans (1.3%) and non-Hispanic white Americans (1.5%).1Alter M.J. Kruszon-Moran D. Nainan O.V. et al.The prevalence of hepatitis C infection in the United States, 1988 through 1999.N Engl J Med. 1999; 341: 556-562Crossref PubMed Scopus (2426) Google Scholar Strikingly, AA also have the lowest rates of sustained clearance of HCV after treatment with alfa interferon (standard or pegylated) with and without ribavirin.2Muir A.J. Bornstein J.D. Killenberg P.G. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites.N Engl J Med. 2004; 350: 2265-2271Crossref PubMed Scopus (500) Google Scholar, 3Jeffers L. Cassidy W. Howell C.D. et al.Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic hepatitis C virus genotype 1.Hepatology. 2004; 39: 1702-1708Crossref PubMed Scopus (235) Google Scholar, 4Conjeevaram H.S. Fried M.W. Jeffers L.J. et al.Peginterferon and ribavirin treatment in African American and Caucasian American patients with chronic hepatitis C genotype 1.Gastroenterology. 2006; 31: 470-477Abstract Full Text Full Text PDF Scopus (437) Google Scholar The basis for this racial difference in efficacy of antiviral therapy is unknown. The study of Viral Resistance to Antiviral Therapy for Chronic Hepatitis C (Virahep-C) was a prospective, multicenter study designed to assess the rates of response to peginterferon alfa-2a plus ribavirin therapy in AA and Caucasian American (CA) patients with chronic hepatitis C and HCV genotype 1 infection and to attempt to elucidate the reasons for racial differences in response rates.4Conjeevaram H.S. Fried M.W. Jeffers L.J. et al.Peginterferon and ribavirin treatment in African American and Caucasian American patients with chronic hepatitis C genotype 1.Gastroenterology. 2006; 31: 470-477Abstract Full Text Full Text PDF Scopus (437) Google Scholar The sustained virologic response (SVR) rate—defined as lack of detectable serum HCV RNA 24 weeks after treatment—was significantly lower among AA than CA patients (28% vs 52%; P < .001). The lower virologic response among AA was apparent during the first month of treatment as shown by differences in rates of decrease in HCV RNA concentrations. Several clinical features that differed between the AA and CA patient cohorts, such as body mass index (BMI), insulin resistance, and total amount of peginterferon and ribavirin taken, were associated with a lower SVR rate in the total study population. However, these factors did not account for the racial disparity in the SVR rate in multivariable regression analysis.4Conjeevaram H.S. Fried M.W. Jeffers L.J. et al.Peginterferon and ribavirin treatment in African American and Caucasian American patients with chronic hepatitis C genotype 1.Gastroenterology. 2006; 31: 470-477Abstract Full Text Full Text PDF Scopus (437) Google Scholar Alpha interferons mediate antiviral effects by binding to the type I interferon receptor located in the plasma membranes of diverse cell types.5Stark G.R. Kerr I.M. Williams B.R.G. et al.How cells respond to interferons.Annu Rev Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3342) Google Scholar Cross-linking of type I interferon receptors activates Jak-1 and Tyk kinases that phosphorylate signaling transducers of activation and transcription 1 and 2 proteins. Phosphorylation induces signaling transducers of activation and transcription 1 and 2 dimerization, translocation to the nucleus, and transcriptional activation of hundreds of interferon-stimulated genes.6Ji X. Cheung R. Cooper S. et al.Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C.Hepatology. 2003; 37: 610-621Crossref PubMed Scopus (104) Google Scholar Hypothetically, defects in either peginterferon pharmacokinetics (ie, absorption, distribution, metabolism, and elimination) or pharmacodynamics (ie, binding to the type I interferon receptor and downstream signal transduction) could result in lower HCV clearance rates. Previous studies have found considerable interindividual variability in peginterferon pharmacokinetics among patients with chronic hepatitis C, although the relationship between pharmacokinetic variability to treatment efficacy is controversial.7Glue P. Rouzier-Panis R. Raffanel C. et al.A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C.Hepatology. 2000; 32: 647-653Crossref PubMed Scopus (239) Google Scholar, 8Sulkowski M. Wright T. Rossi S. et al.Peginterferon alfa-2a does not alter the pharmacokinetics of methadone in patients with chronic hepatitis C undergoing methadone maintenance therapy.Clin Pharmacol Ther. 2005; 77: 214-224Crossref PubMed Scopus (31) Google Scholar, 9Di Bisceglie A.M. Fan X. Chambers T. et al.Pharmacokinetics, pharmacodynamics, and hepatitis C viral kinetics during antiviral therapy: the null responder.J Med Virol. 2006; 78: 446-451Crossref PubMed Scopus (21) Google Scholar Ethnicity and race are important demographic factors that contribute to the variability in pharmacokinetics and pharmacodynamics for many drugs. For example, propranolol clearance is up to 76% higher in AA relative to CA, possibly owing to increased CYP1A2- or CYP2D6-mediated drug metabolism.10Sowinski K.M. Burlew B.S. Johnson J.A. Racial differences in sensitivity to the negative chronotropic effects of propranolol in healthy men.Clin Pharmacol Ther. 1995; 57: 678-683Crossref PubMed Scopus (18) Google Scholar, 11Sowinski K.M. Lima J.J. Burlew B.S. et al.Racial differences in propranolol enantiomer kinetics following simultaneous i.v. and oral administration.Br J Clin Pharmacol. 1996; 42: 339-346Crossref PubMed Scopus (28) Google Scholar Also, significant ethnic differences exist in the polymorphic hepatic reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase activity that is important for hepatic metabolism of quinones and activation of anticancer drugs such as mitomycin C.12Hershman D. Weinberg M. Rosner Z. et al.Ethnic neutropenia and treatment delay in African American women undergoing chemotherapy for early-stage breast cancer.J Natl Cancer Inst. 2003; 95: 1545-1548Crossref PubMed Scopus (113) Google Scholar Moreover, lower plasma efavirenz clearance has been associated with a cytochrome P450 2B6 gene (CYP2B6) polymorphism (516G→T) that is more frequent among AA compared with Americans of European descent.13Ribaudo H.J. Haas D.W. Tierney C. et al.Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study.Clin Infect Dis. 2006; 42: 401-407Crossref PubMed Scopus (183) Google Scholar The objective of the present study was to determine the relationship between serum peginterferon pharmacokinetics and pharmacodynamics and early virologic response (EVR) (≥2-log10 decline or undetected serum HCV RNA at week 12) during combination treatment in patients infected with HCV genotype 1 overall and within AA and CA racial groups in the Virahep-C study. A total of 401 patients (196 AA and 205 CA) between 18 and 70 years of age with chronic HCV genotype 1 infections and no previous HCV antiviral treatment were enrolled in the Virahep-C study.4Conjeevaram H.S. Fried M.W. Jeffers L.J. et al.Peginterferon and ribavirin treatment in African American and Caucasian American patients with chronic hepatitis C genotype 1.Gastroenterology. 2006; 31: 470-477Abstract Full Text Full Text PDF Scopus (437) Google Scholar All patients had a serum HCV RNA concentration of 600 IU/mL or greater and 399 patients had a liver biopsy before treatment that showed evidence of chronic hepatitis C. Subjects were treated with peginterferon alfa-2a (Pegasys; Roche Pharmaceuticals, Nutley, NJ) 180 μg subcutaneously weekly and ribavirin (Copegus; Roche Pharmaceuticals) 1000 or 1200 mg per day (based on body weight of 3 d) as outcome. Linear mixed models were used to investigate the association between longitudinal log viral levels over the first 28 days and the pharmacokinetic parameters in the 91 patients with first-dose peginterferon pharmacokinetics data. Such models take into account the correlations between observations within the same patients over time. Because the log viral levels were not linear in time, a square root transformation of time in weeks was performed to approximate viral levels with a linear model. The covariates included in the model were race, Cmax, Cmin, Tmax, AUC, and their interactions with time. The relationships between 28-day peginterferon levels (dependent variable) and demographic and clinical covariates such as race, age, viral level, and renal function were evaluated using linear regression analysis. Spearman rank correlations were used to explore the relationships between peginterferon levels, 2,5-OAS levels, and HCV RNA levels at different time points. A correlation coefficient (r) of 0.30 or greater with a P value of less than .05 was deemed to be significant. For all other analysis, a P values of less than .05 was used to determine the statistical significance. A linear mixed model of HCV RNA levels as outcome and peginterferon and 2,5-OAS levels along with race as covariates was used to assess the relationships of viral levels with peginterferon levels and 2,5-OAS levels. A separate linear mixed model for peginterferon concentrations was fit to assess its relationship with race and the 2,5-OAS levels over time (days treated as categories). For this model, robust standard errors were used for tests of significance. Association of EVR with race, peginterferon levels, and 2,5-OAS levels were investigated by using log-linear regression and results are reported as estimates of relative risks and confidence intervals. Table 1 shows the baseline characteristics of 333 patients who received full doses of peginterferon during the first 28 days of therapy. Compared with CA patients, AA patients had a higher BMI and were more likely to have a history of diabetes and of hypertension. In addition, AA patients also had a significantly lower serum alanine aminotransferase, albumin, and total bilirubin level than CA patients (P < .05). Also, AA patients were more likely to have HCV genotype 1b than CA patients (P = .005). There were no statistically significant differences in the baseline serum HCV RNA levels, patient age, estimated duration of HCV infection, history of alcohol and tobacco use, hepatic steatosis, liver necroinflammatory score, and liver fibrosis score between the 2 racial groups. Similar racial differences in clinical features also were found in the entire cohort of 401 patients enrolled in the Virahep-C study.4Conjeevaram H.S. Fried M.W. Jeffers L.J. et al.Peginterferon and ribavirin treatment in African American and Caucasian American patients with chronic hepatitis C genotype 1.Gastroenterology. 2006; 31: 470-477Abstract Full Text Full Text PDF Scopus (437) Google Scholar Sixty-eight patients with less than 100% adherence to full-dose peginterferon during the first 28 days were excluded. Compared with patients included in the pharmacokinetics study, excluded patients were more likely to be female (48.5% vs 32.1%; P = .01) and to have a lower EVR (50% vs 74.3%; P < .0001), end-of-treatment virologic responses (undetected serum HCV RNA at week 48) (38.1% vs 58.9%; P = .015), and SVR (32.1% vs 41.7%; P = .15). There were no significant differences between included and excluded patients in racial classification, baseline age, body weight, body mass index, serum alanine aminotransferase level, blood hemoglobin level, HCV viral load, hepatic steatosis, Ishak fibrosis score, and prevalence of bridging fibrosis and cirrhosis.Table 1Baseline Patient CharacteristicsCharacteristicAA (n = 160)CA (n = 173)P valueaThe Wilcoxon rank-sum test was used to compare distributions for continuous variables. The Pearson chi-square test was used to compare percentages.Male107 (67%)119 (69%).71Age, ybContinuous variables represented by medians(25th percentile, 75th percentile).49 (45–53)48 (43–52).08Duration of infection, ybContinuous variables represented by medians(25th percentile, 75th percentile).25 (18–32)27.0 (20–33).16Weight, kgbContinuous variables represented by medians(25th percentile, 75th percentile).87.3 (78.9–102.5)82.6 (73.5–97.1).004BMI, kg/m2bContinuous variables represented by medians(25th percentile, 75th percentile).29.5 (26.3–34.0)27.6 (24.8–31.7).003History of diabetes23 (14%)5 (3%).0002History of hypertension69 (43%)39 (23%)<.0001Current alcohol use, drinks/d (P = .50) <1138 (89%)147 (87%).57 1 to <28 (5%)14 (8%).26 ≥29 (6%)8 (5%).67Currently smoking66 (42.3)58 (33.9).12Alanine aminotransferase level, IU/L59.5 (41–88)76 (53–140)<.0001Albumin level, g/dLbContinuous variables represented by medians(25th percentile, 75th percentile).4.1 (3.8–4.3)4.2 (4.0–4.4).0008Total bilirubin level, mg/dLbContinuous variables represented by medians(25th percentile, 75th percentile).0.6 (0.4–0.8)0.7 (0.5–0.9).006Prothrombin time, international normalized ratiobContinuous variables represented by medians(25th percentile, 75th percentile).1.0 (0.9–1.1)1.0 (0.9–1.1).93Ishak necroinflammatory score (0–18)bContinuous variables represented by medians(25th percentile, 75th percentile).10 (8–12)11 (8–13).15Ishak fibrosis score (0–6)bContinuous variables represented by medians(25th percentile, 75th percentile).2 (1–3)2 (1–3).24Bridging fibrosis and cirrhosis54 (34%)69 (40%).28Steatosis (≥5% present), n46 (29%)64 (37%).13HCV subtype, n; P = .002 1a77 (48%)93 (54%).30 1b74 (46%)54 (31%).005HCV RNA level, ×106 IU/mLbContinuous variables represented by medians(25th percentile, 75th percentile).6.4 (5.6–6.7)6.5 (5.7–6.8).26a The Wilcoxon rank-sum test was used to compare distributions for continuous variables. The Pearson chi-square test was used to compare percentages.b Continuous variables represented by medians (25th percentile, 75th percentile). Open table in a new tab Median serum peginterferon concentrations and interquartile ranges (IQRs) from baseline (day 0) through treatment day 84 (wk 12) are shown in Figure 1 (day 0–7 shown in insert). Peginterferon was detectable on day 1 and peak concentrations were achieved by days 2 to 3 after the first injection, followed by a trough level on day 7 (week 1). Peginterferon trough concentrations increased gradually after subsequent doses and reached a steady state at day 56 (week 8). Peginterferon concentrations were significantly higher among AA than CA patients on days 1 (P = .02), 2 (P = .03), 14 (P = .03), and 28 (P = .006). Thereafter, peginterferon concentrations did not differ significantly between the 2 racial groups (P > .68 for days 56 [week 8], 84 [week 12], and 168 [week 24] [data not shown]). Peginterferon pharmacokinetic variables after the first dose were analyzed in 40 AA and 51 CA patients who had a day 3 serum specimen and who also received peginterferon without a dose modification or missed dose for the first 28 days of treatment. Results by racial group are shown in Table 2. Tmax values were less likely to be 3 days or fewer in CA than in AA patients (74% vs 93%; odds ratio, 0.24 [CA vs AA]; P = .045), but Cmax, Cmin, and AUC values after the first dose did not differ significantly between the 2 racial groups. In addition, there was no racial difference in the median peginterferon accumulation ratio, either among the 91 patients with first-dose pharmacokinetic parameters (Table 1) or the total cohort (AA, 2.67; IQR, 1.78–3.71; CA, 2.62; IQR, 1.94–4.32; P = .28). In logistic regression analyses with an indicator variable for Tmax (1: ≤3 d; 0: >3 d) as the dependent variable, patient sex (P = .71), body weight (P = .50), BMI (P = .98), and serum creatinine level (P = .41) were not associated significantly with Tmax. When adjusted for these baseline covariates, the association of race with Tmax did not change appreciably (OR, 0.21; 95% confidence interval [CI], 0.05–0.84; P = .027). No patient demographic or clinical characteristic examined was associated significantly with Cmax and AUC in either univariable or multivariable analyses (data not shown). In the 333 patients who were on full-dose peginterferon during the first 28 days, there were statistically significant unadjusted associations between a higher 28-day peginterferon level and both AA race (regression coefficient b, 2.66; 95% CI, 0.89–4.43; P = .003) and lower BMI (b, −0.38; 95% CI, −0.52 to −0.24; P < .0001). When adjusted for age and sex, these associations remained significant (AA race: regression coefficient b, 3.49; 95% CI, 1.76–5.20; P = .029; BMI: regression coefficient b, −0.44; 95% CI, −0.57 to −0.30; P = .003).Table 2Peginterferon Alfa-2a Noncompartmental Pharmacokinetic ParametersParameterAA (n = 40)CA (n = 51)P valueCmax, ng/mLaCmax, Cmin, AUC, and accumulation ratio values are expressed as median (IQR). P values correspond to 2-sample Wilcoxon rank tests.12.0 (7.7–16.0)10.1 (6.6–13.9).18Cmin, ng/mLaCmax, Cmin, AUC, and accumulation ratio values are expressed as median (IQR). P values correspond to 2-sample Wilcoxon rank tests.6.8 (3.5–8.9)7.6 (4.6–9.9).55Tmax, dbTmax values reported as n(%), P value derived from the Pearson chi-square test of association. 12 (5.0)7 (13.7) 213 (32.5)12 (23.5).045 322 (55.0)19 (37.3) 73 (7.5)13 (25.5)AUC, ng*h/mLaCmax, Cmin, AUC, and accumulation ratio values are expressed as median (IQR). P values correspond to 2-sample Wilcoxon rank tests.1413 (969–1926)1201 (759–1738).24Accumulation ratioaCmax, Cmin, AUC, and accumulation ratio values are expressed as median (IQR). P values correspond to 2-sample Wilcoxon rank tests., cRatio of the week 24 and week 1 peginterferon Cmin values.3.3 (2.6–4.9)2.9 (2.2–4.2).23a Cmax, Cmin, AUC, and accumulation ratio values are expressed as median (IQR). P values correspond to 2-sample Wilcoxon rank tests.b Tmax values reported as n (%), P value derived from the Pearson chi-square test of association.c Ratio of the week 24 and week 1 peginterferon Cmin values. Open table in a new tab Median (serum 2,5-OAS concentrations) and IQR in AA and CA patients from baseline through day 84 (week 12) of peginterferon and ribavirin treatment are shown in Figure 2A (day 0–7 shown in insert). The baseline (day 0) serum 2,5-OAS concentration was significantly higher among AA than CA patients (139.5 vs 106 pmol/dL; P < .0001). Both AA and CA showed a rapid increase in 2,5-OAS concentrations after the first dose of peginterferon with maximum levels between days 3 and 7, and little change in concentrations thereafter. Serum 2,5-OAS concentrations were significantly higher in AA than in CA patients from days 1 to 56 of treatment (Figure 2A). However, the fold-change in serum 2,5-OAS concentrations (relative to day 0) during the first 84 days (12 wk) of therapy were similar in AA and CA patients, except for day 1 (1.53 vs 1.67; P = .02) and day 84 (1.92 vs 2.31; P = .03) when the increase was higher among CA (Figure 2B). Median serum HCV RNA concentrations in AA and CA patients during the first 84 days (12 weeks) of treatment are shown in Figure 3. AA and CA had similar baseline serum HCV RNA levels, but different HCV RNA kinetics. AA had a triphasic HCV RNA pattern. The median HCV RNA level in AA patients decreased 0.9 log10 from days 0 to 3, followed in tandem by a 0.3-log10 increase (rebound) between days 3 and 7 and a gradual (3.0 log10) decline in HCV with a nadir at day 84. In contrast to AA patients, CA patients had a biphasic decline in HCV RNA between day 0 and 84, with a median 1.0-log10 decline from days 0 to 3 followed by a more rapid (2.7 log10) decrease in HCV RNA to a nadir at day 56. Compared with CA patients, AA patients had significantly higher serum HCV RNA concentrations from days 3 through 56. Consistent with the racial difference in viral kinetics, AA had lower rates of undetected serum HCV RNA at weeks 4 (10% vs 24%), 8 (23% vs 46%), and 12 (44% vs 69%) than CA. The association between serum peginterferon, 2,5-OAS, and HCV RNA concentrations during the first 4 weeks of treatment was assessed using the Spearman correlation coefficient (r). There were significant negative correlations between serum peginterferon concentrations and serum HCV RNA on days 1 (r = −0.52), 2 (r = −0.48), 3 (r = −0.38), 7 (r = −0.34), and 14 (r = −0.36) (P < .0001 for each) among CA patients, but only on days 1 (r = −0.37) and 2 (r = 0.35) (P < .0001 for each) among AA patients. With the exception of serum peginterferon on day 3 and 2,5-OAS on day 7 in CA (r = 0.30; P = .006), there were no significant correlations between serum peginterferon and serum 2,5-OAS concentrations in eit
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