Peginterferon pharmacokinetics in African American and Caucasian American patients with hepatitis C virus genotype 1 infection

Abstract

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 alpha-2a (180 microg/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 (>or=2-log(10) 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 alpha-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.

Figure 1. Serum Peginterferon alfa-2a concentrations

Serum peginterferon concentrations were measured by enzyme-linked immunoassay in patients infected with HCV genotype 1 as described in Materials and Methods. Results expressed as median ± interquartile range (IQR). The numbers of observations at each time point ranged between 141 and 153 for AA and 157 and 168 for CA, except for day 3 (AA = 40; CA = 51). Results were compared between AA and CA using the Wilcoxon rank-sum test.

Figure 2. Serum 2,5-OAS Fold-change

Serum 2,5-OAS activity was determined in patients infected with HCV genotype 1 using a commercially available radioimmunoassay (RIA) kit as described in Materials and Methods. The numbers of observations at each time point ranged between 153 and 160 for AA and 159 and 167 for CA, except for day 3 (AA = 72; CA = 84). A) Results expressed as median ± interquartile range (IQR). B) Data expressed as fold change at each day (2,5-OAS concentration /2,5-OAS concentration on day 0). Results were compared between AA ad CA using the Wilcoxon rank-sum test.

Figure 3. Serum HCV RNA Kinetics

Serum HCV RNA concentrations were measured in duplicate using the AmplicorTM assay (sensitivity 50 IU/ml. Roche Molecular Diagnostics). The numbers of observations at each time point ranged between 149 and 160 for AA and 167 and 173 for CA, except for day 3 (AA =72; CA =85). Results were compared between AA and CA using the Wilcoxon rank-sum test.

Figure 4. Serum peginterferon alfa-2a and EVR in AA (A) and CA (B) patients

Serum peginterferon concentrations were measured by ELISA as described in Materials and Methods. EVR was defined as a > 2-log₁₀ decline in serum HCV RNA or undetected serum HCV RNA at week-12 relative to week-0. Results were compared between EVR and NEVR using the Wilcoxon rank-sum test.

Figure 5. Serum 2,5-OAS fold-change and EVR in AA (A) and CA (B) patients

Serum 2,5-OAS concentrations were measured by RIA as described in Materials and Methods. Data expressed as fold change on each day relative to day 0 as described in figure 2. The EVR was defined as in figure 4 and in Materials and Methods. Results were compared between EVR and NEVR using the Wilcoxon rank-sum.