The pharmacokinetics of peginterferon alfa-2a and ribavirin in African American, Hispanic and Caucasian patients with chronic hepatitis C

Authors


Correspondence to:

Dr B. J. Brennan, 340 Kingsland St, Building 721, Nutley, NJ 07110, USA.

E-mail: barbara.brennan@roche.com

Summary

Background

Amongst Caucasian, Hispanic and African Americans with genotype 1 hepatitis C virus (HCV), there is a wide variation in response to treatment with peginterferon alfa-2a (PEG-IFN alfa-2a) and ribavirin.

Aim

To evaluate the pharmacokinetics (PK) of PEG-IFN alfa-2a and ribavirin among these three groups.

Methods

Forty-seven patients with genotype 1 CHC (17 African Americans, 14 Hispanics and 16 Caucasians) received 8 weeks of PEG-IFN alfa-2a (180 &g/week) and ribavirin (1000 or 1200 mg/day). PEG-IFN alfa-2a serum concentrations and ribavirin plasma concentrations were measured following the first dose and at week 8. Pharmacokinetic parameters (Cmax, Tmax, AUC, CL/F) were estimated using noncompartmental methods.

Results

There was no difference in the pharmacokinetic parameters for PEG-IFN alfa-2a following single-dose or steady-state administration between African American or Hispanic patients compared with Caucasian patients. Ribavirin pharmacokinetic parameters were similar between Hispanic and Caucasian patients for single-dose and steady-state administration. The single-dose Cmax was 33% lower (< 0.05) in African American compared with Caucasian patients. Other ribavirin single-dose and steady-state pharmacokinetic parameters were slightly decreased (approximately 20% lower) in African American patients, but were not considered clinically meaningful.

Conclusions

No differences were observed in PEG-IFN alfa-2a pharmacokinetic parameters between African American or Hispanic patients compared with Caucasian patients. For ribavirin, no differences were observed in pharmacokinetic parameters between Hispanic and Caucasian patients. While a trend towards increased ribavirin clearance and decreased exposure was observed in African American patients vs. Caucasian patients, the differences were small and not considered clinically meaningful (Clinical Trial Number: NP17354).

Introduction

Hepatitis C infection is a major cause of morbidity and mortality throughout the world.[1-3] Between 170 and 200 million people are infected with the hepatitis C virus (HCV) worldwide, with three to four million people newly infected each year.[4, 5] At least 70% of those infected are expected to eventually develop chronic hepatitis C (CHC).[6] If not successfully treated, CHC can lead to serious complications such as cirrhosis and hepatocellular carcinoma.[7] CHC is currently the leading indication for liver transplantation in the United States.[8, 9]

For over a decade, the standard of care for CHC was the combination therapy of pegylated interferon (PEG-IFN) plus ribavirin. This combination produces sustained virological response (SVR) rates of up to 66% in randomised multinational trials.[10-13] Efficacy of this therapy is variable, with response dependent largely on viral genotype and race.[14-16] Patients infected with genotype 1 CHC have lower SVR rates compared with those with genotypes 2 and 3.[14, 17, 18] SVR is 52% for genotype 1 CHC patients, while genotype 2 or 3 patients have an SVR rate of 70–80%.[14] Among genotype 1 CHC patients, African Americans have 50% lower SVR rates than Caucasians when treated with PEG-IFN and ribavirin alone.[19] The largest trial to date to examine race and SVR is the Virahep-C study, which enrolled 196 African American and 205 Caucasian patients with genotype 1 CHC.[20] The SVR rates after treatment with PEG-IFN alfa-2a and ribavirin were 28% and 52% in African American and Caucasian patients respectively, controlling for other factors that were independently associated with SVR. In additional studies using conventional interferon in combination with ribavirin, SVR was highest among Caucasian patients (39%), followed by Hispanic (23%) and African American patients (14%).[21, 22] The use of PEG-IFN plus ribavirin increased SVR in African American patients to approximately 30%.[23] However, this SVR was still lower than the 52% SVR observed in the overall CHC population. Recently, the direct-acting antivirals boceprevir and telaprevir were approved for use in combination with PEG-IFN and ribavirin therapy for the treatment of genotype 1 CHC.[24, 25] The addition of either of these protease inhibitors to PEG-IFN and ribavirin, also known as ‘triple therapy,’ has substantially improved SVR rates and possibly shortened the duration of treatment in patients compared with PEG-IFN and ribavirin alone – especially in hard-to-treat patient groups, such as those who had no response to previous PEG-IFN and ribavirin therapy.[26-29] While the SVR rates for triple therapy are nearly double compared with PEG-IFN and ribavirin alone, they are still lower in African American patients than in Caucasian patients. In two phase 3 trials for boceprevir with PEG-IFN and ribavirin (SPRINT-2 and HCV RESPOND-2), SVR was 68% for non–African American patients and 53% for African American patients.[28, 30] African American patients also had a lower response when telaprevir was used in combination with PEG-IFN and ribavirin. In one of the telaprevir phase 3 trials (ADVANCE), SVR was 60% for African American patients compared with 74% in Caucasian and 67% in Hispanic patients.[27] Similar SVR results for each racial/ethnic group were obtained from another telaprevir phase 3 trial (ILLUMINATE).[31]

Factors that contribute to this disparity in response to CHC therapy between racial/ethnic groups are poorly explained by differences in socio-demographic characteristics, compliance to treatment, serum lipid levels or IFN-alpha signalling.[32-36] Recent genome-wide association studies have identified single-nucleotide polymorphisms around the gene coding for IFN-λ-3 (IL28B) that correlate with the treatment response in genotype 1 HCV patients.[37-40] The ‘good response’ variant (rs12979860 CC genotype) is associated with a two- to threefold increase in SVR and clearance rates over the unfavourable variants (rs12979860 CT or TT genotype) for patients treated with PEG-IFN and ribavirin.[41-43] The effect of the different IL28B genotypes on SVR was similar in all racial/ethnic groups tested, including Caucasian, African, Hispanic and Asian, with the CC genotype associated with the most favourable response. However, the genotype frequencies differed between racial/ethnic groups, with only 16% of African American patients with CHC having the favourable CC genotype, compared with 39% of Caucasian and 35% of Hispanic patients with CHC.[44] The difference in the frequency of the favourable CC genotype between patients of different racial/ethnic backgrounds correlates with the difference observed in SVR. In addition, within the favourable CC genotype, SVR rates were still lower for African American patients (53%) compared with Caucasian (82%) and Hispanic patients (≈75%). The difference in frequency of the favourable CC genotype between Caucasian and African American patients accounted for approximately 50% of the observed differences in SVR rates.[44, 45] As genotype frequency does not entirely explain the difference in treatment response between these two races, there may be other factors that contribute to the observed differences in SVR.

The Virahep-C study examined the relationship between the pharmacokinetics (PK) of PEG-IFN alfa-2a and SVR rates between African American and Caucasian patients. PEG-IFN alfa-2a pharmacokinetic variability also could not explain the racial differences in response to treatment. While this limited pharmacokinetic evaluation has been done on PEG-IFN alfa-2a, no study to date has assessed the PK of ribavirin and PEG-IFN alfa-2a in African American, Hispanic and Caucasian groups. The purpose of this study was to determine if there is a correlation between race/ethnicity and PK by evaluating single- and multiple-dose PK of PEG-IFN alfa-2a and ribavirin in African American, Hispanic and Caucasian patients chronically infected with genotype 1 HCV.

Patients and methods

Subjects

A total of 47 patients were enrolled in this study across four centres in the United States. To be eligible, patients had to be African American, Hispanic or Caucasian men or women between 18 and 65 years of age with genotype 1 CHC (as determined by enzyme immunoassay screening). All patients provided written informed consent. For the purposes of this study, patients were included who self-reported their race as African American or Caucasian and their ethnicity as either Hispanic or Latino or Not Hispanic or Latino. Patients were excluded if they received either interferon or ribavirin within 6 months prior to enrolment; smoked more than 10 cigarettes per day; tested positive for hepatitis A, B or human immunodeficiency virus; had decompensated liver disease or liver disease other than CHC; had cirrhosis or transition to cirrhosis; had a neutrophil count <1500 cells/mm3, haemoglobin <12 g/dL in women or <13 g/dL in men, or platelet count <90 000 cells/mm3; had any clinically significant pre-existing diseases; had evidence of active or suspected cancer; had active drug or alcohol abuse; had a history of a major organ transplantation with an existing functional graft; or had retinopathy. A negative pregnancy test for women of childbearing potential and use of effective contraception during the study and for up to 6 months after the last ribavirin dose were required. No concomitant medication was permitted, with the exception of medications to treat adverse events, unless the rationale for exception was provided and agreed upon.

Study design

This was a multicentre, multiple-dose, parallel-group, open-label pharmacokinetic study conducted at four sites in the United States in Hispanic, African American and Caucasian (control group) patients with genotype 1 CHC (NP17354). This study was approved by an independent ethics committee. As this was an exploratory pharmacokinetic study, a sample size of 15 patients per ethnicity group was chosen for this study based on practical considerations for a total of 45 patients. Drug treatment was 180 &g of PEG-IFN alfa-2a (Pegasys, Hoffmann-La Roche Inc, Nutley, USA) injected once weekly in combination with 1000 mg (for patients weighing <75 kg) or 1200 mg (for patients weighing ≥75 kg) of oral ribavirin (Copegus, Hoffmann-La Roche Inc., Nutley, NJ, USA) daily. Ribavirin was given as split doses in the morning and evening with food. Patients were treated for 8 weeks, with a 1-week follow-up period (week 9). Detailed information on patient adherence to study medication was reported in the study case report form. Adherence data reported were based upon the weekly dose of PEG-IFN alfa-2a administered by study staff as well as daily ribavirin taken orally by patients. Patients were asked to return the empty bottles of used ribavirin and unused ribavirin medication at each visit along with the drug diary. Returned medication was counted and justified against the diary entries by study site personnel. Multiple-dose pharmacokinetic assessments of PEG-IFN alfa-2a and ribavirin were performed after 8 weeks of treatment to ensure that steady-state concentrations were achieved. Patient safety, including clinical and laboratory adverse events as well as vital signs, was evaluated throughout the study. Following study completion, patients were provided with options for continuing care.

Blood sampling and analytic methods

Blood samples for PEG-IFN alfa-2a pharmacokinetic assessment in serum were taken predose and at 0.5, 1, 3, 5, 8, 12, 24, 48, 72, 96, 120, 144, and 168 h postdose at weeks 1 (first dose) and 8 (steady state). Blood samples for pharmacokinetic assessment of ribavirin in plasma were taken predose and at 0.5, 1, 3, 4, 5, 6, 8 and 12 h postdose at weeks 1 (first dose) and 8 (steady state). PEG-IFN alfa-2a serum samples were analysed using an enzyme-linked immunosorbent assay method at Quest Pharmaceutical Services (Newark, Delaware). Ribavirin plasma samples were analysed using liquid chromatography–mass spectrometry at Huntingdon Life Sciences (East Millstone, Franklin Township, NJ, USA).

Pharmacokinetic parameters

Serum (PEG-IFN alfa-2a) or plasma (ribavirin) pharmacokinetic data were analysed using standard noncompartmental methods with WinNonlin (Version 4.1.a; Pharsight Corporation, Palo Alto, CA, USA). Actual sampling times were used to calculate the pharmacokinetic parameters. Maximum serum or plasma concentration (Cmax) was determined from the observed highest concentration. Area under the plasma concentration–time curves during a specified time period (AUC0–168 for PEG-IFN alfa-2a and AUC0–12 for ribavirin) on day 1 and (AUC0–τ) at week 8 was calculated using the linear trapezoidal rule. Apparent oral clearance (CL/F) was calculated at week 8 by dividing the dose by the area under the plasma concentration–time curve over the dosing interval (AUC0–τ). The minimum concentration at steady state (Css min) was the minimum concentration during the dosing interval at steady state based on samples collected during that interval.

Statistical method

Analysis of variance (anova) was used to analyse the pharmacokinetic parameters AUC and Cmax. The patient-group comparisons τCaucasianτAfrican American (Hispanic), the residual variance σ2, and the 90% confidence limits for the ethnic group comparisons were estimated from the anova model. For log-transformed variables (AUC, Cmax, and Css min), the ratio of true patient racial/ethnic group means and the confidence limits for the corresponding ratio of means of the untransformed variables were calculated by exponentiation of the least squares means differences and the confidence limits for the transformed values respectively.

Results

Subjects

A total of 47 patients were enrolled (African American, 17; Hispanic, 14; Caucasian, 16), and 43 patients completed 8 weeks of treatment. The pharmacokinetic population included only patients who received at least one dose of either study drug and who completed the baseline pharmacokinetic assessments. Data from patients with consistently low PEG-IFN alfa-2a concentrations (defined as <20% of mean values) were also excluded from the pharmacokinetic analysis. This phenomenon of low or undetectable PEG-IFN alfa-2a serum concentrations has been observed in previous pharmacokinetic studies and is considered to be related to endogenous substances present in the serum that interfere with the ability of the ELISA assay to detect PEG-IFN alfa-2a. Ribavirin and PEG-IFN alfa-2a pharmacokinetic data that were below the limit of quantification were treated as missing and excluded from the analysis. Patients had the right to withdraw from the study at any time for any reason and patients that discontinued ribavirin could still remain on PEG-IFN alfa-2a to allow for maximum inclusion of data.

Data from two patients were not included in the statistical analysis of both ribavirin and PEG-IFN alfa-2a pharmacokinetics. One African American patient had an incomplete sample set collected for week 1 that did not allow for accurate estimation of the PK parameters and withdrew from the study prior to week 8. One Caucasian patient withdrew from the study before receiving any treatment and had no samples at week 1 and week 8. Data from three patients were not included in the statistical analysis of ribavirin pharmacokinetics. Two African American patients withdrew from the study prior to week 8. One Hispanic patient had inaccurate sampling time throughout the dosing interval at week 8 that did not allow for accurate estimation of the PK parameters. However, the week 1 data for all these patients were included to make every effort to maximise the amount of data included in the analysis.

Data from six patients were not included in the statistical analysis of PEG-IFN alfa-2a pharmacokinetics. One African American patient withdrew from the study prior to week 8, but had data collected for week 1. Another African American patient was missing samples, which resulted in a large number of missing data points at week 1 that did not allow for accurate estimation of the PK parameters and withdrew from the study prior to week 8. Another African American patient was excluded as most PEG-IFN alfa-2a levels for week 1 were recorded as below the limit of quantification and for week 8 levels were <15% of the mean values. One Hispanic patient had inconsistent or low values in week 1 and values <20% of mean values in week 8. Another Hispanic patient had inaccurate sampling time and was missing samples throughout the week 8 collection that did not allow for accurate estimation of the PK parameters, but had data collected for week 1. One Caucasian patient was missing samples throughout the week 1 collection that did not allow for accurate estimation of the PK parameters, but had samples collected for week 8.

For the patients who completed 8 weeks of treatment, adherence to study medication was greater than 99% in all groups. Baseline characteristics for the patients in all three groups were well matched with respect to median age, but differed in median body weight and height (Table 1). Hispanic patients were approximately 10 kg lighter and 10 cm shorter than African American and Caucasian patients. Patients in each of the three groups were screened and found to have similar characteristics pertaining to HCV genotype, duration of HCV infection, history of alcohol and tobacco use, liver disease progression, cancer status, organ transplantation status and presence of retinopathy.

Table 1. Summary of demographic characteristics of patients with evaluable PEG-IFN alfa-2a and ribavirin pharmacokinetics
Mean (±s.d.)African AmericanHispanicCaucasian
  1. s.d., standard deviation.

  2. a

    Week 1 reflects the weekly dosing schedule of Peg-IFN and a single dose of ribavirin at day 1.

PEG-IFN alfa-2a (40 kDa)Week 1a (N = 14)Week 8 (N = 13)Week 1a (N = 13)Week 8 (N = 12)Week 1a (N = 14)Week 8 (N = 15)
Female/male5/95/86/76/66/86/9
Age (years)47 ± 746 ± 750 ± 951 ± 949 ± 549 ± 5
Weight (kg)88 ± 1387 ± 1479 ± 1875 ± 1185 ± 1885 ± 17
Height (cm)173 ± 9173 ± 8165 ± 8164 ± 8176 ± 11176 ± 10
RibavirinWeek 1a (N = 16)Week 8 (N = 14)Week 1a (N = 14)Week 8 (N = 13)Week 1a (N = 15)Week 8 (N = 15)
Female/male6/106/86/86/76/96/9
Age (years)45 ± 945 ± 950 ± 950 ± 949 ± 549 ± 5
Weight (kg)87 ± 1685 ± 1679 ± 1876 ± 1185 ± 1785 ± 17
Height (cm)174 ± 8173 ± 8165 ± 8164 ± 8176 ± 10176 ± 10

During the study, two patients required dose reductions of PEG-IFN alfa-2a and two patients required dose reductions of ribavirin. Pharmacokinetic parameters for these patients (Cmax, AUC0–τ, Css min) at steady state were adjusted to the 180 μg dose of PEG-IFN alfa-2a for inclusion in the statistical analysis. All ribavirin data were normalised to a dose of 600 mg to compare the pharmacokinetic parameters among the three groups.

PEG-IFN alfa-2a pharmacokinetic results

Single dose (week 1)

Mean serum concentration–time profiles for PEG-IFN alfa-2a following administration of a single dose were similar among the African American, Hispanic and Caucasian groups at week 1 (Figure 1a). The pharmacokinetic parameters Tmax, Cmax and AUC0–168 for PEG-IFN alfa-2a were also comparable among the three groups (Table 2).

Figure 1.

(a) PEG-IFN alfa-2a mean concentration vs. time profiles following administration of a single dose at week 1. (b) PEG-IFN alfa-2a steady-state mean concentration vs. time profiles at week 8.

Table 2. Summary of PEG-IFN alfa-2a pharmacokinetic parameters
Pharmacokinetic parameter

African American

Mean ± s.d. (% CV)

Hispanic

Mean ± s.d. (% CV)

Caucasian

Mean ± s.d. (% CV)

  1. CV, coefficient of variation; s.d., standard deviation.

  2. a

    Normalised to dose of 180 μg.

Week 1(N = 14)(N = 13)(N = 14)
Tmax (h)83.6 ± 35.4 (42.4)93.6 ± 52.5 (56.1)75.6 ± 28.0 (37.0)
Cmax (ng/mL)9.9 ± 3.6 (36.0)8.7 ± 4.8 (55.4)10.2 ± 4.9 (47.7)
AUC0–168 (ng h/mL)1178 ± 443 (37.6)1046 ± 575 (54.9)1260 ± 577 (45.8)
Week 8(N = 13)(N = 12)(N = 15)
Tmax (h)53.2 ± 40.1 (76.6)36.0 ± 28.3 (78.5)54.3 ± 43.4 (79.8)
Cmax (ng/mL)a19.1 ± 7.2 (37.6)20.0 ± 6.2 (30.8)18.6 ± 8.9 (48.0)
AUC0–τ (ng h/mL)a2553 ± 892 (34.9)2682 ± 777 (29.0)2556 ± 1067 (41.8)
Css min (ng/mL)9.6 ± 3.2 (33.4)11.3 ± 3.5 (31.2)10.1 ± 3.4 (33.8)
CL/F (mL/h)82.7 ± 41.8 (50.5)72.9 ± 22.9 (31.4)83.8 ± 36.7 (43.8)

Serum concentrations of PEG-IFN alfa-2a reached a maximum between approximately 75 and 90 h in all patient groups, with mean Tmax values of 76, 84 and 94 h for Caucasian, African American and Hispanic patients respectively. The mean Cmax values for week 1 of single-dose PEG-IFN alfa-2a were 10.2, 9.9 and 8.7 ng/mL for Caucasian, African American and Hispanic patients respectively. To investigate the effect of race/ethnicity on PEG-IFN alfa-2a exposure, confidence intervals around the ratio of the means for African American vs. Caucasian and Hispanic vs. Caucasian patients were calculated. The geometric mean ratios for Cmax for African American/Caucasian and Hispanic/Caucasian patients were 1.01 and 0.80, with corresponding 90% confidence intervals of 0.73–1.42 and 0.57–1.13 respectively (Table 3). The mean AUC0–168 values were 1260, 1178 and 1046 ng h/mL for Caucasian, African American and Hispanic patients respectively (Table 2). AUC0–168 geometric mean ratios were 0.97 and 0.78 for African American/Caucasian and Hispanic/Caucasian patients, with corresponding 90% confidence intervals of 0.69–1.39 and 0.55–1.12 respectively (Table 3). The interpatient variability of Cmax and AUC0–168 ranged from 36% to 55% across the three patient groups. An anova performed on the single-dose study population determined that race/ethnicity did not have an effect on any of the pharmacokinetic parameters for PEG-IFN alfa-2a.

Table 3. Statistical analysis of week 1 and week 8 PEG-IFN alfa-2a (40 kDa) pharmacokinetic parameters of African American, Hispanic and Caucasian patient groups
WeekParametera (units)CohortNGeometric least squares meanRatio of geometric least squares meanb90% confidence interval ratio
  1. a

    Cmax and AUC normalised to 180-μg dose.

  2. b

    Ratio: comparator race/ethnicity to Caucasian.

1Cmax (ng/mL)African American149.31.01(0.73–1.42)
Hispanic137.30.80(0.57–1.13)
Caucasian149.1
1AUC0–168 (ng h/mL)African American1410930.97(0.69–1.39)
Hispanic138760.78(0.55–1.12)
Caucasian141121
8Cmax (ng/mL)African American1317.81.07(0.82–1.39)
Hispanic1219.11.14(0.87–1.50)
Caucasian1516.7
8AUC0–τ (ng h/mL)African American1323801.01(0.79–1.30)
Hispanic1225771.10(0.85–1.42)
Caucasian152346

Steady state (week 8)

PEG-IFN alfa-2a mean serum concentration–time profiles following steady-state administration at week 8 were similar for all ethnic groups (Figure 1b). Tmax occurred earlier in Hispanic patients, at 36 h, compared with 53 and 54 h for African American and Caucasian patients respectively (Table 2). However, these values are within the range observed in previous clinical studies.[11, 13, 20, 23, 46-49] The steady-state pharmacokinetic parameters Cmax, AUC0–τ, Css min and CL/F for PEG-IFN alfa-2a were comparable among the three ethnic groups (Table 2).

The mean Cmax values at week 8 for steady-state PEG-IFN alfa-2a were 17, 18 and 19 ng/mL for Caucasian, African American and Hispanic patients, respectively, with corresponding geometric mean ratios for African American/Caucasian and Hispanic/Caucasian patients of 1.07 and 1.14 and 90% confidence intervals of 0.82–1.39 and 0.87–1.50 respectively (Table 3). The mean AUC0–τ values were 2556, 2553 and 2682 ng h/mL for Caucasian, African American and Hispanic patients respectively (Table 2). AUC0–τ geometric mean ratios for week 8 were 1.01 and 1.10 for African American/Caucasian and Hispanic/Caucasian patients, with corresponding 90% confidence intervals of 0.79–1.30 and 0.85–1.42 respectively (Table 3). The interpatient variability of Cmax and AUC0–τ across all ethnic groups ranged from 29% to 48%. The Css min values were 10.1, 9.6 and 11.3 ng/mL and CL/F values were 84, 83 and 73 mL/h for Caucasian, African American and Hispanic patients respectively (Table 2). No correlations between African American race or Hispanic ethnicity and steady-state pharmacokinetic parameters of PEG-IFN alfa-2a were observed.

Ribavirin pharmacokinetic results

Single dose (week 1)

Following a single oral dose of 600 mg ribavirin at week 1, mean plasma concentration–time profiles were similar for all ethnic groups (Figure 2a). Tmax values were 2.1, 2.6 and 1.8 h for Caucasian, African American and Hispanic patients respectively (Table 4). The mean Cmax for African American and Hispanic patients decreased by 33% and 13% respectively, compared with that for Caucasian patients. Race/ethnicity had a weak effect (< 0.1) on ribavirin Cmax at week 1 after a single dose. The geometric mean ratios for Cmax for African American/Caucasian and Hispanic/Caucasian patients were 0.67 and 0.87, with corresponding 90% confidence intervals of 0.50–0.88 and 0.65–1.16 respectively (Table 5). The single-dose Cmax in the African American patient group was significantly different from that in the Caucasian patient group (< 0.05). No differences in ribavirin Cmax were observed between Hispanic and Caucasian patients. The AUC0–12 in African American and Hispanic patients was decreased by 21% and 9% respectively, compared with that in Caucasian patients. The geometric mean ratios were 0.79 and 0.91 for African American/Caucasian and Hispanic/Caucasian patients, with corresponding 90% confidence intervals of 0.63–1.01 and 0.71–1.16 respectively (Table 5). However, there was no effect of African American race or Hispanic ethnicity on AUC0–12 when compared with the Caucasian patient group. Interpatient variability of Cmax and AUC0–12 ranged from 31% to 48%.

Figure 2.

(a) Ribavirin mean concentration vs. time profiles following administration of a single dose at week 1. (b) Ribavirin steady-state mean concentration vs. time profiles at week 8.

Table 4. Summary of ribavirin pharmacokinetic parameters
Parameter

African American

Mean ± s.d. (% CV)

Hispanic

Mean ± s.d. (% CV)

Caucasian

Mean ± s.d. (% CV)

  1. CV, coefficient of variation; s.d., standard deviation.

  2. a

     Normalised to dose of 600 mg.

Week 1(N = 16)(N = 14)(N = 15)
Tmax (h)2.6 ± 1.2 (45.1)1.8 ± 1.3 (69.4)2.1 ± 1.1 (52.2)
Cmax (ng/mL)a717.6 ± 327.4 (45.6)906.6 ± 387.6 (42.8)1073.5 ± 511.3 (47.6)
AUC0–12 (ng h/mL)a4359 ± 1876 (43.0)4751 ± 1476 (31.1)5356 ± 2091 (39.1)
Week 8(N = 14)(N = 13)(N = 15)
Tmax (h)2.1 ± 1.5 (73.1)2.7 ± 2.3 (86.5)2.6 ± 2.1 (78.1)
Cmax (ng/mL)a3284 ± 1626 (49.5)4025 ± 1634 (40.6)3821 ± 1188 (31.1)
AUC0–τ (ng h/mL)a31 160 ± 14 806 (47.5)39 718 ± 15 920 (40.1)35 803 ± 10 918 (30.5)
Css min (ng/mL)1930 ± 663 (34.3)1956 ± 447 (22.8)2184 ± 643 (29.4)
CL/F (L/h)23.5 ± 11.2 (47.4)17.4 ± 6.9 (39.8)18.4 ± 6.3 (34.0)
Table 5. Statistical analysis of week 1 and week 8 ribavirin pharmacokinetic parameters of African American, Hispanic and Caucasian patient groups
WeekParametera (units)CohortNGeometric least squares meanRatio of geometric least squares meanb90% Confidence interval ratio
  1. a

    Cmax and AUC normalised to 600-mg dose.

  2. b

    Ratio: comparator race/ethnicity to Caucasian.

1Cmax (ng/mL)African American166450.67(0.50–0.88)
Hispanic148370.87(0.65–1.16)
Caucasian15966
1AUC0–12 (ng h/mL)African American1639750.79(0.63–1.01)
Hispanic1445360.91(0.71–1.16)
Caucasian155006
8Cmax (ng/mL)African American1429380.81(0.62–1.04)
Hispanic1337341.02(0.79–1.33)
Caucasian153645
8AUC0–τ (ng h/mL)African American1428 1790.82(0.64–1.06)
Hispanic1336 9861.08(0.84–1.39)
Caucasian1534 208

Steady state (week 8)

At week 8, ribavirin concentrations reached steady state and mean plasma concentrations remained constant throughout the 12 h dosing interval (Figure 2b).[47]Tmax values were 2.6, 2.1, and 2.7 h for Caucasian, African American and Hispanic patients respectively (Table 4). Css min for the three patient groups ranged between 1930 and 2184 ng/mL. The steady-state ribavirin Cmax and AUC0–τ were 19% and 18% lower respectively, in African American patients compared with Caucasian patients. The geometric mean ratios for Cmax and AUC0–τ for African American/Caucasian patients were 0.81 and 0.82, with corresponding 90% confidence intervals of 0.62–1.04 and 0.64–1.06 respectively (Table 5). This decrease in exposure appeared to result from an increase in ribavirin CL/F (estimated as dose/AUC0–τ) of approximately 28% in African American patients compared with Caucasian patients. Although African American patients trended towards a decreased steady-state Cmax and AUC and an increased CL/F, this difference was not considered to be clinically meaningful.

Hispanic patients had a slightly higher ribavirin exposure than Caucasian patients. Cmax and AUC0–τ were approximately 2% and 8% higher respectively, and CL/F was about 5% lower in Hispanic patients compared with Caucasian patients. The interpatient variability in ribavirin Cmax and AUC0–τ ranged from 31% to 50% and was similar between patient groups.

Safety

Most patients reported adverse events that are commonly experienced during treatment with interferon (e.g. fatigue, headaches, chills, pain, nausea, diarrhoea, arthralgia). Three patients required epoetin alfa for reduced haemoglobin levels. The majority of adverse events were mild or moderate in intensity in all three groups, and no patient withdrew from the study for safety reasons. The majority of patients had laboratory test results in the normal range for each parameter. No vital sign abnormalities were observed for blood pressure, heart rate or temperature.

Discussion

Patient race/ethnicity substantially affects the likelihood of response to CHC therapy. In this study, single-dose and steady-state PK of PEG-IFN alfa-2a and ribavirin were determined for African American, Hispanic and Caucasian patients with genotype 1 CHC. No differences based on African American race or Hispanic ethnicity were observed in pharmacokinetic parameters for PEG-IFN alfa-2a following single-dose and steady-state administration.

For ribavirin, no differences were observed between Hispanic and Caucasian patients following single-dose and steady-state administration. The single-dose Cmax (week 1) for ribavirin was the only pharmacokinetic parameter that was significantly lower (< 0.05) in African American patients compared with Caucasian patients, with a 33% decrease. Other ribavirin pharmacokinetic parameters also were lower in African American compared with Caucasian patients, with the mean Cmax and AUC0–τ at steady state 19% and 18% lower, respectively. Additionally, the CL/F was 28% higher in the African American compared with the Caucasian ethnic group. The differences between these parameters did not reach statistical significance, but this may be a reflection of the small sample size of approximately 15 patients per arm. These results indicate that the differences in ethnic group response to PEG-IFN alfa-2a and ribavirin therapy cannot be explained by PK. We cannot completely dismiss the possibility of differences in ribavirin pharmacokinetics by race as only plasma ribavirin exposures were measured and this may not be the relevant compartment for determining a pharmacokinetic-pharmacodynamic relationship for this drug. However, measuring ribavirin concentrations in compartments other than plasma (e.g. intracellular or hepatic) is technically challenging and previous studies have indicated a relationship between SVR and ribavirin plasma levels. Therefore, measuring ribavirin in plasma was considered appropriate for this study.[50]

Ribavirin was administered orally, daily with food because this is consistent with the prescribing information and allows the best representation of the real-life situation. Due to the long t1/2, ribavirin accumulates significantly between single dose and steady-state conditions (6–7 fold). Also, because of the long t1/2, the steady-state AUC0–τ is the more relevant PK parameter to evaluate as the limited PK sampling schedule (0–12 h) on Day 1, as a result of the q12h dosing schedule, does not allow for full characterization of the single dose AUC, where sampling for 3–5 t1/2 would generally be required. The effect of food on the ribavirin formulation used in the present study was previously evaluated in a PK study and there was a relatively minor effect of food on AUC (~1.4-fold increase) relative to the degree of accumulation that occurs between day 1 and steady state.[51] As this study was performed in a patient population over 8 weeks of treatment, it is unrealistic to expect patients to take each dose of ribavirin during the study with a standardised meal. Therefore, patients were instructed to take the dose with food, consistent with the prescribing information. Because of the extensive accumulation, it is unclear what the impact of a single standardised meal only on the PK sampling days would be.

In a population pharmacokinetic analysis of pooled ribavirin data from earlier clinical trials, the covariate ‘race,’ for African American patients only, achieved statistical significance, but did not meet the predefined criteria (change in CL/F oral clearance of 20%) for inclusion in the final population model.[49] Taking the results from the population pharmacokinetic analysis together with the data from the present study, there appears to be a trend for a slight increase in ribavirin CL/F in African American vs. Caucasian patients. While this is an interesting finding, this slight difference in ribavirin exposure is unlikely to contribute to the significant differences in SVR rates between African American and Caucasian patients receiving PEG-IFN and ribavirin therapy. Additionally, the population pharmacokinetic analysis found ribavirin clearance to be correlated with lean body weight. In contrast, this study determined that the 28% increase in CL/F in African American patients could not be explained by differences in body weight between the African American and Caucasian ethnic groups, as both groups were similar in this covariate (Table 1).

The Virahep-C study compared SVR rates between African American and Caucasian patients with genotype 1 CHC.[20, 48] Racial differences in response were evident as early as week 4 of treatment, with an SVR rate of only 28% in African American patients compared with 52% in Caucasian patients receiving PEG-IFN and ribavirin therapy (< 0.0001). This difference could not be explained by variability in baseline viral load, gender, age, weight or other factors, as these had been controlled for within the study. The authors concluded that race remained significantly and independently associated with SVR. In addition, the Virahep-C study found no difference in single-dose PEG-IFN alfa-2a Cmax and AUC0–τ between African American and Caucasian patients, which the present study also confirmed. The same correlation with race occurred in studies that have used one of the two recently approved direct-acting antivirals in combination with PEG-IFN and ribavirin. While overall SVR rates were higher using the triple therapy compared to PEG-IFN with ribavirin alone, African American patients with CHC consistently had lower SVR than Caucasian or Hispanic patients.

Recently, single-nucleotide polymorphisms near the IL28B gene were identified as the strongest baseline predictor of SVR to PEG-IFN and ribavirin therapy in patients with CHC.[52] IL28B status was not evaluated in this study because the data were collected before the IL28B correlation was determined and thus was not part of the study objectives. The primary objective of this study was to examine the PK parameters of different race/ethnicities for PEG-IFN and ribavirin. In addition, the relatively small size of our study would be too small to enable any meaningful conclusions to be drawn about the correlation between race/ethnicity, IL-28 status and PK parameters. Patients with the ‘good response’ CC genotype had a twofold higher rate of SVR compared with patients with the unfavourable TT genotype.[44] The frequency of the CC genotype was highest in Asian patients, followed by Caucasian, Hispanic and African American patients, which correlated with the different response to PEG-IFN and ribavirin treatment in these groups. Within the CC genotype, African American patients had slower rates of viral kinetics and lower SVR compared with other races/ethnicities. In addition, African American ancestry remained an independent negative predictor of outcome.[41, 44] As the primary objective of the present study was to assess pharmacokinetic differences, viral kinetic endpoints were not measured as part of the study. In triple-therapy studies with direct-acting antivirals in combination with PEG-IFN and ribavirin, IL28B variations seemed to play an attenuated role, as SVR was increased significantly across all IL28B genotypes compared with standard therapy, where only the CC genotype was correlated with a favourable response.[53-55] The new triple therapy is therefore advantageous to African American patients because they have the lowest frequency of CC genotype and the lowest SVR, even with the new combination therapies available. Using the IL28B genotype of a patient, along with other factors such as ethnicity, gender and comorbidities, will help physicians select the appropriate therapeutic combination or decide whether to treat CHC patients with PEG-IFN and ribavirin alone.

The clinical importance of these PK findings remains ambiguous until further studies are conducted to identify the cause of poor treatment response to PEG-IFN alfa-2a and ribavirin therapy in African American patients infected with genotype 1 CHC.

Acknowledgements

Declaration of personal interests: Barbara J. Brennan, Peter N. Morcos, Ka Wang, Steven D. Blotner and Joseph F. Grippo are employees of F. Hoffmann-La Roche. Royce Morrison is employed by Charles River Clinical Services Northwest and Comprehensive Clinical Development, is a core committee member of DIA Clinical Pharmacology SIAC, a board member of the Association of Clinical Pharmacology Units and the Northwest Association for Biomedical Research and owns stock in Charles River, LITMUS and XenoPort. Mark Sulkowski is on the scientific advisory board of Roche/Genentech and has a research grant to Johns Hopkins University. Declaration of funding interests: This study was funded by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this manuscript, furnished by Denise Kenski, PhD and Sue Currie, PhD of Health Interactions, was provided by Genentech Inc. and F. Hoffmann-La Roche Ltd.

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