Clinical Trial Result Information

Protocol number
NP17354

Title of Study
A multiple-dose, parallel-group, open-label study of the pharmacokinetics of Copegus (ribavirin) and Pegasys (peginterferon alfa-2a) in Blacks, Hispanics and Caucasians infected with Chronic Hepatitis C (CHC).

Sponsor
Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
PEGASYS

Generic name
peginterferon alfa-2a (40KD)

Therapeutic area
Hepatitis C, Chronic

Clinical study summary
This multi-center, parallel-group, open-label study evaluated the influence of ethnicity on single- and multiple-dose pharmacokinetics in patients with chronic hepatitis C virus (CHC) genotype 1 infection. Three groups, comprised of Blacks, Hispanics, or Caucasians, were given 1000 to 1200 mg of oral ribavirin daily, based on body weight, and 180 μg of subcutaneous (sc) pegylated interferon alfa-2a once weekly for 8 weeks.

Study center(s)
4 centers in the United States.

Phase of development
IV

Objectives
To evaluate the influence of ethnicity on single- and multiple-dose pharmacokinetics of ribavirin and pegylated interferon alfa-2a in patients with chronic HCV genotype 1 infection.

Methodology
After a screening period of ≤35 days, patients received weekly sc injections of peginterferon alfa-2a (40KD) (180 μg) and daily oral ribavirin (1000 or 1200 mg) for 8 weeks. Blood samples for pharmacokinetic assessments of ribavirin were collected at pre-dose (0) and at intervals up to 12 hours post-dose at Weeks 1 and 8. Samples for pegylated interferon alfa-2a were taken at pre-dose (0) and at intervals up to 168 hours post-dose at Weeks 1 and 8. Safety assessments at all study visits included clinical adverse events, laboratory test results, and vital signs.

Number of patients (planned/analyzed)
45 planned; 47 enrolled (Blacks, 17; Hispanics, 14; Caucasians, 16).

Diagnosis and main criteria for inclusion
Male and female patients ≥18 years of age with proven CHC genotype 1 infection. Excluded were patients with other forms of hepatitis; other forms of chronic liver disease; history or evidence of hepatic malignancy; history of immunologically mediated disease, treatment with antineoplastic or immunomodulatory agents; or previous ribavirin or interferon treatment.

Test product, dose and mode of administration or test procedure
Ribavirin, 1000 or 1200 mg/po/daily. Peginterferon alfa-2a (40KD), 180 µg/sc/once weekly.

Duration of treatment
8 weeks

Criteria for evaluation (efficacy, safety)
Pharmacokinetics: AUC_0-12h and C_max of plasma ribavirin.
Safety: AUC_0-168h and C_max of serum peginterferon alfa-2a (40KD). Clinical adverse events and laboratory adverse events; laboratory test results; and vital signs, including electrocardiograms.

Statistical methods
Pharmacokinetics: analysis of variance was used to analyze all primary and secondary pharmacokinetic parameters at Weeks 1 and 8.

Safety: Descriptive statistics were used to summarize safety parameters by ethnic group.

Summary (efficacy, safety, other results)
Pharmacokinetic Results: Ribavirin mean C_max values of Black patients at Week 1 were lower than values for Caucasian patients and were significantly different (P<0.05) when compared with Caucasian patients, while C_max values for Hispanic patients were not different from Caucasian patients. At Week 8, neither Black nor Hispanic patients showed a difference in C_max values when compared with Caucasian patients. No differences in ribavirin AUC_0-last at Week 1 or AUC_0-τ at Week 8 were seen between Black and Caucasian patients, and no differences in ribavirin AUC_0-last at Week 1 or AUC_0-τ at Week 8 were seen between Hispanic and Caucasian patients. Peginterferon alfa-2a (40KD) serum values for C_max and AUC_0-last at Week 1 and C_max, AUC_0-τ, and C_{ss min} at Week 8 were very similar in all 3 ethnic groups.

Safety Results: The majority of adverse events during the 8 weeks of treatment were mild or moderate in intensity in all 3 groups. There were no deaths or premature withdrawals for safety reasons during this 8-week study. The most common clinical adverse events in all groups were those known to be associated with interferon therapy and included fatigue, headache, chills, pain, nausea, diarrhea, arthralgia, and anemia. One serious adverse event (atrial fibrillation of moderate intensity), which resolved with no sequelae, occurred in a Caucasian patient. During the study, no patients in any ethnic group experienced a decrease in neutrophil count to <0.5 x 10⁹/L, a decrease in platelet count to <20 x 10⁹/L, or a decrease in hemoglobin concentration to <8.5 g/dL. Two Black patients and 3 Caucasian patients experienced a decrease in neutrophil count to between 0.50 x 10⁹/L and 0.75 x 10⁹/L. In 2 Hispanic patients, hemoglobin concentration decreased during the study to <10 g/dL (9.9 g/dL and 9.8 g/dL).

Conclusions
No ethnicity-based differences were observed in ribavirin pharmacokinetic parameters between Hispanic and Caucasian patients, and no ethnicity-based differences were observed in the pharmacokinetic parameters of peginterferon alfa-2a (40KD) between Black and Caucasian patients or Hispanic and Caucasian patients. A trend toward an increase in ribavirin clearance and a decrease in exposure was observed in Black patients as compared with Caucasian patients. At steady state, this trend did not reach statistical significance and is therefore unlikely to have clinical significance. No gross differences were seen in overall safety profiles among the 3 ethnic groups or in specific laboratory parameters related to treatment.

Date of report
5/1/2005

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