The treating nurse recorded adverse events on a standard form and rated the severity as mild, moderate, severe, or life threatening. Patients were evaluated and laboratory tests were scheduled at weeks 2, 4, 8, 12 and 16, and then at 6-week intervals until week 24 of the untreated follow-up period. Dose modification of PEG-IFN ��-2a (40KD) from 270 ��g week?1, to 180 selleck chemical ��g week?1, to 135 ��g week?1, to 90 ��g week?1 and to 45 ��g week?1 was permitted in patients who experienced either clinical or laboratory adverse events. Adverse events thought to be related to ribavirin were treated with a dose reduction initially by 200 mg day?1, and then, if no improvement was seen, to 600 mg day?1 provided the patient was without significant cardiovascular disease and had a fall in haemoglobin <10 g dl?1 and >8.

5 g dl?1 or a patient had stable cardiovascular disease and a fall in haemoglobin >2 g dl?1 any time during treatment. Ribavirin was discontinued if a patient without significant cardiovascular disease had a fall in haemoglobin <8.5 g dl?1 or a patient with stable cardiovascular disease had a haemoglobin <12 g dl?1 after 4 weeks on 600 mg of ribavirin. Statistical analysis All PK parameters were summarized using descriptive statistics. Virological response and safety data were summarized using descriptive statistics. These analyses were performed using Microsoft Excel (version 2000; Microsoft Inc., Redmond, WA, USA) and S-Plus version 7.0 student edition (Insightful Corp., Seattle, WA, USA) software.

The planned sample size of 20 patients per group was designed to detect an increase in exposure, with ��80% power, assuming the AUC in the PEG-IFN ��-2a (40KD) 270 ��g week?1 was 1.4 times that of the PEG-IFN ��-2a (40KD) 180 ��g week?1 group, an intersubject coefficient of variation of 45%, and statistical significance to be 0.05. Results Patient characteristics Patients were recruited from August 2002 to March 2004. A total of 42 patients were recruited for this study. Two never started treatment and so were not included in any of the analyses. One patient in the 270 ��g week?1 PEG-IFN ��-2a (40KD) group received only 6 weeks of treatment, so was not included in the PK or efficacy analyses. Baseline characteristics were generally similar between the two groups (Table 1).

Table 1 Patient characteristics in the two treatment groups at baseline Pharmacokinetic assessment PK parameters of PEG-IFN ��-2a (40KD) after the first dose (day 1) and at steady state (week 12) are summarized in Table 2. An approximate 1.5-fold increase in mean AUC0�C168 h and Cmax at steady state was observed in the 270-��g compared with the 180-��g arm. The apparent clearance was approximately 0.1 l h?1 for both doses. These indicate Brefeldin_A a linear dose�Cexposure relationship in the study dose range. The accumulation rate from day 1 to week 12 was approximately 2.3-fold for both 180 and 270 ��g week?1 doses.