Pharmacokinetics and response of obese patients with chronic hepatitis C treated with different doses of PEG‐IFN α‐2a (40KD) (PEGASYS®)

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Obesity is a negative predictor of successful treatment in patients with chronic hepatitis C treated with peginterferon (PEG‐IFN) and ribavirin. • Obese patients may have suboptimal exposure of PEG‐IFN contributing to the poor responses seen in this patient population. • In non‐obese patients doses of PEG‐IFN α‐2a (40KD) up to 360 µg week−1 have shown dose proportional pharmacokinetics. WHAT THIS STUDY ADDS • Here we show that among obese patients treated with the standard dose of PEG‐IFN α‐2a (40KD) (180 µg week−1) drug exposure was lower than that found in a large set of unpublished data among non‐obese patients, but was generally similar to exposures found in a large set of unpublished data among similarly obese patients receiving the same dose of PEG‐IFN α‐2a (40KD). • By increasing the dose of PEG‐IFN α‐2a (40KD) from 180 µg week−1 to 270 µg week−1 one can increase PEG‐IFN α‐2a (40KD) exposure, thereby potentially compensating for the apparent reduction in drug exposure in obese patients. AIMS To evaluate whether higher doses of peginterferon α‐2a (40KD) [PEG‐IFN α‐2a (40KD)] can compensate for lower exposure observed among obese patients with chronic hepatitis C (CHC) treated with the standard dose of PEG‐IFN α‐2a (40KD). METHODS Noncirrhotic, obese (body mass index ≥30 kg m−2) patients with CHC participated in a single‐centre, open‐label study. Patients were randomized to 180 or 270 µg week−1 PEG‐IFN α‐2a (40KD) + ribavirin (1000/1200 mg day−1) for 48 weeks. Blood samples were collected predose and up to 168 h after the first dose and at week 12 for pharmacokinetic analysis. Trough serum concentrations (Ctrough) were determined up to week 24. RESULTS In the 180 µg week−1 group mean ± SD steady‐state (week 12) estimates of AUC0–168 (ng h−1 ml−1), Cmax (ng ml−1) and CL/F (l h−1) were 2154 ± 919, 13.8 ± 6.7 and 0.102 ± 0.051, respectively. In the 270 µg week−1 group, estimates were 3374 ± 1844, 23.4 ± 10.7 and 0.090 ± 0.042, respectively. The mean (range) Ctrough (ng ml−1) was 11.2 (4.4–18.5) in the 180 µg week−1 group and 16.1 (0.4–44.2) in the 270 µg week−1 group. Overall, 14 of 20 (70%) and 16 of 20 (80%) patients in the 180 µg week−1 and 270 µg week−1 groups were infected with hepatitis C virus genotype 1 or 4. In the 180 µg week−1 and 270 µg week−1 groups 14 of 20 (70%) and 15 of 19 (79%) patients, respectively, achieved a sustained viral response. Safety was similar between groups. CONCLUSIONS Mean PEG‐IFN α‐2a (40KD) exposure was dose proportional from 180 to 270 µg week−1. Increasing PEG‐IFN α‐2a (40KD) from 180 to 270 µg week−1 achieves higher serum drug exposure in obese patients.