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 center dot Obesity is a negative predictor of successful treatment in patients with chronic hepatitis C treated with peginterferon (PEG-IFN) and ribavirin. center dot Obese patients may have suboptimal exposure of PEG-IFN contributing to the poor responses seen in this patient population. center dot In non-obese patients doses of PEG-IFN alpha-2a (40KD) up to 360 mu g week(-1) have shown dose proportional pharmacokinetics. WHAT THIS STUDY ADDS center dot Here we show that among obese patients treated with the standard dose of PEG-IFN alpha-2a (40KD) (180 mu g week(-1)) drug exposure was lower than that found in a large set of unpublished data among non-obese patients, but was generally similar to exposures found in a large set of unpublished data among similarly obese patients receiving the same dose of PEG-IFN alpha-2a (40KD). center dot By increasing the dose of PEG-IFN alpha-2a (40KD) from 180 mu g week(-1) to 270 mu g week(-1) one can increase PEG-IFN alpha-2a (40KD) exposure, thereby potentially compensating for the apparent reduction in drug exposure in obese patients. To evaluate whether higher doses of peginterferon alpha-2a (40KD) [PEG-IFN alpha-2a (40KD)] can compensate for lower exposure observed among obese patients with chronic hepatitis C (CHC) treated with the standard dose of PEG-IFN alpha-2a (40KD). 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 mu g week(-1) PEG-IFN alpha-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 (C-trough) were determined up to week 24. In the 180 mu g week(-1) group mean +/- SD steady-state (week 12) estimates of AUC(0-168) (ng h(-1) ml(-1)), C-max (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 mu g week(-1) group, estimates were 3374 +/- 1844, 23.4 +/- 10.7 and 0.090 +/- 0.042, respectively. The mean (range) C-trough (ng ml(-1)) was 11.2 (4.4-18.5) in the 180 mu g week(-1) group and 16.1 (0.4-44.2) in the 270 mu g week(-1) group. Overall, 14 of 20 (70%) and 16 of 20 (80%) patients in the 180 mu g week(-1) and 270 mu g week(-1) groups were infected with hepatitis C virus genotype 1 or 4. In the 180 mu g week(-1) and 270 mu g week(-1) groups 14 of 20 (70%) and 15 of 19 (79%) patients, respectively, achieved a sustained viral response. Safety was similar between groups. Mean PEG-IFN alpha-2a (40KD) exposure was dose proportional from 180 to 270 mu g week(-1). Increasing PEG-IFN alpha-2a (40KD) from 180 to 270 mu g week(-1) achieves higher serum drug exposure in obese patients.