Influence of chronic hepatitis C infection on cytochrome P450 3a4 activity using midazolam as an in vivo probe substrate

Purpose: Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders. Methods: Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n = 107) and in treatment-naive patients (n = 35) and interferon-null responders (n = 24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference). Results: The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56-0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39-0.53) compared to volunteers. The mean area under the concentration-time curve (AUC_inf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively. Conclusions: The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.