vitamin-k-semiquinone-radical and Hepatitis-C--Chronic

The aim of this study was to evaluate the effects of danoprevir in combination with low-dose ritonavir (danoprevir/r) and placebo plus low-dose ritonavir on the pharmacokinetics of probe drugs for cytochrome P450 (CYP) 3A and CYP2C9, in patients with chronic hepatitis C.. A total of 54 patients infected with hepatitis C virus genotype 1 received an oral drug cocktail (2 mg midazolam, 10 mg warfarin and 10 mg vitamin K) before and after 14 days of dosing with either danoprevir/r or placebo plus low-dose ritonavir (placebo/r). Serial pharmacokinetic samples were collected up to 24 (midazolam) and 72 (S-warfarin) h post-dose. Plasma concentrations of midazolam, α-hydroxymidazolam and S-warfarin were measured using validated assays. Pharmacokinetic parameters were estimated using non-compartmental analysis, and geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) for the differences between baseline and post-dosing values were calculated.. Danoprevir/r and placebo/r significantly increased midazolam area under the time-concentration curve (AUC0-∞) and reduced the midazolam metabolic ratio while S-warfarin AUC0-∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC0-∞ was 9.41 (8.11, 10.9) and 11.14 (9.42, 13.2) following danoprevir/r and placebo/r dosing, respectively, and the S-warfarin GMR (90 % CI) AUC0-∞ was 0.72 (0.68, 0.76) and 0.76 (0.69, 0.85), respectively. The effects of danoprevir/r and placebo/r appeared to be qualitatively similar.. Substantial inhibition of CYP3A- and modest induction of CYP2C9- activity were observed with danoprevir/r and low-dose ritonavir.

Topics: Adult; Antiviral Agents; Aryl Hydrocarbon Hydroxylases; Cyclopropanes; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Drug Interactions; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Isoindoles; Lactams; Lactams, Macrocyclic; Male; Midazolam; Middle Aged; Proline; Ritonavir; Sulfonamides; Vitamin K; Warfarin; Young Adult

Prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha fetoprotein (AFP) are biomarkers for hepatocellular carcinoma (HCC). However, their performance in patients with cirrhosis related to hepatitis C virus (HCV) treated with direct-acting antiviral agents (DAA) is unknown.. To evaluate PIVKA-II and AFP as HCC predictors in DAA-treated patients with HCV-related cirrhosis METHODS: In this single centre study, patients with cirrhosis from chronic HCV infection and with a sustained virological response (SVR) to DAA were tested for PIVKA-II and AFP (Fujirebio, Japan) at the start of DAA treatment (baseline), end of treatment (EOT) and at HCC diagnosis.. We included 400 patients with mean age 65 (24-92); 56% were men. From baseline to EOT, PIVKA-II did not change (35 vs 35 mAU/mL, P = 0.43) while AFP significantly decreased (12 vs 6 ng/mL, P < 0.0001). After 52 (3-66) months from baseline, 34 (8.5%) patients developed de novo HCC; median AFP 9 (2-12 868) ng/mL and PIVKA-II 80 (22-1813) mAU/mL. EOT-PIVKA-II (HR 3.05, P < 0.0001) and AFP (HR 2.77, P = 0.001) independently predicted HCC together with diabetes (HR 6.12, P < 0.001) and GGT (HR 1.01, P = 0.03). The 4-year cumulative probability of HCC was 24% vs 2% in patients with EOT-PIVKA-II > or ≤41 mAU/mL (P < 0.0001), and 26% vs 9% for EOT-AFP > or ≤15 ng/mL (P = 0.02). By combining EOT-PIVKA-II and AFP, the 4-year probabilities of HCC were 3% in patients testing negative for both markers, 18% in patients positive for both, and 38% in patients positive for at least one (P < 0.0001).. In patients with HCV-related cirrhosis treated with DAA, PIVKA-II and AFP independently predicted HCC, while their combination improved risk stratification.

Topics: Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antiviral Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Protein Precursors; Prothrombin; ROC Curve; Vitamin K