Suchergebnisse

BackgroundAtazanavir (ATV) causes an exposure dependent elevation of unconjugated hyperbilirubinemia (HBR) as a result of UGT1A1 inhibition. Zinc sulphate reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total and conjugated bilirubin following single dose and 14 daily doses of zinc sulphate (ZnSO4) and its impact on ATV pharmacokinetics (PK).MethodsHIV‐infected individuals stable on ATV/ritonavir (r) containing regimens with a total bilirubin level > 25 mmol/L were administered 125 mg once daily of as solvazinc effervescent tablets for 14 days. ATV and bilirubin concentrations were measured pre‐ATV‐dose, 2, 4, 6, 8 and 24 hours post‐ATV‐dose before ZnSO4 intake initiation (phase 1), after a single dose of ZnSO4 (phase 2), and following 14 days of ZnSO4 intake (phase 3). Changes in bilirubin and ATV concentrations in the absence and presence of ZnSO4 were evaluated by geometric mean ratios (GMR) and 90% confidence intervals (CI, phase 1 as reference).ResultsAll 16 male patients completed the study maintaining virologic suppression throughout. ZnSO4 was well tolerated. We observed statistically significant declines in total bilirubin Cmax and AUC0–24 of −12 and −13% after single dose ZnSO4 and −19 and −20% after steady state, compared to reference phase; GM Cmax decreasing from 57 nmol/L before zinc intake to 50 and 46 nmol/L after ZnSO4 single dose and steady state, respectively. No significant changes in conjugated bilirubin were observed, indicating that the changes were secondary to declines in the unconjugated fraction (data pending). ATV GMR (90% CI) for Ctrough, Cmax and AUC were −16% (−33 to +6), −8% (−20 to +8) and −12% (−23 to +0.1) after single dose ZnSO4, but changed by −26% (−38 to −11) −18% (−30 to −3) and −22% (31 to −12) after multiple dose ZnSO4 compared to reference. All individuals with the exception of one (whose levels were low throughout the study) maintained ATV concentration above the suggested MEC of 150 ng/mL.ConclusionsThe intake of ZnSO4 led to a moderate decrease in total bilirubin maximum concentration and overall exposure. However, a decrease in ATV concentrations was also observed. ZnSO4 supplementation may represent a useful tool in the management of ATV‐related HBR.