The effect of zinc sulphate supplementation on atazanavir/ritonavir-associated hyperbilirubinemia

Background: Atazanavir (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 (ZnSO 4 ) and its impact on ATV pharmacokinetics (PK). Methods: HIV-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 ZnSO 4 intake initiation (phase 1), after a single dose of ZnSO 4 (phase 2), and following 14 days of ZnSO 4 intake (phase 3). Changes in bilirubin and ATV concentrations in the absence and presence of ZnSO 4 were evaluated by geometric mean ratios (GMR) and 90% confidence intervals (CI, phase 1 as reference). Results: All 16 male patients completed the study maintaining virologic suppression throughout. ZnSO 4 was well tolerated. We observed statistically significant declines in total bilirubin C max and AUC 0-24 of -12 and -13% after single dose ZnSO 4 and -19 and -20% after steady state, compared to reference phase; GM C max decreasing from 57 nmol/L before zinc intake to 50 and 46 nmol/L after ZnSO 4 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 C trough , C max and AUC were -16% (-33 to +6), -8% (-20 to +8) and -12% (-23 to +0.1) after single dose ZnSO 4 , but changed by -26% (-38 to -11) -18% (-30 to -3) and -22% (31 to -12) after multiple dose ZnSO 4 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. Conclusions: The intake of ZnSO 4 led to a moderate decrease in total bilirubin maximum concentration and overall exposure. However, a decrease in ATV concentrations was also observed. ZnSO 4 supplementation may represent a useful tool in the management of ATV-related HBR. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Jackson A et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18305 http://www.jiasociety.org/index.php/jias/article/view/18305 | http://dx.doi.org/10.7448/IAS.15.6.18305