Coadministration of Atazanavir-Ritonavir and Zinc Sulfate: Impact on Hyperbilirubinemia and Pharmacokinetics

Atazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO4. HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25mmol/liter received 125 mg daily of ZnSO4 as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4 initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4 were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO4 was well tolerated. Statistically significant declines in total bilirubin Cmax and AUC0–24 of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubin Cmax and AUC0–24 of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for Ctrough, Cmax, and AUC0–24 were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO4 decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO4 supplementation may be useful in management of ATV-related HBR in selected patients.