title: Coadministration of atazanavir-ritonavir and zinc sulfate: impact on hyperbilirubinemia and pharmacokinetics.
abstract: 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 ZnSO(4). HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25 mmol/liter received 125 mg daily of ZnSO(4) 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; ZnSO(4) was well tolerated. Statistically significant declines in total bilirubin C(max) and AUC(0-24) 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 AUC(0-24) of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for C(trough), C(max), and AUC(0-24) 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 ZnSO(4) decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO(4) supplementation may be useful in management of ATV-related HBR in selected patients.
authors.affiliation: St. Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Graeme
authors.initials: G
authors.lastname: Moyle
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Yapa
authors.forename: Natalia
authors.initials: N
authors.lastname: Seymour
authors.forename: Lisa
authors.initials: L
authors.lastname: Ringner-Nackter
authors.forename: Zeenat
authors.initials: Z
authors.lastname: Karolia
authors.forename: Brian
authors.initials: B
authors.lastname: Gazzard
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000032:analysis; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D006932:Hyperbilirubinemia / Q000188:drug therapy / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult; D019287:Zinc Sulfate / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019287:Zinc Sulfate; D019438:Ritonavir; D001663:Bilirubin