Atazanavir

Metabolism

In an analysis of a randomized comparison of atazanavir and nelfinavir in 467 patients cardiovascular risk modelling was used to estimate the impact of dyslipidemia [ ]. Concentrations of total cholesterol and low-density lipoprotein cholesterol increased significantly more among patients who used nelfinavir (24% and 28%) than among those who used atazanavir (4% and 1%). Overall, the relative risk of coronary disease, adjusted for risk status, age, and sex, was increased by 50% for nelfinavir versus atazanavir over the next 10 years in men or women, regardless of the presence or absence of other coronary risk factors.

Liver

In the first phase 2 licensing study the protease inhibitor atazanavir 200 mg, 400 mg, and 500 mg was evaluated against nelfinavir 750 mg tds in combination with a didanosine and stavudine backbone [ ]. The 400 mg dose of atazanavir was chosen for further development. Most of the adverse events in this study were grade 1–2 and the rates of grade 3–4 were comparable across the regimens. Jaundice was the most prominent adverse effect of atazanavir and was clearly dose related (6%, 6%, 12% for the three dosing arms) and was not observed in the nelfinavir arm. Rises in bilirubin were predominantly due to the unconjugated form. There was no correlation with raised transaminases.

Preclinical data support the hypothesis that atazanavir-associated hyperbilirubinemia is attributable to inhibition of uridine diphosphate glucuronosyltransferase (UDP-GT) 1A1 [ ]. This is also the apparent mechanism for the reversible rise in bilirubin that occurs with indinavir [ ]. Grade 3–4 rises in transaminases were significantly more frequent in patients infected with hepatitis B or C (20–40%) than in patients with negative hepatitis B and C serology (2–12%).

In a study of once-a-day ritonavir-boosted atazanavir in 23 children and adolescents total bilirubin increased significantly (to over 18 mmol/l) in 17 children [ ]. This was attributed to competitive inhibition of uridine diphosphate glucuronyl transferase (UGT) activity by atazanavir.

The most common adverse effect of atazanavir was a rise in total bilirubin concentration (mostly indirect/unconjugated bilirubin): in 26% of those who continued treatment with atazanavir 400 mg/day (n = 139), 44% of those who took atazanavir 600 mg/day (n = 144), and 13% of those who had previously taken nelfinavir followed by atazanavir 400 mg/day (n = 63) [ ]. There were grade 4 rises in bilirubin (to over five times the upper of limit normal) in 3% of patients taking atazanavir 600 mg/day and in 1% of patients taking atazanavir 400 mg/day. Jaundice was reported more often in those taking atazanavir 600 mg/day compared with those taking 400 mg/day (22% versus 13%).

Hyperbilirubinemia and jaundice occurred during administration of atazanavir in all 23 healthy volunteers taking part in a 30-day follow-up study; there was a 52% increased minimum plasma concentration with co-administration of darunavir [ ].