Therapeutic range for atazanavir defined

Data presented during Thursday’s poster discussion sessions at the Twelfth Annual Retrovirus Conference in Boston provided new information regarding the therapeutic range of drug levels of the protease inhibitor atazanavir (Reyataz). On the basis of this study, a concentration of between 150 and 850ng/ml is likely to be recommended as the optimum concentration range for the drug.

Clinical trials have shown that up to 45% of people who take atazanavir can develop elevations in bilirubin, a breakdown product of red blood cells. Although these elevations, termed hyperbilirubinaemia, are not harmful, they cause the skin and the whites of the eyes to turn yellow. This can be distressing and potentially stigmatising.

Researchers from Italy attempted to clarify the range of blood levels of atazanavir that should be used in patients, by identifying concentrations that are high enough to suppress HIV but not so high that they cause hyperbilirubinaemia. They assessed atazanavir levels in 38 patients enrolled in the Atazanavir Expanded Access Programme, two thirds of the whom were using ritonavir to boost atazanavir levels.

The investigators assessed the ‘trough’ levels (C_trough) of atazanavir in blood samples taken just before the drug dose was given. This was done at weeks 4 and 12 of the study. They also measured viral loads, CD4 cell counts at the start of the study and at weeks 4 and 12.

Thirty-two (84%) of the patients had detectable viral load at baseline, with a median of 26,900 copies/ml. After 12 weeks there was a median viral load reduction of 2.2 log₁₀, with 80% of patients achieving a viral load below 50 copies/ml or a viral load decrease of 2 log₁₀ or more.

Overall, the median level of atazanavir was 402 ng/ml. However, when they stratified these results by atazanavir concentration, the investigators found that concentrations greater than 150ng/ml were associated with virological response, while lower concentrations tended to lead to virological failure (p = 0.007). They therefore defined 150ng/ml as a useful lower cut-off for the drug’s therapeutic range.

Genotypic resistance testing revealed that each patient had a median of three PI-associated mutations. Furthermore, patients with fewer than five resistance mutations also had a better chance of virological success (p = 0.025).

To define the drug’s upper limit, the researchers also measured the levels of total and unconjugated bilirubin at weeks 4 and 12. Both measures increased by week 12, by a median of 0.8 and 0.6mg/dl respectively. At this time point, 25% of the patients had unconjugated bilirubin levels greater than 2 mg/dl, considered to be the maximum safe level by the researchers.

Both total and unconjugated bilirubin levels were correlated with atazanavir concentrations (total: RR = 0.47, p = 0.008; unconjugated: RR = 0.46, p = 0.009). However, after stratifying their results from week 12, the investigators found that 46% of the patients with atazanavir concentrations greater than 850 ng/ml had unconjugated bilirubin levels above 2mg/dl, but only 17% of those with lower levels (p = 0.002). On the basis of this finding, they defined 850 ng/ml as a reasonable upper limit for atazanavir’s therapeutic range.

The researchers conclude that the ideal therapeutic range of atazanavir trough levels is between 150 and 850ng/ml, since these levels had the highest probability of virologic response and the lowest probability of unconjugated bilirubin increase.

However, in response to a question raised during the poster discussion, investigator Daniel Gonzalez de Requena admitted that this upper limit does not represent a safety limit, but one above which a ‘cosmetic’ side-effect becomes more common.