• Population Pharmacodynamic (PD) Assessment of the Safety and Antiretroviral Activity of BMS-232632
  Abstract 507
  Authored by E. Omara (Bristol-Myers Squibb, Princeton, NJ), B. Cirincione (Cognigen Corp., Buffalo, NY), V. Mummaneni (Bristol-Myers Squibb, Princeton, NJ), T. Grasela (Cognigen Corp., Buffalo, NY), D. Grasela (Bristol-Myers Squibb, Princeton, NJ)
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Atazanavir (BMS-232632) is a once-daily protease inhibitor with a favorable resistance profile in vitro. Atazanavir is relatively well tolerated; however, isolated elevations of serum bilirubin levels, primarily of unconjugated bilirubin, with associated jaundice may pose some difficulties regarding patient acceptance and adherence.

Using a population pharmacokinetic (PK) model developed previously, pharmacokinetic and pharmacodynamic analyses were performed on interim Phase II data to assist in dose selection. In the analysis, 56 patients received 200, 400 or 500mg of atazanavir once daily for two weeks as monotherapy, then added stavudine (zerit, d4T) and videx (didanosine, ddI). Plasma HIV RNA and bilirubin levels were obtained at baseline and after two weeks. Logistic regression analyses were performed evaluating AUC as a predictor of failure to achieve a 1.5 log10 copies/mL decrease in HIV RNA or probability of bilirubin elevation >2.5 gm/dL.

Logistic regression showed that patients with lower atazanavir AUC levels were less likely to achieve a 1.5 log10 copies/mL reduction in viral load (p=0.0164), while patients with higher atazanavir AUC levels were more likely to have a bilirubin elevation >2.5 gm/dL (p=0.0002). In dose comparisons, the mean/median steady-state AUC (ng hr/mL) values for 400 versus 500mg were 23.5/23.1 and 36.4/31.7, respectively. The associated probabilities of achieving a 1.5 log10 copies/mL reduction in viral load at these doses were 0.78/0.77 and 0.9/0.86, respectively, whereas the probabilities for bilirubin elevation were 0.171/0.168 and 0.338/0.269, respectively.

The authors conclude "The 400mg once-daily dose of [atazanavir] provides an effective reduction of HIV RNA and minimizes the probability of hyperbilirubinemia. Overall, these results support selection of the 400mg dose for Phase III evaluation." This is a bit of an unusual presentation and conclusion, especially since the hyperbilirubinemia that occurs with atazanavir is relatively harmless, and there is a decrease in chance of virologic success, although small, with the 400mg versus the 500mg dose. One wonders if a more appropriate treatment strategy would be to start with the 500mg dose to maximize the chance of virologic success with dose reduction to 400mg when and if hyperbilirubinemia -- and perhaps jaundice -- develops.