Population Pharmacodynamic (PD) Assessment of the Safety and Antiretroviral Activity of Atazanavir (BMS-232632)

Authors: O’Mara E, Cirincione B, Mummaneni V, Grasela TH, Grasela D
Conference: ICAAC
Keywords: anti-infectives, azapeptide, bilirubin, d4T, ddI, didanosine, HAART, HIV, hyperbilirubinemia, infectious disease, logistic regression, PK, PK/PD, protease inhibitor, RNA, safety, sparse sampling, stavudine, steady state
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Background: Atazanavir (BMS-232632), currently in Phase III development, is a well-tolerated, once-daily protease inhibitor (PI) which does not appear to elevate cholesterol or triglyceride blood levels and has a favorable resistance profile in vitro. Using a population pharmacokinetic (PK) model developed previously, PK/PD analyses were performed on interim Phase II data to assist in dose selection.

Methods: Sparse PK sampling was performed at weeks 2, 4, 12, 24, and 48 during a randomized Phase II study. Patients received 200, 400, or 500 mg once daily for 2 weeks as monotherapy, then combined with stavudine (d4T) and didanosine (ddI) thereafter. The PK model was a 2-compartment mixture model allowing for 2 populations of absorption rate constant and volume of the central compartment. Bayesian parameter estimates were utilized to predict individual values for the area under the plasma concentration-time curve (AUC) as the exposure measure. Plasma HIV RNA and bilirubin (bili) levels were obtained at baseline and after 2 weeks. Logistic regression analyses were performed evaluating AUC as a predictor of failure to achieve a 1.5 log decrease in HIV RNA or probability of bili elevation >2.5 mg/dL.

Results: Fifty-six patients had PK, HIV RNA and bili data. Logistic regression identified AUC as a significant predictor of failure to achieve 1.5 log reduction in HIV RNA (P=0.0164), where failure to respond was more likely in patients with lower AUC values. Conversely, the probability of bili elevation >2.5 mg/dL was greater in patients with higher AUC values (P=0.0002). In dose comparisons, the mean/median steady state AUC (ng•hr/mL) values for 400 mg versus 500 mg were 23.5/23.1 and 36.4/31.7, respectively. The associated probabilities of achieving the HIV RNA reduction at these doses were 0.78/0.77 and 0.9/0.86, whereas the probabilities for bili elevation were 0.171/0.168 and 0.338/0.269, respectively.

Conclusions: The 400-mg 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 400-mg dose for Phase III evaluation.

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); Chicago, Illinois; December 2001

E. O’Mara, B. Cirincione, V. Mummaneni, T. Grasela, D. Grasela