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The pharmacokinetics and pharmacogenomics of efavirenz and lopinavir/ritonavir in HIV-infected persons requiring hemodialysis

Gupta, Samir Ka; Rosenkranz, Susan Lb; Cramer, Yoninah Sb; Koletar, Susan Lc; Szczech, Lynda Ad; Amorosa, Valeriannae; Hall, Stephen Da

doi: 10.1097/QAD.0b013e32830e011f
Basic Science

Objective: To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis.

Design: Prospective, observational study of HIV-infected hemodialysis patients receiving one 600 mg tablet daily of EFV (N = 13) or three 133.3/33.3 mg capsules twice daily of LPV/RTV (N = 13).

Methods: Twenty-four-hour EFV and 12-h LPV/RTV pharmacokinetics were assessed. Geometric mean ratios were calculated using historical controls with normal renal function. The effects of several candidate gene polymorphisms were also explored.

Results: The geometric mean [95% confidence interval (CI); percentage of coefficient of variation (% CV)] Cmin, Cmax, and area under the curve (AUC) for the EFV group were 1.81 μg/ml (0.93, 3.53; 103%), 5.04 μg/ml (3.48, 7.29; 72%), and 71.5 μg h/ml (43.2, 118.3; 93%), respectively. These parameters were 2.76 μg/ml (1.86, 4.11; 53%), 8.45 μg/ml (6.41, 11.15; 52%), and 69.6 μg h/ml (55.6, 87.2; 37%) for LPV and 0.08 μg/ml (0.05, 0.14; 63%), 0.58 μg/ml (0.44, 0.76; 41%), and 3.74 μg h/ml (2.91, 4.80; 37%) for RTV. The AUC geometric mean ratios (90% CI) for EFV, LPV, and RTV were 132% (89, 197), 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group. Higher EFV concentrations were associated with the CYP2B6 516G>T polymorphism.

Conclusion: The pharmacokinetics of EFV and LPV/RTV in hemodialysis suggests that no dosing adjustments are necessary in treatment-naive patients. As HIV-infected hemodialysis patients are disproportionately black, the increased frequency of the CYP2B6 516G>T polymorphism may lead to higher EFV levels. The potentially lower LPV trough levels in this population suggest that LPV/RTV should be used with caution in protease-inhibitor-experienced patients.

aIndiana University School of Medicine, Indianapolis, Indiana, USA

bStatistical and Data Analysis Center/Harvard University School of Public Health, Boston, Massachusetts, USA

cThe Ohio State University, Columbus, Ohio, USA

dDuke University Medical Center, Durham, North Carolina, USA

eUniversity of Pennsylvania, Philadelphia, Pennsylvania, USA.

Received 2 November, 2007

Revised 5 June, 2008

Accepted 13 June, 2008

Correspondence to Samir K. Gupta, MD, MS, Wishard Hospital, OPW-430, 1001 W. 10th Street, Indianapolis, IN 46202, USA. E-mail: sgupta1@iupui.edu

© 2008 Lippincott Williams & Wilkins, Inc.