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

TitleThe pharmacokinetics and pharmacogenomics of efavirenz and lopinavir/ritonavir in HIV-infected persons requiring hemodialysis.
Publication TypeJournal Article
Year of Publication2008
AuthorsGupta SK, Rosenkranz SL, Cramer YS, Koletar SL, Szczech LA, Amorosa V, Hall SD
JournalAIDS
Volume22
Issue15
Pagination1919-27
Date Published2008 Oct 1
ISSN1473-5571
KeywordsAdult, Anti-HIV Agents, Benzoxazines, Drug Combinations, Female, HIV Infections, HIV Protease Inhibitors, HIV-1, Humans, Kidney Failure, Chronic, Lopinavir, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Pyrimidinones, Renal Dialysis, Reverse Transcriptase Inhibitors, Ritonavir
Abstract

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 microg/ml (0.93, 3.53; 103%), 5.04 microg/ml (3.48, 7.29; 72%), and 71.5 microg h/ml (43.2, 118.3; 93%), respectively. These parameters were 2.76 microg/ml (1.86, 4.11; 53%), 8.45 microg/ml (6.41, 11.15; 52%), and 69.6 microg h/ml (55.6, 87.2; 37%) for LPV and 0.08 microg/ml (0.05, 0.14; 63%), 0.58 microg/ml (0.44, 0.76; 41%), and 3.74 microg 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.

DOI10.1097/QAD.0b013e32830e011f
Alternate JournalAIDS
PubMed ID18784455
PubMed Central IDPMC2675161
Grant ListAI38855 / AI / NIAID NIH HHS / United States
AI68636 / AI / NIAID NIH HHS / United States
M01 RR000750 / RR / NCRR NIH HHS / United States
M01 RR000750-330859 / RR / NCRR NIH HHS / United States
RR000080 / RR / NCRR NIH HHS / United States
RR000095 / RR / NCRR NIH HHS / United States
RR00034 / RR / NCRR NIH HHS / United States
RR00052 / RR / NCRR NIH HHS / United States
RR00750 / RR / NCRR NIH HHS / United States