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Antiretroviral Levels With Two Common Regimens in Nonfrail Older Patients
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2nd International Workshop on HIV and Aging, October 27-28, 2011, Baltimore, Maryland
Mark Mascolini
Concentrations of antiretrovirals in two common regimens--efavirenz or atazanavir/ritonavir plus tenofovir/emtricitabine (TFV/FTC)--did not differ substantially between HIV-positive people over 55 and historical controls in a small pilot study [1]. Results suggested that declining kidney function did not affect renally cleared drugs in these nonfrail individuals.
Researchers at the University of North Carolina (UNC) Chapel Hill and SUNY Buffalo planned this pilot study to assess the pharmacokinetics of individual drugs in these two regimens as a prelude to future long-term population pharmacokinetic/pharmacodynamic studies.
All study participants were 55 or older taking one of the two regimens steadily with at least 90% adherence in the past 30 days. The investigators excluded people with the frailty phenotype, those taking other drugs known to interact with study drugs, and people with clinically significant lab abnormalities. Study participants made a screening visit, a PK visit with 24-hour intensive sampling after they took their drugs at their usual time, and a follow-up visit.
The UNC/SUNY team compared antiretroviral concentrations in these people with those in historical controls who were not necessarily taking exactly the same regimens. However, atazanavir controls were taking tenofovir to account for tenofovir's effect in lowering atazanavir exposure.
The study involved 6 people on efavirenz (with TFV/FTC as Atripla) and 6 on atazanavir/ritonavir (plus TFV/FTC). Age averaged 60.7 in the efavirenz group and 58.7 in the atazanavir group. Three people in each group were Caucasian and 3 African American. Numbers of women and men were 4 and 2 on efavirenz and 2 and 4 on atazanavir. Both groups had taken their current regimen for about 3.5 years. CD4 counts averaged 683 in the efavirenz group and 952 in the atazanavir group. Respective creatinine clearances were 69.4 +/- 25.0 mL/min and 70.9 +/- 7.46 mL/min.
Tenofovir maximum concentration (Cmax) was marginally lower with efavirenz (ratio 0.87) and atazanavir (0.94) in the study group than in historical controls. Compared with historical data, FTC Cmax was slightly higher with efavirenz (1.26) and atazanavir (1.31). Tenofovir 24-hour area under the concentration-time curve (AUC0-24) was lower with efavirenz (0.92) and atazanavir (0.90) than in historical controls, whereas FTC AUC0-24 was higher with efavirenz (1.75) and atazanavir (1.31).
Efavirenz Cmax was moderately lower in study participants than in historical controls (ratio 0.84), whereas atazanavir Cmax was slightly higher in the study group (1.09). Efavirenz AUC0-24 was virtually equivalent in study participants and historical controls (1.05), while atazanavir AUC0-24 was marginally lower (0.88).
None of these differences between study concentrations and historical controls reached statistical significance, as would be expected with the small sample size.
The efavirenz and atazanavir results surprised the investigators, who expected higher efavirenz concentrations and markedly lower atazanavir exposures.
Creatinine clearance did not explain these PK results because both tenofovir and FTC are renally excreted, and tenofovir concentrations were lower than in historical controls while FTC levels were higher. The investigators concluded that renal filtration and secretion were intact in this study group.
The researchers plan to calculate intracellular tenofovir diphosphate and FTC triphosphate levels and protein-free efavirenz and atazanavir exposure. They also plan a sparse-sampling analysis in frail and nonfrail HIV-positive people of all age. Ultimately they hope to determine whether age-specific dosing recommendations for these antiretrovirals are warranted.
Reference
1. Dumond JB, Adams JL, Prince HMA, et al. Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: a pilot study. 2nd International Workshop on HIV and Aging. October 27-28, 2011. Baltimore, Maryland. Abstract: O_12.
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