Pharmacokinetics of ART Regimens in Older HIV Patients
Objectives The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented.
Methods HIV-infected subjects ≥55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography–ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration–time curve over 24 h (AUC0-24h) and maximal concentration (Cmax)]. These parameters were compared with historical values from the general HIV-infected population.
Results Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8–13% decreased TFV AUC0-24h and Cmax, and 19–78% increased FTC and RTV AUC0-24h and Cmax. Decreased ATV AUC0-24h (12%) and increased Cmax(9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax. Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects.
Conclusions This study demonstrates that the PK of these ARVs are altered by 5–78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients.
As a direct result of improved antiretroviral (ARV) treatment, patients with chronic HIV infection in the USA are living longer. Non-AIDS-related diseases are therefore a more frequent cause of death. From 2006 to 2009, the 60–64-year-old age group saw the largest increases in the number of patients living with HIV/AIDS, with the largest age demographic in the 44–49-year-old age group (19%). These numbers will continue to increase as life expectancy increases. An estimated one-half of those living with HIV will be > 50 years old by 2015.
Although older HIV-infected adults typically demonstrate excellent virological response to the initiation of antiretroviral therapy, immunological recovery is frequently diminished compared with younger patients, with a slower and blunted recovery of CD4 cells after ARV initiation. This results in increased mortality and an overall worse prognosis. Every 10 years of additional chronological age provides 35 fewer CD4 cells/μL during a year of treatment. Advanced disease at diagnosis and senescence may partially explain this phenomenon. However, the contribution of altered ARV pharmacokinetics (PK) and the resultant risk for adverse events has not been investigated.
Known physiological changes during aging can affect drug absorption, distribution, metabolism and excretion, and these changes have been shown to affect clinical outcomes. However, little is known about these effects on the PK of ARVs used to treat this growing population of HIV-infected patients. Modest evidence suggests that cellular activation, such as that seen with aging and HIV infection, may increase intracellular phosphorylase activity in elderly people, potentially resulting in increased toxicity of nucleoside reverse transcriptase inhibitors (NRTIs). The active intracellular phosphorylated forms of tenofovir (TFV) and emtricitabine (FTC), two such agents, have not been studied in older patients.
The present investigation sought to characterize the PK of two common, first-line ARV regimens in HIV-infected patients ≥ 55 years old in order to provide PK parameter estimates for optimal sample design for a population pharmacokinetic/pharmacodynamic (PK/PD) investigation of the effects of aging on ARVs.
Abstract and Introduction
Abstract
Objectives The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented.
Methods HIV-infected subjects ≥55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography–ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration–time curve over 24 h (AUC0-24h) and maximal concentration (Cmax)]. These parameters were compared with historical values from the general HIV-infected population.
Results Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8–13% decreased TFV AUC0-24h and Cmax, and 19–78% increased FTC and RTV AUC0-24h and Cmax. Decreased ATV AUC0-24h (12%) and increased Cmax(9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax. Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects.
Conclusions This study demonstrates that the PK of these ARVs are altered by 5–78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients.
Introduction
As a direct result of improved antiretroviral (ARV) treatment, patients with chronic HIV infection in the USA are living longer. Non-AIDS-related diseases are therefore a more frequent cause of death. From 2006 to 2009, the 60–64-year-old age group saw the largest increases in the number of patients living with HIV/AIDS, with the largest age demographic in the 44–49-year-old age group (19%). These numbers will continue to increase as life expectancy increases. An estimated one-half of those living with HIV will be > 50 years old by 2015.
Although older HIV-infected adults typically demonstrate excellent virological response to the initiation of antiretroviral therapy, immunological recovery is frequently diminished compared with younger patients, with a slower and blunted recovery of CD4 cells after ARV initiation. This results in increased mortality and an overall worse prognosis. Every 10 years of additional chronological age provides 35 fewer CD4 cells/μL during a year of treatment. Advanced disease at diagnosis and senescence may partially explain this phenomenon. However, the contribution of altered ARV pharmacokinetics (PK) and the resultant risk for adverse events has not been investigated.
Known physiological changes during aging can affect drug absorption, distribution, metabolism and excretion, and these changes have been shown to affect clinical outcomes. However, little is known about these effects on the PK of ARVs used to treat this growing population of HIV-infected patients. Modest evidence suggests that cellular activation, such as that seen with aging and HIV infection, may increase intracellular phosphorylase activity in elderly people, potentially resulting in increased toxicity of nucleoside reverse transcriptase inhibitors (NRTIs). The active intracellular phosphorylated forms of tenofovir (TFV) and emtricitabine (FTC), two such agents, have not been studied in older patients.
The present investigation sought to characterize the PK of two common, first-line ARV regimens in HIV-infected patients ≥ 55 years old in order to provide PK parameter estimates for optimal sample design for a population pharmacokinetic/pharmacodynamic (PK/PD) investigation of the effects of aging on ARVs.
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