• aging;
  • intracellular pharmacokinetics;
  • pharmacokinetics


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References


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.


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.


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.


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.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

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 [1]. 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%) [2]. 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 [2].

Although older HIV-infected adults typically demonstrate excellent virological response to the initiation of antiretroviral therapy [3, 4], immunological recovery is frequently diminished compared with younger patients [3, 5], 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 [6, 7]. Advanced disease at diagnosis [4] 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 [8, 9]. 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 [10], potentially resulting in increased toxicity of nucleoside reverse transcriptase inhibitors (NRTIs) [11]. The active intracellular phosphorylated forms of tenofovir (TFV) and emtricitabine (FTC), two such agents, have not been studied in older patients [12-14].

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.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study design and population

Twelve HIV-infected adults ≥ 55 years old were recruited from the University of North Carolina (UNC) Healthcare Infectious Diseases Clinic in Chapel Hill, NC. The protocol was approved by the UNC Biomedical Institutional Review Board and the protocol listed on (NCT01180075). Six currently adherent subjects for each of two regimens, either TFV 300 mg/FTC 200 mg/efavirenz (EFV) 600 mg administered once daily (Atripla™; Bristol-Myers Squibb, New York, NY) or TFV 300 mg/FTC 200 mg (Truvada™; Gilead Sciences, Foster City, CA), atazanavir (ATV) 300 mg (Reyataz™; Bristol-Myers Squibb, New York, NY) and ritonavir (RTV) 100 mg (Norvir™; Abbott Laboratories, Chicago, IL) administered once daily, provided informed consent and underwent screening. This was a convenience sample, selected to provide preliminary PK information for future work. Adherence was defined as three or fewer missed doses in the previous 30 days, with no missed doses in the 3 days immediately preceding pharmacokinetic sampling. Subjects received their regimen for at least 2 weeks prior to sample collection. Screening consisted of vital signs, a physical examination, basic laboratory studies (performed within 45 days of enrolment), and frailty phenotyping. Frailty phenotyping was performed as in Fried et al. [15] by the Clinical and Translational Research Center Bionutrition Core at UNC, and included answering questions regarding unintentional weight loss, fatigue and physical activity, in addition to measuring grip strength and walk times. Subjects with unstable vital signs, with abnormal laboratory values meeting the DAIDS (Division of Acquired Immunodeficiency Syndrome, National Institute of Allergy and Infectious Diseases, National Institutes of Health) Grade 1 anaemia criterion (haemoglobin < 10 mg/dL) or DAIDS Grade 2 criteria for other laboratory abnormalities, or displaying the frailty phenotype were excluded. Cognitive status was not assessed and cognitive impairment was not an exclusion criterion. For subjects receiving ATV, Grade 2 total bilirubin elevations (up to 2.5 times the upper limit of normal) were allowed, with clinical documentation that the elevation was related to ATV administration and clinically insignificant. Subjects receiving concomitant medications expected to alter the PK parameters of a study drug by ≥30% were excluded; subjects receiving ATV were excluded for concomitant proton pump inhibitor or a histamine-2 receptor inhibitor therapy.

PK visit

Subjects were admitted to the NC TraCS Institute Clinical and Translational Research Center (CTRC) approximately 2 hours prior to their home dosing time for the ARV regimen for vital signs, a complete blood count (CBC) to check for anaemia prior to sampling, a brief physical examination, and adherence questioning. Subjects also completed dosing cards for the 3 days prior to their PK visit, and cards were reviewed by study personnel at admission. Blood samples were collected in K2EDTA tubes (BD Diagnostics, Franklin Lakes, NJ) for plasma processing and CPT tubes (BD Diagnostics) for peripheral blood mononuclear cells (PMBCs) at −0.5, 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24 hours following a witnessed dose. Subjects receiving TFV/FTC/EFV took their dose on an empty stomach and did not eat for at least 4 hours post-dose; TFV/FTC/ATV/RTV subjects took their dose with a standard research meal at their typical time of medication administration. A whole blood sample was also obtained for future pharmacogenomic analyses. Adverse event questionnaires [16] were administered prior to discharge. Subjects returned for a brief follow-up visit within 30 days of the PK visit which included vital signs, a CBC, a brief physical examination, and adverse event questionnaires.

Sample collection and processing

Within 1 hour after collection, K3EDTA tubes stored on ice were processed by centrifugation at 3000 g at 4°C for 10 minutes. The resultant plasma was aliquoted into labelled cryovials, and stored at −80°C until analysis. Within 2 hours after collection, CPT tubes stored at room temperature were centrifuged at 1300 g for 30 minutes at room temperature with the brake off. After washing the gel with cold 0.9% normal saline, the PBMC-containing plasma was centrifuged at 350 g for 10 minutes at 4°C. After the supernatant had been discarded, cells were re-suspended in red blood cell lysis buffer and allowed to sit at room temperature for 2 minutes. After the addition of 10 mL of cold 0.9% normal saline and centrifugation at 300 g for 5 minutes at 4°C, cells were prepared for counting using Trypan blue exclusion and a Countess Cell Counter (Life Technologies, Grand Island, NY, USA). After counting, cells were lysed with 70:30 methanol:water solution, and the methanolic extracts obtained after 15 minutes on ice followed by centrifugation at 800 g for 10 minutes at 4°C were stored at −80°C until analysis.

Concentration analysis

TFV, FTC, EFV, ATV and RTV concentrations in plasma were determined using validated high-performance liquid chromatography–ultraviolet detection (HPLC-UV) methods [17, 18]. All methods were validated as mandated by the industry guidance set by the US Department of Health and Human Services, Food and Drug Administration and Center for Drug Evaluation and Research [19]. For all the above analytes, the dynamic range is 10–10 000 ng/mL. Tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations were determined using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods with an Agilent 1200 HPLC system connected to an Agilent 6410 triple quadrupole mass spectrometer (Agilent Technologies, Santa Clara, CA). Briefly, methanolic extracts underwent protein precipitation with 1:1 methanol/1mM ammonium phosphate solution containing the internal standards (13C TFV, 13C 15N FTC and 13C TFV-DP), followed by evaporation to dryness under nitrogen and reconstitution with 1 mM ammonium phosphate. The analytes were eluted from a Waters Xbridge™ C18 (2.1 × 20 mm, 5 μm particle size) analytical column (Waters Corporation, Milford, MA) in series with a Thermo Scientific BioBasic AX (50 × 2.1 mm, 5 μm particle size) column (Thermo Fisher Scientific, Waltham, MA). Data were collected using Agilent LC-MS/MS MassHunter Chromatography software, with positive ion m/z transitions of 448.1/270.1 (TFV-DP) and 488.1/130 (FTC-TP) using electrospray ionization. The dynamic range of the assay is 1–1000 ng/mL; raw concentration values are normalized for cell counts and molecular mass of the analyte, with final concentration values reported as femtomoles/106 cells. All calibrators and quality control samples were within 15% of the nominal value for both within-day and between-day runs.

All drug concentration measurements were performed at the UNC Center for AIDS Research Clinical Pharmacology and Analytical Chemistry Laboratory. The laboratory participates in national and international proficiency testing of its methods, and consistently achieves > 95% accuracy in this testing.

Pharmacokinetic and statistical analysis

After preliminary graphical analysis, noncompartmental analysis for each drug was performed using Phoenix Win Nonlin v6.1 (Pharsight, Inc., Cary, NC). The maximal concentration (Cmax) and time of maximal concentration (Tmax) were determined by visual inspection. Area under the concentration–time curve over 24 hours (AUC0-24h) was determined using the trapezoidal rule (linear up/log down interpolation). Terminal half-life was calculated from the log-linear slope of the elimination phase. PK parameter estimates for extracellular drugs (TFV, FTC, EFV, ATV and RTV) were compared with values reported either in the drug's Full U.S. Prescribing Information or the literature. Because of the variable nature of intracellular metabolite concentrations, AUC (linear trapezoidal rule) and average PBMC concentrations across dosing intervals are presented.

To compare these results with published PK parameters for extracellular drugs in the general HIV-infected population, the mean or median PK parameter available in the literature that as closely represented the study design and data analysis as possible was used to calculate ratios for the Cmax (peak concentrations) and AUC (drug exposure) of the older cohort:general population. For each subject, the parameter of interest was divided by the literature value, and the median ratio for all subjects is reported. Statistical comparisons were made using the Wilcoxon rank sum test in sas jmp7 (SAS Institute, Cary, NC) at a significance level of α = 0.05. Because of differing sampling schemes and analytical methodologies between our study and other published reports of TFV-DP and FTC-TP, statistical comparisons were not made for these metabolites.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Subject demographics and safety evaluation

Twelve subjects were screened and enrolled. Demographic data for subjects by regimen are presented in Table 1. Overall, the average (mean ± standard deviation) age was 59.7 ± 3.9 years, the average body mass index (BMI) was 29.9 ± 5.4 kg/m2, and the average creatinine clearance was 70.1 ± 17.6 mL/min. Equal numbers of Caucasians and African Americans were enrolled on each regimen, and half of all subjects were female. Eleven of twelve subjects had undetectable HIV RNA concentrations at screening; one subject, who had initiated TFV/FTC/EFV within the last month, had a viral load of 1372 HIV-1 RNA copies/mL at screening which was < 50 copies/mL 3 months later. Mean (± standard deviation) CD4 lymphocyte counts were 818 ± 370 cells/μL for all subjects. Subjects reported no missed doses, and all doses in the 3 days prior to the PK visit were taken within 3 hours of the scheduled administration time. With the exception of one TFV/FTC/ATV/RTV subject who had a dose that was 1.5 hours late, all other doses immediately prior to the PK visit were taken within 30 minutes of the scheduled administration time.

Table 1. Subject demographics by regimen
Baseline characteristicTFV/FTC/EFV subjectsTFV/FTC/ATV/RTV subjects
(n = 6)(n = 6)
  1. Data are presented as mean ± standard deviation, or number (percentage), unless otherwise specified. Creatinine clearance was calculated using the Cockcroft–Gault equation (inline image, multiplied by 0.85 for women [44]; actual body weight was used unless the subject was > 20% above their ideal body weight, in which case adjusted body weight was used).

  2. ATV, atazanavir; BMI, body mass index; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TFV, tenofovir.

Age (years)60.7 ± 5.458.7 ± 1.4
Caucasian3 (50%)3 (50%)
African American3 (50%)3 (50%)
Female4 (66.7%)2 (33.3%)
Male2 (33.3%)4 (66.7%)
Duration with HIV (years)14.3 ± 10.38.4 ± 3.9
Duration on current regimen (years)3.5 ± 3.653.4 ± 1.7
CD4 T-cell count (cells/μL)683 ± 226952 ± 455
HIV RNA < 50 copies/mL (n/total)5/66/6
Creatinine clearance (mL/min)69.4 ± 25.070.9 ± 7.46
BMI (kg/m2)27.6 ± 5.632.2 ± 4.5

This cohort of older HIV-infected subjects tolerated intensive PK sampling well.

No subjects experienced significant changes in CBC values between sampling and follow-up. One subject reported developing a sore throat that spontaneously resolved and was deemed by the study physician not to be related to the study intervention.

Noncompartmental analysis (NCA)

Concentration–time profiles for each drug are presented in Figure 1a-e. NCA parameter estimates are reported in Table 2 for each drug in each regimen. TFV and FTC parameter estimates are provided separately for each regimen. The terminal half-life and Tmax for FTC were statistically different between regimens (p < 0.05); no statistically significant differences were observed for TFV PK parameters by regimen (all p > 0.05).


Figure 1. Time-concentration profiles of (a) tenofovir (TFV), (b) emtricitabine (FTC), (c) efavirenz (EFV), (d) atazanavir (ATV) and (e) ritonavir (RTV). Individual subject profiles are shown in dashed lines, with median/25th -75th percentile plots overlaid. For TFV and FTC, each regimen is shown individually, with an overall median. ATV, atazanavir; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TFV, tenofovir.

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Table 2. Noncompartmental pharmacokinetics (PK) parameter estimates for each drug, by regimen
 DrugTerminal half-life (h)Tmax (h)Cmax (ug/L)C24h (ug/L)AUC0-24h (h/μg/L)
  1. ATV, atazanavir; AUC0-24h, area under the concentration–time curve from 0 to 24 hours; Cmax, maximal concentration; C24h, concentration at the end of the 24-h dosing interval; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TFV, tenofovir; Tmax, time of maximal concentration.

TFV/FTC/EFVTFV13.7 (12.4, 31.6)3.0 (1.5, 12)295 (223, 421)96.8 (66.5, 112)3.43 × 103 (3.05 × 103, 4.05 × 103)
FTC6.24 (5.07, 6.57)4.0 (2.1, 6.1)1780 (1410, ,050)126 (81.0, 210)1.41 × 104 (1.03 × 104, 1.91 × 104)
EFV44.9 (26.6, 68.2)4.5 (3.0–8.0)3403 (2840, 6120)2180 (1460, 3620)6.08 × 104 (4.60 × 104, 9.60 × 104)
TFV/FTC/ATV/RTVTFV11.1 (9.47, 14.1)1.5 (1.0–2.1)319 (275, 417)62.1 (51.0, 80.9)3.33 × 103 (2.92 × 103, 4.23 × 103)
FTC8.53 (7.49, 9.66)1.9 (1.0–6.0)1840 (1470, 2130)78.5 (62.8, 116)1.05 × 104 (8.54 × 103, 12.4 × 104)
ATV6.00 (3.75, 12.0)2.0 (1.0–6.0)3750 (2120, 4610)605 (452, 1000)3.47 × 104 (2.55 × 104, 3.85 × 104)
RTV5.61 (4.18, 7.05)2.5 (1.0–6.0)1440 (725, 1880)57.3 (27.2, 92.5)6.54 × 103 (7.87 × 103, 1.25 × 104)

A summary of comparisons to historical values in the adult HIV-infected population for both regimens is presented in Table 3. Compared with published values for TFV [20], FTC [21], and EFV [22], several differences are noted. The AUC0-24h and Cmax of TFV were slightly lower in the TFV/FTC/EFV cohort, with a median ratio of 0.92 for AUC0-24h and a median ratio of 0.87 for Cmax. In contrast, the AUC0-24h and Cmax of FTC were found to be higher in our cohort, with a median ratio of 1.75 for AUC0-24h and a median ratio of 1.26 for Cmax. For EFV, AUC0-24h was similar to historic controls (median ratio of 1.05), with a lower Cmax (median ratio of 0.84). These differences did not achieve statistical significance.

Table 3. Median ratios for each drug, by regimen, in comparison to literature values
  1. ATV, atazanavir; AUC0-24h, area under the concentration–time curve from 0 to 24 hours; Cmax, maximal concentration; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TFV, tenofovir.


For the subjects receiving TFV/FTC/ATV/RTV, comparison to the same TFV [20]/FTC [21] reference parameters indicated similar results for FTC (median ratios of 1.31 for both AUC0-24h and Cmax) and TFV (median ratio 0.90 for AUC0-24h and 0.94 for Cmax). For ATV/RTV co-administered with TFV at a dose of 300 mg ATV + 100 mg RTV [23], ATV exposures in this cohort were lower (median ratio of 0.88 for AUC0-24h) with a higher Cmax (median ratio of 1.09). For RTV, higher AUC0-24h and Cmax were seen, with a median AUC0-24h ratio of 1.19 and a median Cmax ratio of 1.78. These differences did not achieve statistical significance.

Intracellular metabolite analysis

For TFV-DP, the median AUC0-24h and its interquartile range (IQR) and the mean concentration over the dosing interval by regimen are reported in Table 4. The comparators available in the literature [24] included mean concentrations over the dosing interval, with a reported value of 76.1 fmol/106 cells compared with a mean (± standard deviation) of 128 ± 78 fmol/106 cells for EFV subjects and 112 ± 78 fmol/106 cells for ATV/RTV subjects in this study, suggesting higher TFV-DP concentrations in older subjects.

Table 4. Tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) mean concentrations over a dosing interval and area under the concentration–time curve (AUC), by regimen
RegimenAnalyteMean concentration over dosing interval (fmol/106 cells; mean ± SD)AUC [h/fmol/106 cells; median (IQR)]
  1. ATV/RTV, atazanavir/ritonavir; EFV, efavirenz; IQR, interquartile range; SD, standard deviation.

EFVTFV-DP128 ± 782410 [1450,5030]
ATV/RTV112 ± 772110 [1470,2720]
EFVFTC-TP2830 ± 83069400 [53500,79000]
ATV/RTV3160 ± 119064400 [56400,70100]

Median AUC0-24h (with IQR) and mean concentration over the dosing interval for FTC-TP are also reported by regimen in Table 4. The comparators available in the literature [21] include the median 4-h post-dose concentration, with a reported value of 4000 fmol//106 cells compared with a median (IQR) of 3110 [2100,4120] fmol/106 cells for EFV subjects and 3100 [2389,3346] fmol/106 cells for ATV/RTV subjects in this study, suggesting lower FTC-TP concentrations in older patients.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

In this PK study of two of the recommended first-line ARV regimens [25] in older HIV-infected adults, noncompartmental PK parameters were similar to historic controls. ATV, EFV and RTV all undergo significant cytochrome P450-mediated metabolism, and liver mass is known to decrease with age [26-28]. Based on a population PK report, higher EFV exposures were expected [29], potentially as a result of decreased auto-induction of EFV metabolism through CYP3A, but were not seen in this small study of nonfrail subjects ≥ 55 years old. Because of its acid-dependent absorption profile and the potential effects of altered metabolism [30], decreased ATV exposures were expected. Although exposure was similar, peak concentrations decreased, which may be explained by altered absorption [23, 30]. RTV concentrations and exposure did increase; however, given the complicated PK profile of this drug, it is not possible to determine what factors may be influencing this observation at this time, and it merits further exploration.

The observed difference between FTC terminal elimination half-life and Tmax in the TFV/FTC/EFV and TFV/FTC/ATV/RTV regimens does not appear to be related to a drug–drug interaction or differences in renal function between groups; although the mean creatinine clearance value in the EFV group was lower, this was primarily driven by a single subject. TFV, which is also renally cleared, showed similar trends, but exposure and peak concentrations were lower. Both drugs are substrates for drug transporters [31], and the potential effects of aging on drug transport activity have not been well characterized [32]. A recent publication in aged mice suggests both age-related and gender-specific changes in transporter expression [33]; these data offer a basis for further exploration of transporter effects on TFV and FTC disposition.

This is one of the few studies to collect intensive PBMC samples and report TFV-DP and FTC-DP values at 11 points over a 24-h dosing regimen, and the first to look at these metabolites specifically in the elderly population. The observed changes between concentrations in the dosing interval compared with historical data may reflect differences in the intracellular metabolic pathways for the drugs as a result of increased cellular activation in older patients. FTC is preferentially metabolized in resting cells [34], whereas TFV may be metabolized in either resting or activated cells [35]. In the study used for comparison for TFV-DP [24], a polymorphism in the gene coding for multidrug resistance protein 4 and tenofovir renal clearance were related to intracellular concentrations, suggesting that alterations in transporter activity could contribute to altered TFV-DP concentrations in older patients.

As chronological age alone may not adequately describe physiological changes that occur with disease processes, studying frail older individuals may provide new insight. Frailty is described as a clinical syndrome of decreased functional reserves that increases morbidity and mortality. Frailty is probably caused by altered biochemical processes in the body, as demonstrated by increased concentrations of inflammatory markers such as tumour necrosis factor (TNF)-α, interleukin (IL)-6, and C-reactive protein [15]. A characteristic phenotype has been described [15] and applied to the HIV-infected population, which demonstrates this phenotype at earlier ages than in the general population [36, 37]. Significant decreases in drug clearance of 50% or greater have been demonstrated in frail elderly individuals for acetaminophen [38], metoclopramide [39] and antipyrine [40] compared with younger, healthier subjects. This increase in exposure is probably attributable to a combination of decreased renal clearance and cytokine-induced down-regulation of metabolic enzymes [41]. Increased exposure probably contributes to increased toxicity of drugs in frail patients.

The overall goal of this investigation was to use intensive PK sampling and parameters in an otherwise healthy HIV-infected population, and so frail subjects were purposely excluded. Only older subjects were enrolled to provide estimates of PK parameters in this population; 55 years of age was selected as the minimum age for inclusion at the time of study initiation. Subsequent research and discussion in the literature suggest that HIV-infected patients may be considered ‘elderly’ at 50 rather than 55 years of age [42].

As a consequence of the small numbers of subjects involved in this investigation, traditional statistical comparisons have limited ability to show differences between these subjects and historic controls. A limitation of this report is the use of historical controls rather than concomitant enrolment of younger subjects using the same study design and analytical methods for drug concentrations. For the extracellular drugs studied, study designs for the comparator data used similar intensive-sampling schemes and analytical methods, and therefore statistical comparisons are presented. For the intracellular metabolites, intensive-sampling schemes are rarely used because of the complexity of cell processing, and analytical methodology varies considerably from laboratory to laboratory. As data for comparison using the methods employed here were not readily available in the literature, values are provided only as a point of reference without formal statistical comparisons.

These data will be used to design a larger, population-based PK/PD study in HIV-infected patients to quantify differences based on age or other patient-specific characteristics, frailty being one such characteristic. Population PK/PD modelling seeks to characterize variability in drug disposition and effect in a patient population in order to make dosing recommendations based on patient characteristics, and is a powerful and increasingly accepted [43] tool for identifying subpopulations that may benefit from alternative dosing strategies. Ultimately, population PK/PD modelling aims to inform clinicians of any necessary dosing recommendations specific for older HIV-infected populations.

In conclusion, this investigation provides a rationale and background for further examination of the area of ARV pharmacokinetics and aging. Subsequent investigations will include the enrolment of a cohort with a broad age range and the presence of the frailty phenotype for a population PK/PD analysis.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The authors wish to thank the participating subjects, as well as the staff of the UNC Healthcare Infectious Disease Clinic for their assistance with recruitment. We also thank the nurses of the UNC CTRC for their assistance in conducting study visits. Phoenix Win Nonlin was provided to the Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy by Certara as a member of the Pharsight Academic Center of Excellence Program.

Conflicts of interest

KBP and ADMK have received research funding from Gilead Sciences for unrelated projects. ADMK has served on a Bristol Myers-Squibb advisory board in the last 3 years.

Funding sources

Funding was received from the Society of Infectious Diseases Pharmacists Young Investigator Award (JBD), the UNC Center for AIDS Research (5P30AI050410-13; JBD, RW, SJ, SM, NW, CS and ADMK), the NC TraCS Institute (UL1RR025747; JBD) and NIH/NIAID (K23AI093156-JBD; K23AI077355-KBP).


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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