These are the first intensive pharmacokinetic data on the combination of atazanavir-ritonavir and TDF in young adults. The atazanavir concentrations observed in our patients in the presence of tenofovir were similar to what was previously observed in older adults receiving this combination (25
). The Puzzle 2 pharmacokinetic substudy included 10 HIV-infected males aged 33 to 59 receiving atazanavir-ritonavir plus TDF and at least one other nucleoside reverse transcriptase inhibitor. In that study, the mean (percent coefficient of variation [%CV]) atazanavir AUC0-24
, and CL/F
values were 39,231 ng·hr/ml (59), 3,443 ng/ml (41), 665 ng/ml (84), and 9.8 liter/hr (51), very similar to the values observed in our patients. This compares with mean (%CV) atazanavir AUC0-24
, and CL/F
values of 53,761 ng·hr/ml (66), 5,233 ng/ml (58), 862 ng/ml (97), and 5.6 liter/hr (66) when atazanavir is administered without TDF in HIV-infected adults (Reyataz product information; Bristol-Myers Squibb). We also found weight to be significantly predictive of atazanavir CL/F
. These data suggest that higher doses of atazanavir may be required in very-large patients to achieve the same exposures. Unlike the results of several previous studies (17
), we did not detect a strong and statistically significant correlation between atazanavir concentrations and total bilirubin levels. The atazanavir AUC and Cmax
values were very weakly (positively) correlated with total bilirubin concentrations (0.02 and 0.04, respectively) in this study. The correlation between the atazanavir Cmin
and total bilirubin was 0.37, and this increased to approximately 0.5 if we removed the data for three subjects with total bilirubin concentrations of >4 mg/dl. We can only assume that the correlation with Cmin
and total bilirubin concentrations was not significant in our study due to the small sample size and also, possibly, the racial heterogeneity of our patient population. The majority of our subjects were African American; however, several previous studies identifying a correlation included mainly Caucasian subjects. Also, it could be possible that UGT1A1 activity is greater in this age group. There are no published data correlating bilirubin and atazanavir concentrations in children or adolescents.
The tenofovir prescribing information reports the mean (%CV) tenofovir AUC0-24
from seven patients as 3.3 μg·hr/ml (42) and 326 ng/ml (37) (tenofovir [Viread] prescribing information; Gilead, Foster City, CA [accessed January 14, 2007]), very similar to the values observed in our patients. In the aforementioned Puzzle 2 substudy, the tenofovir AUC0-24
, and C24
values were 2.3 μg·hr/ml, 234 ng/ml, and 45 ng/ml (28
), also comparable to the concentrations observed in our patients. A separate study of 28 healthy volunteers aged 19 to 43 found that the tenofovir AUC0-24
, and C24
values were increased 37%, 34%, and 29%, respectively, when TDF was given with atazanavir-ritonavir (1
). Based on those findings, we anticipated that tenofovir concentrations in our patients would be higher than the values reported in the literature for tenofovir without a protease inhibitor, but this was not the case. The lower-than-anticipated tenofovir concentrations found in our study subjects may be due to faster tenofovir clearance as a result of increased creatinine clearance in this young age group. Indeed, we found estimated creatinine clearance to be significantly predictive of tenofovir clearance. Tenofovir concentrations were also lower in obese subjects.
This was the first study to describe TFV-DP concentrations in young adults and in combination with atazanavir-ritonavir. The TFV-DP concentrations observed in this study were similar to those described previously by Hawkins et al. (8
) in subjects 31 to 65 years of age (median, 85 to 110 fmol/million cells) and by Kiser et al. (14
) in subjects aged 25 to 60 (mean ± standard deviation, 76 ± 40 fmol/million cells). The previous study by Kiser at al. also found tenofovir AUC and renal function to be associated with intracellular TFV-DP concentrations (14
There are limitations to this study. First, this was an observational trial that did not allow within-person comparisons of changes in tenofovir pharmacokinetics after the addition of atazanavir-ritonavir and/or changes in atazanavir pharmacokinetics after the addition of tenofovir. Therefore, we are only able to describe our subjects' pharmacokinetic parameters and make comparisons to historical data. Also, several PBMC pellet samples arrived hemolyzed or frozen. These were included in the analyses, which may have affected TFV-DP quantification in unpredictable ways.
Although we may have expected higher tenofovir concentrations in our subjects, based on a previous interaction study of healthy volunteers, the atazanavir concentrations observed in this study were similar to historical data. The fact that 16 of 22 subjects had HIV-1 RNA less than or equal to 400 copies/ml suggests that the tenofovir and atazanavir exposures were therapeutic in the majority of these subjects. There are some concentration-effect data for atazanavir with which to compare our data. In the BMS-089 study, in which subjects received stavudine and lamivudine in combination with either atazanavir alone or ritonavir-boosted atazanavir, 85% of treatment-naïve subjects with atazanavir troughs between 327 to 764 ng/ml had an undetectable viral load at week 48 of treatment (3
). However, there are very limited data correlating tenofovir levels with response. A previous study of TDF in 18 children aged 8.3 to 16.2 found that tenofovir serum AUCs in virologic responders (median, 3,800 ng·hr/ml) were higher than in nonresponders (median, 2,510 ng·hr/ml) (10
). The geometric mean tenofovir exposures in our study subjects (2,762 ng·hr/ml) were closer to the exposures in the “virologic nonresponder” subjects in that study. Considering that atazanavir and atazanavir-ritonavir have been shown to increase tenofovir concentrations in prior studies, our findings provide a basis for concern about tenofovir exposures in young adults not receiving atazanavir-ritonavir or another protease inhibitor. Specifically, could tenofovir exposures in young adults be even lower when used in regimens that do not include atazanavir or ritonavir? If they are lower, does this have implications for virologic response in this age group? Unfortunately, there are very limited concentration-effect data with tenofovir; thus, it is currently unclear what the lower threshold for tenofovir exposures should be. The lack of exposure-response relationships in our study may also be a function of the heterogenous patient population included (i.e., the study included treatment-naïve and experienced subjects, and the other nucleoside reverse transcriptase inhibitor(s) the subjects were taking were not controlled for).
In conclusion, the pharmacokinetic characteristics of atazanavir, ritonavir, and tenofovir in these young adults are consistent with historical data, though we anticipated higher tenofovir concentrations, based on a tenofovir/atazanavir-ritonavir interaction study of healthy volunteers. Additional studies of exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.