196 μg/mL, 6.384 μg/mL, and 41.952 μg·h/mL and were 31, 4 and 16% higher following TDF coadministration. After TDF alone, the steady-state geometric mean TFV Cmin, Cmax and AUC were 0.052 μg/mL, 0.262 μg/mL and 2.590 μg·h/mL, respectively. These values decreased by 12, 25 and 15%, respectively, after FPV coadministration Y-27632 price and by 9, 18 and 7%, respectively, after FPV/RTV coadministration. During FPV/RTV dosing, the geometric

mean ritonavir Cmin, Cmax and AUC were 0.177 μg/mL, 0.858 μg/mL and 5.104 μg·h/mL, respectively (data not shown). During TDF coadministration, these increased slightly in groups C and D [GMR (90% CI) 1.09 (0.80–1.49) for AUC0−24 h, 1.12 (0.81–1.55) for Cmax, and 1.05 (0.79–1.40) for Cmin]. The regimens were generally well tolerated, although possibly drug-related maculopapular rash was observed in 38% (15 of 39) of the subjects: during FPV dosing alone in six subjects (three grade 1, two grade 2 and one

grade 3), during FPV/TDF dosing in four subjects (two grade 1 and two grade 2), during FPV/RTV+TDF dosing in four subjects (all grade 2), and during FPV/RTV dosing in one subject (grade 4). Laboratory parameters remained stable over the study period. Our results show that, when TDF is coadministered with either unboosted FPV or FPV/RTV, a small reduction in GSK1120212 price TFV exposure and increase in APV exposure occur. In previous TDF–FPV/RTV coadministration studies, the effect of adding an FPV regimen to a TDF regimen was not evaluated. However, two studies that evaluated APV pharmacokinetics following the addition of TDF 300 mg qd to an FPV/RTV 700/100 mg bid or 1400/200 mg

qd regimen noted negligible increases in steady-state APV Cmin values (by 4% [15] and 2% [19], respectively). The APV and TFV pharmacokinetic changes observed in our study were unlikely to be clinically important because the steady-state geometric mean TFV Cmin remained within the range reported in HIV-infected patients treated with TDF 300 mg qd without concurrent FPV [22–24], and the geometric find more mean APV Cmin for unboosted FPV (0.351 μg/mL) and FPV/RTV (2.88 μg/mL) during TDF coadministration remained 2.4- and 19.7-fold higher than the documented protein binding-adjusted 50% inhibitory concentration (IC50) for wild-type HIV isolates (0.146 μg/mL), respectively [25]. The pattern of plasma Cmin and AUC changes that we observed during TDF–FPV and TDF–FPV/RTV coadministration was different from the pattern reported when TDF was given with ATV [10,26], ATV/RTV [10,11,27], LPV/RTV [12,13,24,28] or indinavir (IDV) [13] (increase in TFV and decrease in PI), DRV or brecanavir (BCV) (increase in TFV and PI) [14,29], nelfinavir (NFV) (no change in TFV and decrease/no change in NFV and/or active metabolite M8) [30,31], saquinavir (SQV) (increase in TFV and increase/no change in SQV) [22,32], or TPV/RTV (no change/increase in TFV and decrease in TPV) [33]. Interactions between TDF and PIs can potentially occur at the kidney and/or the gut level.