Background:  We hypothesize that ritonavir (r) may decrease tipranavir (TFV) renal clearance (CLR) via inhibition of active efflux on the apical side of renal proximal tubule cells. The objective of this study was to investigate the effects of lopinavir (LPV)/r on the CLR of TFV in HIV-infected subjects.

Methods:  HIV-infected subjects, aged 18 to 65 years, with HIV-1 RNA ≤50 copies/mL, CD4 counts ≥200 cells/mm³, on stable tenofovir disoproxil fumarate (TDF)-containing regimens ≥4 weeks, and estimated glomerular filtration rates (GFR) > 60 mL/min, without diabetes, hypertension, and hepatitis C, were matched for age, race, and gender and enrolled into 1 of 2 groups. Group 1 included subjects on TDF 300 mg daily plus LPV/r 400/100 mg twice daily plus other nucleoside reverse transcriptase inhibitor (NRTI). Group 2 included subjects on TDF 300 mg daily plus other NRTI or non-NRTI (NNRTI), but no protease inhibitors (PI). All subjects had 24-hour blood and urine collections for TFV quantification following a standardized breakfast and observed dosing. Peripheral blood mononuclear cells were isolated at pre-dose and 5 and 24 hours post-dose for measurement of intracellular TFV-diphosphate (TFV-DP) by LC/MS/MS. TFV plasma pharmacokinetics were determined by non-compartmental methods using 136 mg of TFV in the 300-mg TDF tablet. Log-transformed TFV CLR was compared (t-test) between groups. The study was 80% powered to detect a 50% difference at the α = 0.05 level with 11 subjects per group. Regression was used to examine the effects of covariates on TFV CLR. Similar exploratory analyses of TFV-DP were conducted.

Results:  In all, 30 subjects completed study, of whom 73% were male, mean (±SD) age 42 (±9.4) years, 20% black. Weight, BSA, serum creatinine, estimated GFR, and CD4 count did not differ between groups. Mean (±SD) TFV AUC, CL/F, CLR, fraction excreted, and TFV-DP were 4.1 mg*hr/L (±1.3), 37.4 L/hr (±14.5), 12 L/hr (±3.5), 34% (±7), and 76 fmol/106 cells (±40). Mean (±SD) TFV CLR in group 1 was 11.3 L/hr (±2.4) vs 12.8 (±4.4) in group 2. After adjusting for estimated GFR, Group 2 had TFV CLR values 1.16 times greater than those in Group 1 (p = 0.045). No difference in TFV-DP was apparent between groups. TFV CLR, GFR, and AUC were univariately associated with TFV-DP. For every 1 L/hr increase in CLR there was an 8% decrease in TFV-DP (p = 0.002).

Conclusions:  After adjusting for GFR, this study found a lower TFV CLR in subjects taking LPV/r vs those not taking a PI, consistent with a renal interaction between TFV and LPV/r. Further elucidation of the mechanism of this interaction and its implications in various patient populations is warranted.