Background: The recommended tenofovir disoproxil fumarate (TDF) dose is 300 mg every 48 hours for adults with moderate renal function impairment (creatinine clearance 30-49 mL/min). Coadminsitration of TDF with lopinavir/ritonavir (LPV/r) increases plasma tenofovir (TFV) concentrations in adults with normal renal function. We compared the plasma and intracellular pharmacokinetics (PK) of TDF 300 mg every 48 hours in HIV-infected adults with moderate renal function impairment receiving LPV/r and NNRTI-based antiretroviral therapy.
Methods: Data were collected within a phase I, non-randomized, open-label pharmacokinetic study of TDF in patients with renal dysfunction (ClinicalTrials.gov Identifier: NCT01671982). Consenting HIV-positive adults with a confirmed creatinine clearance (CrCL) 30 to <50 mL/min receiving TDF 300 mg every 48 hours per standard of care as part of a LPV/r- or NNRTI-based ART and an HIV-1 RNA viral load (VL) <50 copies/mL were included. HBs-antigen positive adults were excluded. Intensive steady-state 48-hour blood sampling for PK assessment was performed, blood samples were collected pre-dose and then at 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 12, 24, 36, 48 hours post-dose. Peripheral blood mononuclear cells (PBMCs) were also collected at 48 hours post-dose for assessment on intracellular tenofovir di-phosphate concentrations. PK parameters were calculated using non-compartmental analysis.
Results: 40 HIV-infected adults (55% female) were enrolled. Median (range) age was 56 years (39-82), weight 51 kg (38-80), serum creatinine (SCr) 1.3 mg/dL (0.8-2.1), CrCL 43.9 mL/min (30.9-49.7) and CD4 count 502 cells/mm3 (113-1063). Tenofovir PK data were evaluable from 19 subjects receiving an NNRTI- (9 nevirapine and 10 efavirenz) and 18 receiving LPV/r-based HAART. Tenofovir plasma and intracellular PK parameters are presented in the table below:
Mean tenofovir plasma AUC0-24 was 1.7-fold higher with coadminsitration of LPV/r compared to NNRTIs.
Conclusions: Tenofovir plasma exposure was significantly higher with LPV/r versus NNRTI based ART in patients with moderate renal function impairment. In contrast, trough intracellular TFV-diphosphate concentrations were similar between the two ART regimens.