Background: Use of unboosted atazanavir (ATV) with tenofovir disoproxil fumarate (TDF), although attractive from a clinical view point, has not been tested in trials and is not currently recommended because of the risk of suboptimal ATV pharmacokinetics (PK). In order to improve ATV exposure, plasma and intracellular (IC) PK of ATV in patients administered with ATV 400 mg once daily and TDF/emtricitabine (FTC) and switched to ATV 200 mg twice daily were studied.
Methods: On day 0, 10 subjects on ATV 400 mg plus TDF/FTC once daily underwent intensive plasma and IC PK evaluation and bilirubin measurement. Patients were subsequently switched to ATV 200 mg twice daily for 10 days. On day 11, they once again underwent intensive PK and bilirubin evaluation.
Results: Switch to 200 mg twice daily led (in plasma) to a significant increase of the observed concentration at the end of dosing interval (C(trough); ratio twice daily/once daily 2.20; P=0.005), with a decrease from 60% to 20% of suboptimal values, a significant decrease of the maximum concentration (C(max); ratio twice daily/once daily 0.47; P=0.022), whereas no differences of other PK parameters or bilirubin were observed. IC ATV concentrations at 400 once daily showed higher C(trough) (ratio peripheral blood mononuclear cells [PBMCs]/plasma 2.86; P=0.005) and longer half-life (ratio PBMCs/plasma 1.44; P=0.007) as compared with plasma. After the switch, IC ATV accumulation showed changes similar to plasma.
Conclusions: Switch to 200 mg twice daily appeared to optimize plasma and IC ATV PK, by increasing the determinant of efficacy (C(trough)) and decreasing C(max), without significant effect on total ATV plasma exposure and bilirubin. Dosage of 200 mg might provide an option to patients showing suboptimal ATV exposure with standard unboosted dosing.