Pharmacokinetics and safety of twice-daily atazanavir 300 mg and raltegravir 400 mg in healthy individuals

Abstract

Background

Atazanavir plus raltegravir 300/400 mg twice daily is being explored as a ritonavir- and nucleoside- sparing treatment strategy. The pharmaco-kinetics and safety of this combination in healthy individuals were evaluated.

Methods

A total of 22 healthy individuals received raltegravir 400 mg on days 1–5, atazanavir 300 mg on days 6–12 and atazanavir plus raltegravir 300/400 mg on days 13–26, twice daily with a light meal. Serial blood samples were collected 12 h after the morning dose on days 5, 12 and 26; safety assessments, clinical laboratory data and serial electrocardiograms (ECGs) at 0, 2 and 6 h were obtained.

Results

Raltegravir coadministration reduced atazanavir geometric mean maximum plasma concentration (C_max), area under the plasma concentration–time curve from 0 to 12 h post-dose (AUC_0–12) and trough plasma concentration (C_min) by 11%, 17% and 29%, respectively, compared with atazanavir alone. Geometric mean atazanavir C_min was 817 ng/ml (range 250–1,550) with raltegravir coadministration. Atazanavir increased raltegravir geometric mean C_max, AUC_0–12 and C_min by 39%, 54% and 48%, respectively. All adverse events were of mild or moderate intensity. Hyperbilirubinaemia and ECG PR increases with atazanavir were similar to those of atazanavir/ritonavir once daily. No corrected QT prolongations were noted. Mean QRS increase from baseline was 11.0 ms (range 2–25) after receiving atazanavir for 7 days; no further QRS increase was noted and no QRS interval was >120 ms with raltegravir coadministration. No ECG changes were observed with raltegravir alone.

Conclusions

Coadministration of atazanavir and raltegravir 300/400 mg twice daily decreased atazanavir AUC_0–12 and C_min relative to atazanavir alone, and increased AUC_0–12 of raltegravir relative to raltegravir alone. Atazanavir and raltegravir alone and coadministered appeared safe and well-tolerated.