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

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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 (Cmax), area under the plasma concentration–time curve from 0 to 12 h post-dose (AUC0–12) and trough plasma concentration (Cmin) by 11%, 17% and 29%, respectively, compared with atazanavir alone. Geometric mean atazanavir Cmin was 817 ng/ml (range 250–1,550) with raltegravir coadministration. Atazanavir increased raltegravir geometric mean Cmax, AUC0–12 and Cmin 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 AUC0–12 and Cmin relative to atazanavir alone, and increased AUC0–12 of raltegravir relative to raltegravir alone. Atazanavir and raltegravir alone and coadministered appeared safe and well-tolerated.

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