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

• Published in: Antiviral therapy Vol. 15; no. 8; pp. 1107 - 1114
• Main Authors: Zhu, Li, Butterton, Joan, Persson, Anna, Stonier, Michele, Comisar, Wendy, Panebianco, Deborah, Breidinger, Sheila, Zhang, Jenny, Bertz, Richard
• Format: Journal Article
• Language: English
• Published: London International Medical Press 01.01.2010
• Subjects: Adolescent; Adult; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Anti-HIV Agents - blood; Anti-HIV Agents - pharmacokinetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Atazanavir Sulfate; Biological and medical sciences; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Electrocardiography; Female; Heart - drug effects; Humans; Male; Medical sciences; Middle Aged; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Oligopeptides - blood; Oligopeptides - pharmacokinetics; Pharmacology. Drug treatments; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - blood; Pyridines - pharmacokinetics; Pyrrolidinones - administration & dosage; Pyrrolidinones - adverse effects; Pyrrolidinones - blood; Pyrrolidinones - pharmacokinetics; Raltegravir Potassium; Time Factors; Young Adult; Antiretroviral agent; Atazanavir; Healthy subject; Enzyme; Toxicity; Enzyme inhibitor; Peptidases; Integrase inhibitor; Hydrolases; Antiviral; Safety; Pharmacokinetics; Protease inhibitor; Raltegravir
• ISSN: 1359-6535; 2040-2058; 2040-2058
• DOI: 10.3851/IMP1673

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