Multiple-dose pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in patients with HIV-1 infection.

Abstract

BACKGROUND AND OBJECTIVE:

This study aimed to investigate the multiple-dose pharmacokinetics of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in antiretroviral-naive patients with HIV-1 infection.

METHODS:

This was an international, randomized, double-blind, placebo-controlled, multicentre, dose-ranging study. Patients received 10 days' oral placebo or apricitabine 200, 400, 600 or 800 mg twice daily or 800 or 1200 mg once daily. On days 1 and 8, blood and urine samples were collected over 24 hours for pharmacokinetic analysis. Apricitabine triphosphate pharmacokinetics were investigated in peripheral blood mononuclear cells (PBMCs) on day 8.

RESULTS:

Overall, 63 patients (mean age 33.9 +/- 8.7 years; mean weight 71.6 +/- 15.4 kg) were randomized, and 62 patients completed the study. Apricitabine was rapidly absorbed, with peak plasma concentrations attained within approximately 1.5-2.5 hours. Pharmacokinetics were linear over the range 200-800 mg twice daily. Apricitabine was predominantly excreted via the kidneys, with no significant accumulation during repeated administration. Steady-state conditions were attained by day 8. Apricitabine triphosphate exposure in PBMCs was roughly proportional to the dose of apricitabine across the dose range 200-800 mg twice daily, with adequate correlations between plasma exposure to apricitabine (9910 ng/mL per 65 kg for 800-mg twice-daily administration) and PBMC exposure to apricitabine triphosphate (maximum concentration [C(max)] = 5.55 +/- 1.94 pmol/million cells for 800-mg twice-daily administration). Apri-citabine was well tolerated.

CONCLUSION:

Apricitabine shows essentially linear pharmacokinetics during repeated administration in patients with HIV-1 infection.

• Authors: Pedro Cahn, Maria Rolon, Isabel Cassetti, LeeAnn Shiveley, Tom Holdich, James Sawyer
• Journal: Clinical drug investigation (Clin Drug Investig) Vol. 28 Issue 2 Pg. 129-38 ( 2008) ISSN: 1173-2563 [Print] New Zealand
• PMID: 18211121 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Capsules
• Nucleosides
• Reverse Transcriptase Inhibitors
• Deoxycytidine
• Amylases
• apricitabine

Topics

• Administration, Oral
• Adult
• Amylases (biosynthesis, blood)
• Area Under Curve
• Biological Availability
• CD4 Lymphocyte Count
• Capsules
• Deoxycytidine (analogs & derivatives, chemistry, pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• HIV Infections (drug therapy)
• HIV-1 (drug effects, growth & development)
• Half-Life
• Headache (chemically induced)
• Humans
• Nasal Obstruction (chemically induced)
• Nucleosides (administration & dosage, pharmacokinetics, therapeutic use)
• Reverse Transcriptase Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
• Stereoisomerism