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


CONCLUSIONS
Apricitabine shows essentially linear pharmacokinetics during repeated administration in patients with HIV-1 infection.
Cahn
Pedro
P
Fundación Huésped, Buenos Aires, Argentina.
Rolon
Maria
M
Cassetti
Isabel
I
Shiveley
LeeAnn
L
Holdich
Tom
T
Sawyer
James
J
D000284:Administration, Oral; D000328:Adult; D000681:Amylases / Q000096:biosynthesis / Q000097:blood; D019540:Area Under Curve; D001682:Biological Availability; D018791:CD4 Lymphocyte Count; D002214:Capsules; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D015508:Nasal Obstruction / Q000139:chemically induced; D009705:Nucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013237:Stereoisomerism
D002214:Capsules; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D000681:Amylases; C508042:apricitabine