Pharmacokinetics of single oral doses of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in healthy volunteers.
BACKGROUND
Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor that is undergoing clinical development for the treatment of HIV-1 infection. This study was performed to investigate the pharmacokinetics of single oral doses of apricitabine in healthy volunteers.


METHODS
A total of 26 healthy volunteers (14 males, 12 females) took part in this study. Participants received single oral doses of apricitabine 400 mg, 800 mg and 1600 mg in ascending order at intervals of at least 1 week. Concentrations of apricitabine in plasma and urine were monitored over 24 hours after dosing.


RESULTS
Apricitabine was rapidly absorbed after oral administration, with peak plasma concentrations (Cmax) being attained approximately 1.5-2 hours after dosing. Plasma concentrations declined in a log-linear manner over at least 12 hours, with an elimination half-life of approximately 3 hours. The majority of the dose (65-80%) was excreted in the urine as unchanged drug within 24 hours. The pharmacokinetics of apricitabine were largely linear with respect to dose. In the overall study population, the area under the concentration-time curve (AUC) decreased by 4% with a dose of 800 mg and by 14% with the 1600 mg dose compared with the value predicted from the 400 mg dose. In females, however, there was a slightly greater departure from linearity: AUC decreased by 8% with a dose of 800 mg, and by 21% with a dose of 1600 mg. When pharmacokinetic parameters were normalised for bodyweight, there were no significant differences between values in males and females. There was no evidence of enantiomeric interconversion of apricitabine. All doses of apricitabine were well tolerated.


CONCLUSIONS
Apricitabine is rapidly absorbed and shows predictable pharmacokinetics after oral administration. Clearance is predominantly by renal excretion of the unchanged drug, which suggests a low potential for interactions with drugs that are subject to hepatic metabolism.
Holdich
Tom
T
Shire Pharmaceuticals Ltd, Basingstoke, UK.
Shiveley
LeeAnn
L
Sawyer
James
J
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid / Q000379:methods; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012737:Sex Factors; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods; D013997:Time Factors
D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; C508042:apricitabine