final program.qxd - Parallels Plesk Panel

OP 4.2
Development of Aprictabine
Dr Susan Cox, Avexa, Richmond, Australia
Background
Apricitabine (ATC) is a deoxycytidine analogue in phase IIb development for the treatment
of HIV infection. Prior to 2006 ATC was named variously as BCH10618, SPD754 and
AVX754. In vitro and in vivo studies undertaken previously identified a promising
tolerability profile, with antiretroviral activity against clinical isolates resistant to both 3TC
and TAMs and a more than 1.6 log10 reduction in viral load over 10 days monotherapy in
treatment naïve subjects. ATC is neither a substrate nor an inducer of CYP450
isoenzymes and is principally eliminated as unchanged drug in the urine. ATC is dosed
twice daily at present and is a candidate for the management of patients who are resistant
to 3TC or FTC. An ongoing study is currently investigating the potential for ATC to
provide superior antiretroviral activity to 3TC in the presence of the M184V mutation in
reverse transcriptase. Studies have shown that co-administration of more than one
deoxycytidine analogue may result in clinically significant antagonism. Avexa is presently
completing a series of further in vitro and in vivo studies prior to initiation of a phase III
clinical program.
ABSTRACTS
Methods
Two in vitro studies have been completed to expand the understanding of the virological
profile of ATC. In the first of these, HIV-1 (HXB2) harbouring M184V was repeatedly
passaged with increasing concentrations of ATC in order to identify if ATC (which can
maintain M184V in vitro) would select for further mutation in reverse transcriptase. In the
second experiment the IC50s for ATC and approved NRTI were investigated against a
panel of clinical isolates containing K65R in the presence or absence of M184V. Three
further clinical pharmacology studies have either been completed or are ongoing. In the
first of these studies 16 healthy volunteers were administered ATC 800 mg twice daily
alone and with up to 960 mg per day of Septrin (Trimethoprim/Sulphamethoxazole).
A second study is investigating the pharmacokinetics of ATC in the presence of steady
state concentrations of a protease inhibitor, tipranavir. Finally a thorough QTC study is
underway in accordance with regulatory guidance.
Results
Passaging M184V virus in the presence of ATC for up to 8 weeks did not result in the
selection of further mutations in reverse transcriptase. The IC50s for other NRTI against
K65R and M184V+K65R were within the range of fold changes from wild type previously
reported elsewhere. For ATC the fold changes for K65R viruses ranged from 2.1 to 3.2
and for K65R+M184V from 2.5 to 4.2, in agreement with previous data in the HXB2
background. Co-administration of ATC with Septrin resulted in an increase in ATC
AUC0-12 of 55% and in Cmax of 22%, similar to that seen previously for 3TC.
Conclusions
Apricitabine displays only limited fold changes in activity against HIV-1 viruses harbouring
important resistance mutations in reverse transcriptase. Other than the known class
interaction with other deoxycytidine nucleoside analogues, ATC shows little potential for
meaningful interactions with other ART.
“ Focusing FIRST on PEOPLE “ 45 w w w . i s h e i d . c o m