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Efficacy and Novel Pharmacology of Elvucitabine in a 7 Day Placebo Controlled Monotherapy Study
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Jules Levin
ICAAC, Sept 30, 2006, San Francisco
P. COLUCCI1, J. POTTAGE 2, H. ROBISON 2, D. SCH_RMANN 3, M. DONOHUE 2, R. GUGLIOTTI 2, M. P. DUCHARME 1;
1MDSPS and U de Montreal, Montreal, Canada, 2Achillion Pharmaceuticals, Inc., New Haven, CT, 3Charite U Med, Berlin, Germany.
Elvucitabine (ELV) is an L-cytosine nucleoside with potent in vitro anti-HIV activity (IC50 = 1ng/mL in PBMCs) and a prolonged T_ (∼ 100 hours). Previous results showed that 10 mg ELV QD co-administered with Kaletra was safe and efficacious at reducing viral load. To study antiviral effects attributable to ELV, a 7 day monotherapy study of ELV was conducted in HIV subjects sensitive to ELV.
Twenty-four HIV subjects received ELV 10mg or placebo QD (1:1). After ELV monotherapy, ELV treated subjects were given Kaletra (q12h) for 21 days to decrease the likelihood of the emergence of resistance. Samples were collected over 28 days for plasma (ELV) PK, intracellular (ELV-TP) PK and HIV RNA levels determination. PK/PD analyses were conducted with standard noncompartmental methods.
Results
Plasma ELV & PBMC ELV-TP T_ were approx. 100 hours and plasma and PBMC concentrations were detectable up to 14 days after the last dose.
At Day 7, HIV RNA copies decreased a mean 0.85 log10 (p-value < 0.001) for ELV treated subjects.
HIV RNA copies continued to decrease in an ELV concentration dependent manner after Day 7. ELV concentrations remained above the IC50 until Day 21.
On Day 21, the maximum decrease in HIV RNA copies from baseline was 1.72 log10.
Steady-state ELV concentrations are expected to be higher and further decrease the HIV RNA copies.
ELV subjects had a CD4 increase of 62 cells/mm3 at Day 7. No ELV associated safety issues or emergence of resistance were observed.
The authors concluded, these results confirm that ELV monotherapy demonstrates significant antiviral activity over 7 days. ELV's long plasma and intracellular T_ and concentration dependent efficacy may provide a better barrier to resistance than antiviral agents with short half lives. This study serves as a basis for future clinical trials with innovative dosing schemes of ELV in combination with other antiretroviral agents.
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