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The Different Clinical Pharmacology of Elvucitabine (β-L-Fd4C)
Enables the Nuke Drug to be Given in a Safe and Effective Manner with
Innovative Dosing Regimens

Reported by Jules Levin
ICAAC Dec 18, 2005 Wash DC

Elvucitabine (ELV) is a L-cytosine nucleoside with potent in vitro
anti-HIV activity (IC50 of 1ng/mL in PBMCs) and a prolonged T1/2 (>
100 hours). At doses > 50 mg/day, ELV was associated with bone marrow
toxicity. PK/PD modeling suggested that lower daily doses would be
effective and non-toxic. This study was done to validate the results
of the modeling and further investigate the ELV clinical pharmacology
using dosing of both once daily and every 48 hours.

In the NATAP report linked to below from the 2003 Resistance Workshop
in Los Cabos, Mexico, you can read about the toxicity that stopped
development of this drug at higher doses than examined in the study
presented at ICAAC. The drug has shown potent activity against 3TC
resistance and against HBV. Serious bone marrow suppression was
experienced by 4 patients in 100mg group and 2 patients in the 50mg
group. 4 patients (3 in 50mg group, 1 in 100 mg group) with mild to
moderate maculopapular rash which resolved with drug discontinuation.
10/20 patients receiving 100mg dose and 6/24 patients receiving the 50
mg dose experienced a decrease of 2,000 white blood cells or more. 3
patients in 50mg group and 3 in 100mg group experienced decrease of
1500 to 2000 cells. 4 in 50mg group and 3 in 100mg group experienced
1000 to 1500 decrease in cells. And 4 patients in 50mg group and 0 in
the 100mg group experienced decrease of 1000 or less cells.
http://www.natap.org/2003/resistance/day3.htm

24 HIV patients received ELV 5 or 10mg once daily or 20mg every 48
hours for 21 days with concomitant Kaletra (400mg lopinavir/100mg
ritonavir, q12h) treatment. Plasma samples were collected over 35 days
for ELV concentrations. Plasma HIV RNA was measured over 28 days.
PK/PD analyses were done using noncompartmental and compartmental
analyses.

As predicted by PK/PD modeling, ELV was efficacious and non-toxic at
the doses administered. At Day 21 vs. baseline, HIV RNA copies
decreased 1.8, 1.9 and 2.0 log10 for the 5mg qd, 10 mg qd and 20 q48h
cohorts.

Due to the long ELV T1/2, Kaletra was continued to Day 35 for the 2
higher doses. Of note, ELV concentrations at Day 28 were 3x above the
IC50. The continued activity 7 days after stoppage of ELV supports
less frequent dosing (qw & biw) suggested by the modeling. There was a
trend toward a greater efficacy of the 20 mg q48h cohort, verified by
a higher percentage decrease in HIV log copies from baseline. No
cohort had safety issues or emergence of resistance.

The authors concluded that these results further validate that ELV is
safe and effective. ELV's attractive pharmacological profile may allow
it to display a significantly better barrier to resistance than other
agents as it is less affected by compliance issues and may display
higher and prolonged IQ ratios. Further evaluation of ELV with less
frequent dosing regimens is warranted.

Reference
P. COLUCCI1,2, J. POTTAGE 3, H. ROBISON 3, D. SCHURMANN 4, I. M.
HOEPELMAN 5, A. SEAMAN 3, M. P. DUCHARME 1,2;
1MDSPS, Montreal, Canada, 2U. of Montreal, Montreal, Canada,
3Achillion Pharmaceuticals, Inc., New Haven, CT, 4Charité, U. Med.
Berlin, Berlin, Germany, 5U. Med. Ctr., Utrecht, The Netherlands.
Presentation Number: LB-27

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