Elvucitabine, a new nucleoside analogue, has the potential for once-weekly dosing, according to results presented by manufacturer Achillion at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington DC.
Development of the drug has been slow due to the emergence of bone marrow suppression in six of 56 patients recruited to a phase Ib dose ranging study. This study tested doses of 50mg or 100mg once daily; all patients who received the 100mg dose experienced a decline of at least 1,000 cells in their white blood cell counts.
Achillion subsequently began to explore whether lower daily doses would prove as effective, and discovered that effective levels of elvucitabine might persist for up to one week after dosing (the drug has a half-life of over four days).
The company designed a study to test whether dosing every other day was effective, and to measure how long effective elvucitabine levels might persist after the drug was stopped.
The study recruited 24 patients, all of whom received lopinavir/ritonavir (Kaletra) twice daily plus either 5 or 10mg of elvucitabine once daily or 20mg every 48 hours. Elvucitabine treatment was stopped after 21 days, but Kaletra dosing was continued out to day 35 for patients who received the two highest doses in order to protect against the development of resistance to elvucitabine (a similar strategy is recommended when stopping other drugs with long half-lives, such as efavirenz, since the long period of suboptimal drug levels raises the risk of developing drug resistance. In contrast, stopping Kaletra monotherapy appears to be much less prone to trigger resistance because levels of lopinavir fall very quickly).
At day 21 viral load had fallen by –1.8log, -1.9log and –2.0log respectively. The difference in viral load reductions was non-significant.
At day 28 elvucitabine levels remained three times higher than the IC50 (the drug concentration required to inhibit virus replication by 50%).
Although Achillion will pursue initial licensing with a once daily dosing schedule, the company is likely to explore less frequent dosing schedules after licensing.
Colucci P et al. The different clinical pharmacology of elvucitabine (beta-L-Fd4C) enables the drug to be given in a safe and effective manner with innovative drug dosing.. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, abstract LB , 2005.