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Abstract
A phase I study to explore the safety, tolerability, and pharmacokinetics of Fosalvudine Tidoxil in patients infected with HIV-1
Cahn P.1, Reuss F.2, Rolon M.3, Wit F.4, Boehm E.2, Lange J.5
1Fundacion Huesped, Buenos Aires, Argentina, 2Heidelberg Pharma GmbH, Hamburg, Germany, 3Hospital Juan Fernandez, Buenos Aires, Argentina, 4IATEC, Amsterdam, Netherlands, 5IATEC/Academic Medical Center, Amsterdam, Netherlands
Background: The nucleoside analogue Alovudine (FLT) has potent anti-HIV activity and considerable toxicity. Fosalvudine Tidoxil is a pro-drug of FLT covalently linked with a lipid-moiety. Compared to the parent compound the toxicity of Fosalvudine is expected to be significantly lower because of altered pharmacokinetic properties. Furthermore, a continuous slow cell-associated release of the FLT-monophosphate is expected to result in effective concentrations of the antiviral drug for a longer time-span, compatible with once-daily oral administration. This study evaluates the safety, tolerance and pharmacokinetics of Fosalvudine in HIV-1-infected patients.
Methods: This is a single-dose, open-label, phase-I, single-center study. Twenty-four ART-naïve HIV-1-infected patients in 4 consecutive dose-groups of six patients received one single oral dose of 5, 10, 20, or 40mg Fosalvudine with 7 days of follow-up.
Results: No clinically significant clinical or laboratory adverse events occurred.
Fosalvudine became detectable in plasma 2 hours after intake of 5mg and 1 hour after intake of 10, 30 or 40mg. Fosalvudine was still detectable in all patients of all dose-groups 24 hours after intake. Pharmacokinetic parameters of Fosalvudine Tidoxil by non-compartmental analysis (median and range):
Conclusion: A single dose of 5-40mg Fosalvudine Tidoxil appears to be safe and well-tolerated. The AUC increases with increasing doses, although non-proportionality cannot be excluded due to the low number of patients. The terminal half-life of Fosalvudine Tidoxil is short compared to the dosing interval. Clinically relevant accumulation of the pro-drug is not expected during multiple dosing. A multiple dosing study will be conducted.
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