Single oral doses of CF101, a new adenosine A3 receptor agonist, in healthy young men W Carey, E Clark, S Warrington, M Boyce, W Kerns1, P Fishman1, I Cohn1, M Silverman1& K Fong2 HMR, Central Middlesex Hospital, London, 1CanFite BioPharma Ltd, Israel, & 2Calvert Laboratories Inc, USA.

Print abstract Search PubMed for: Carey W Clark E Warrington S Boyce M Kerns W Fishman P Cohn I Silverman M Fong K

CF101 (IB-MECA, methyl 1-[N6-(3-iodobenzyl)-adenin-9-yl] -ß-D-ibofuronamide, MW 510.29), is a selective A₃ adenosine receptor agonist.We compared single oral doses of CF101 solution (1, 5 and 10 mg in 30% Cremophor RH40) with placebo with respect to safety, tolerability, pharmacokinetics (PK) and pharmaco-dynamics (PD) in 3 groups of 5 (4 on active drug and 1 on placebo) healthy young men in a double-blind study. We took blood samples before and after dosing, to assay plasma CF101, serum G-CSF, GM-CFC (granulocyte-macrophage colony forming cells) and CD34+ cells, and neutrophils. The study was approved by a local ethics committee.

CF101 displayed first order kinetics, and concentrations were proportional to dose (Table 1). T_max (time to peak concentration, C_max) was short. Half-life (_t½) and apparent plasma clearance (CL/F) were independent of dose.

Table 1: mean (SD) PK parameters (n=4 for all groups).

^a median (range) ^b Area under concentration-time curve, to infinity

Single oral doses of CF101 up to 5 mg were safe, but, compared with placebo, CF101 increased mean heart rate (Figures 1 and 2). There was no important change in BP. Also, the 10 mg dose caused nausea and vomiting in 2 subjects.

At 4-8 h after dosing, CF101 caused a dose-related increase in peak neutrophil count (10 mg group: median 11.34 x 10⁹/L (range 6.77-12.63) v placebo 4.40 x 10⁹/L (2.34-8.88); the neutrophil count returned to baseline by 24 h. There were no significant changes in plasma G-CSF concentration, or GM-CFC or CD34+ cell counts.

Figure 1: Mean semi-recumbent heart rate after CF101 (n=4)

Figure 2: Change in heart rate (beats/min) with plasma CF101.

In conclusion, 10 mg CF101 was not tolerated because of increases in heart rate, and nausea and vomiting; the maximum tolerated dose was 5 mg.