Repeated oral doses of CF101, a new adenosine A3 receptor agonist, in healthy young men A van Troostenburg, 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: Van Troostenburg A Clark E Warrington S Boyce M Kerns W Fishman P Cohn I Silverman M Fong K

In single doses up to 5 mg orally, CF101 was safe and well tolerated, but a 10 mg dose increased heart rate and caused nausea and vomiting (Carey et al, 2003).
We compared repeated oral doses of CF101 suspension (2, 3, 4, and 5 mg in 0.5% methyl cellulose, 12-hourly for 7 days) and placebo with respect to safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in 4 groups of 7 (5 on active drug and 2 on placebo) healthy young men in a double-blind, parallel group study. We took frequent blood samples on Days 1 and 7 to assess PK of CF101. The study was approved by a local ethics committee.Plasma concentrations of CF101 were dose proportional, and the pharmacokinetics did not change after repeated dosing.

Table 1: Mean (SD) plasma PK parameters after repeated 12-hourly doses of CF101 (Day 7) (n=5 in each group).

^a median (range) NB - see Carey et al for definitions.

There was a weakly dose-dependent increase in mean heart rate on Day 1. After 5 mg CF101, mean semi-recumbent heart rate increased by a maximum of 22 beats/min (6 h post-dose), and 40 beats/min standing (3 h post-dose). On Day 7, the effect of CF101 on heart rate was attenuated.

(Figure 1).Figure 1: Standing heart rate on Days 1 and 7.

There was a modest dose-dependent increase in absolute neutrophil count on Day 1, but not on Day 7. Median peak neutrophil count after 5 mg CF101 was 5.67 x 10⁹/L at 8 h post-dose on Day 1.

Repeated oral doses of up to 4 mg CF101 were safe and well tolerated, but the 5 mg CF101 dose was less well tolerated. Most of the adverse events were after that dose: nervous system disorders (headache and 'drowsiness') were most common. 2 adverse events were vascular disorders (hot flushes and dizziness on standing). Tolerance developed to the effect on heart rate.

CF101 was safe and well tolerated at the 4 mg 12-hourly dose level, and merits further clinical studies.~

W Carey, E Clark, S Warrington et al, this meeting.