The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor

Abstract

The recommended phase II dose is 0.126 mg/m2/h given as a continuous 96-h infusion every 28 days. The dose limiting toxicity of FK866 is thrombocytopenia. Pharmacokinetic data suggest an increase in the plasma Css in relation to the escalation of FK866.

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

“…Although it is being developed as an anticancer drug, APO866 could quite easily be considered a new disease-modifying antirheumatic drug for rheumatoid arthritis. The half-life of APO866 in humans is ϳ8 hours (20), which is similar to that seen with methotrexate. Although APO866 has a potential role as a single agent for the treatment of rheumatoid arthritis, it may, similar to methotrexate, work best if administered in combination with other agents.…”

“…Studies later revealed that APO866 caused NADϩ depletion through competitive inhibition of the NAMPT activity of PBEF (45). In light of the success of the inhibitory effects of APO866 in several in vivo studies, Holen et al (20) carried out an open-label, phase I clinical trial in which 26 patients with solid tumor malignancies were given escalating doses of APO866 (up to 0.126 mg/m 2 /hour, which is equivalent to our dose of 0.04 mg/kg/hour in mice). The half-life of APO866 in these human trials was between 7.9 hours and 76.5 hours.…”

“…To maintain therapeutic systemic levels of APO866, mice were continuously infused with 0.25 l/hour APO866 for up to 14 days, via an Alzet 1002 osmotic pump (Durect) that was implanted subcutaneously, posterior to the scapulae. A maximum tolerated dose of APO866 of 0.126 mg/m 2 /hour in human clinical trials and 0.18 mg/m 2 /hour in rats has been reported (20). The equivalent dose for mice was converted to mg/kg, using the following formula: mg/m 2 ϭ km ϫ mg/kg, in which km represents a unique value that is assigned to each animal species (i.e., for mice, the km is 3, based on a weight of 20 gm) (22).…”

“…The recently developed small molecule inhibitor APO866 has been shown to act as a competitive inhibitor of PBEF/NAMPT activity by inhibiting binding of its natural substrate, nicotinamide (14,15). Moreover, in vivo, APO866 displays antiinflammatory effects, and favorable results have been obtained with APO866 treatment in murine tumor models and models of inflammation (16)(17)(18)(19)(20)(21).…”

Targeting cancer metabolism: a therapeutic window opens

“…NAMPT inhibition can also be toxic to lymphocytes 122 , suggesting that use of NAMPT inhibitors in patients might be limited by immunosuppression. Mild lymphopenia was observed in early trials of NAMPT inhibitors, but thrombocytopenia was the dose limiting toxicity 123 . Limited clinical efficacy has been observed thus far, although work is ongoing to develop more potent compounds and define those patients most likely to benefit from NAMPT inhibition 124 .…”