Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903,in healthy volunteers

AP1903 is a novel gene-targeted drug that is being developed for use in dru g-regulated cell therapies. An intravenous, single-blind, placebo- and sali ne-controlled, ascending-dose study was performed to evaluate the safety, t olerability, and pharmacokinetics of AP1903. Twenty-eight normal healthy ma le volunteers were randomized into five dosage groups of AP1903 (0.01,0.05, 0.1,0.5, and 1 mg/kg). Within each group, 4 volunteers received a single do se of AP1903, 1 volunteer received an equal volume of placebo, and 1 receiv ed an equal volume of normal saline, The only exception was in the 0.5 mg/k g group, in which 4 volunteers were dosed: 3 received AP1903 and 1 received normal saline. All dosages were administered as intravenous infusions over 2 hours. Clinical safety parameters were monitored, and serial blood and u rine samples were collected for analysis of AP1903. No drug-related adverse events were observed at any of the dose levels with the possible exception of facial flushing in 1 volunteer at the 1.0 mg/kg dose level. AP1903 plas ma levels were directly proportional to the administered dose, with mean C- max values ranging from approximately 10 to 1275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations reve aled a rapid distribution phase, with plasma levels being reduced to approx imately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hour s postdose, respectively, AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at do ses well above the anticipated therapeutic dose. (C) 2001 the American Coll ege of Clinical Pharmacology.