title: Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers.
abstract: AP1903 is a novel gene-targeted drug that is being developed for use in drug-regulated cell therapies. An intravenous, single-blind, placebo- and saline-controlled, ascending-dose study was performed to evaluate the safety, tolerability, and pharmacokinetics of AP1903. Twenty-eight normal healthy male 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 dose of AP1903, 1 volunteer received an equal volume of placebo, and 1 received an equal volume of normal saline. The only exception was in the 0.5 mg/kg 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 urine 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 plasma levels were directly proportional to the administered dose, with mean Cmax values ranging from approximately 10 to 1,275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations revealed a rapid distribution phase, with plasma levels being reduced to approximately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hours postdose, respectively. AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at doses well above the anticipated therapeutic dose.
authors.affiliation: ARIAD Gene Therapeutics, Inc., Cambridge, Massachusetts 02139, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Iuliucci
authors.forename: S D
authors.initials: SD
authors.lastname: Oliver
authors.forename: S
authors.initials: S
authors.lastname: Morley
authors.forename: C
authors.initials: C
authors.lastname: Ward
authors.forename: J
authors.initials: J
authors.lastname: Ward
authors.forename: D
authors.initials: D
authors.lastname: Dalgarno
authors.forename: T
authors.initials: T
authors.lastname: Clackson
authors.forename: H J
authors.initials: HJ
authors.lastname: Berger
mesh_terms: D000328:Adult; D019540:Area Under Curve; D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009930:Organic Chemicals; D016037:Single-Blind Method
chemical_list: D003432:Cross-Linking Reagents; D009930:Organic Chemicals; C423866:AP 1903 reagent