Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication.


PF614, a novel trypsin activated abuse protection (TAAP) prodrug of oxycodone, is being studied as chronic pain analgesic with extended release and abuse resistant properties. A series of nonclinical safety studies were conducted to support PF614 introduction to clinical trials. Ames assays (PF614 and its metabolites), comet assay (PF614 ≤ 50 mg/kg/day oral gavage in rats) and micronucleus assay (PF614 ≤ 175 mg/kg/day oral gavage in rats) were negative. hERG assay IC50 for PF614 was ≥300 μM. PF614 (0.1 and 10 μM) showed a low permeability in Caco-2 cells (≤1.17 x 10-6 cm/s) and was not a P-gp or BCRP substrate or inhibitor. The mean percent unbound PF614 among all concentrations in plasma ranged from 91.2 to 98.4, 79.4 to 100, and 52.9-79.9% in rat, dog, and human, respectively. Also, PF614 was metabolically stable in rat, dog, and human hepatocytes with no metabolites identified. Safety pharmacology study in dog indicated moderately lower heart rate at ≥ 2 mg/kg oral gavage doses. Toxicity studies of PF614 in rat and dog with daily oral doses of 25 and 18 mg/kg, respectively, for 14 Days were well tolerated with favorable safety profile supporting its further clinical evaluation.


Joshi, P S; Sanakkayala, N; Kirkpatrick, L; Terse, Pramod;


  • ATP Binding Cassette Transporter, Subfamily B, Member 1/ metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2/ metabolism
  • Abuse-Deterrent Formulations
  • Analgesics, Opioid/ toxicity
  • Animals
  • Caco-2 Cells
  • Dogs
  • Electrocardiography/ drug effects
  • Female
  • Hepatocytes/ drug effects
  • Hepatocytes/ metabolism
  • Humans
  • Male
  • Mutagenicity Tests
  • Neoplasm Proteins/ metabolism
  • Oxycodone/ toxicity
  • Prodrugs/ toxicity
  • Rats
  • Transcriptional Regulator ERG/ metabolism
  • Trypsin

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