Premium
Phase 1 Study of Safety, Tolerability, and Pharmacokinetics of PTC299, an Inhibitor of Stress‐Regulated Protein Translation
Author(s) -
Weetall Marla,
Davis Thomas,
Elfring Gary,
Northcutt Valerie,
Cao Liangxian,
Moon YoungChoon,
Riebling Peter,
Dali Mandar,
Hirawat Samit,
Babiak John,
Colacino Joseph,
Almstead Neil,
Spiegel Robert,
Peltz Stuart W.
Publication year - 2016
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.240
Subject(s) - medicine , tolerability , pharmacokinetics , pharmacology , bioavailability , vascular endothelial growth factor , adverse effect , vegf receptors
PTC299 is a novel small molecule that specifically blocks the production of protein from selected mRNAs that under certain conditions use noncanonical ribosomal translational pathways. Hypoxia, oncogenic transformation, and viral infections limit normal translation and turn on these noncanonical translation pathways that are sensitive to PTC299. Vascular endothelial cell growth factor (VEGF) is an example of a transcript that is posttranscriptionally regulated. Single doses of PTC299 (0.03 to 3 mg/kg) were administered orally to healthy volunteers in a phase 1 single ascending‐dose study. In a subsequent multiple ascending‐dose study in healthy volunteers, multiple‐dose regimens (0.3 to 1.2 mg/kg twice a day or 1.6 mg/kg 3 times a day for 7 days) were evaluated. PTC299 was well tolerated in these studies. As expected in healthy volunteers, mean plasma VEGF levels did not change. Increases in C max and AUC of PTC299 were dose‐proportional. The target trough plasma concentration associated with preclinical efficacy was achieved within 7 days at doses of 0.6 mg/kg twice daily and above. These data demonstrate that PTC299 is orally bioavailable and well tolerated and support clinical evaluation of PTC299 in cancer, certain viral infections, or other diseases in which deregulation of translational control is a causal factor.