PF-6263276

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.

Accurate methods to determine dermal pharmacokinetics are important to increase the rate of clin. success in topical drug development.We investigated in an in vivo pig model whether the unbound drug concentration in the interstitial fluid as determined by dermal open flow microperfusion (dOFM) is a more reliable measure of dermal exposure compared to dermal biopsies for seven prescription or investigational drugs.In addition, we verified standard dOFM measurement using a recirculation approach and compared dosing frequencies (QD vs. BID) and dose strengths (high vs. low drug concentrations).Domestic pigs were topically administered seven different drugs twice daily in two studies.On day 7, drug exposures in the dermis were assessed in two ways: (1) dOFM provided the total and unbound drug concentrations in dermal interstitial fluid, and (2) clean punch biopsies after heat separation provided the total concentrations in the upper and lower dermis.DOFM showed sufficient intra-study precision to distinguish interstitial fluid concentrations between different drugs, dose frequencies and dose strengths, and had good reproducibility between studies.Biopsy concentrations showed much higher and more variable values.Standard dOFM measurements were consistent with values obtained with the recirculation approach.DOFM pig model is a robust and reproducible method to directly determine topical drug concentration in dermal interstitial fluid.Dermal biopsies were a less reliable measure of dermal exposure due to possible contributions from drug bound to tissue and drug associated with skin appendages.