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Combined measures (PK/PD)

The option exists to combine endogenous measures indicated along with exogenous to provide PK/PD data. In the example below microdialysis was performed to collect samples which were analysed for the drug compound A and KP metabolite 3-hydroxykynurenine (3-HK) over a 6 hour time course.

UPLC-MS/MS analysis of microdialysates demonstrating impact of compound A (KMO inhibitor) at 10 and 100mg/kg doses on 3-HK. Note the relative levels of 3-HK provide an indication of the appropriate dosing to correctly impact the KMO branch of kynurenine metabolism, i.e., 100mg/kg results in a rise in 3-HK (undesirable), whereas 10mg/kg appears to be the correct dose based on a decline in 3-HK levels.

Reference: G.N. Smagin, D. P. BUDAC, M. Cajina, A. Lee, B. M. Campbell, G. Li, C. Sanchez, C. Forray, V.S. Palamarchouk, D. Song ; In vivo characterization of CNS penetrant KMO inhibitor using microdialysis coupled with a novel high content LC/MS/MS method. SFN Meeting 2016, Poster 217.16/G29