New in vivo mouse PK data

[mattodd]

Courtesy of MMV and TCGLS we have obtained new mouse in vivo PK data on OSM-S-106 (MMV025100). Files received are linked here and in Mat's ELN here.

This analysis was done because:

1. The compound is of interest, particularly, as is becoming more likely, it has a new mechanism of action (ASN tRNA synthetase).
2. The existing human microsomal and rat hepatocyte clearance data are very good, and for a compound that is clearly low MW and developable.
3. We need to generate a portfolio of data to enable a new grant proposal for new medchem in this series.

The data obtained here are for mice, for which the in vitro data are not so good.

Stephen Brand's perspective was:

1. The IV clearance looks consistent with in-vitro (high in-vitro and in-vivo) – but you would need to do a calculation factoring in PPB, scaling factors etc. to know what is predicted.
2. Volume is higher than he’d anticipate for a small polar sulfonamide, which probably helps with the half-life.
3. Bioavailability F% is low, as expected.

What's needed now, I think:

• To try to put these data into MMVsola in order to predict a human dose. Stephen suggested we play with the tool, in part to figure out which parameters could be modified to maximum effect - e.g. if we improved the potency from ca 100 nM to ca 10 nM would that generate a satisfactory dose prediction? If we improved volume of distribution 5-fold, etc. These become grant proposal targets.
• To find out whether the GSK potency data we already have were from a hypoxanthine assay, and whether we have a hill slope from that assay, since this is informative. If we do not have that, then Stephen might be able to request it from Swiss TPH. Update: STPH NF54 IC50 + hill has been requested. Done, data in IC50 and Hill Slope data from STPH Hypoxanthine assay #27
• Another species in vivo data. There is the possibility we could ask e.g. Sue Charman if she's be willing to run the compound in rat, to obtain comparable data to mouse (and we also already have rat hep data). IV only needed, as a comparator. Another possibility is rat mic data
• Data from a parasite reduction ratio experiment (PRR) that is being run at TCGLS. Stephen is willing to request this, which is excellent. Update: Has now been requested.
• We need an assessment of how easy resistance is to develop (a "minimum inoculum for resistance", or MIR), which I think is something along the lines of what is needed in order to generate a 3 x IC90. MalDA obviously generated resistant mutants, and we just need a quantitative assessment of this (which is generally target-, rather than molecule-, specific). Generally you'd want an MIR < 6.
• Housekeeping: these new data need linking on the wiki.

Any help in playing with MMVsola, based on the data we already have in the wiki and the data we have in these new reports would be MASSIVELY appreciated...