A novel Css-MRTpo approach to simulate oral plasma concentration–time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite in humans using chimeric mice with humanized livers

Abstract

1. A Css-MRTpo superposition method was devised to predict (retrospectively) oral plasma concentration–time profiles of PF-04937319 and its MIST-related metabolite, M1, in humans using chimeric mice with humanized liver.

2. Original PK data were taken from a published report in which PF-04937319 and M1 were given to chimeric mice orally and/or intravenously. Human CL and Vss were predicted by single-species allometry and MRTiv,pred were calculated as Vss,pred/CL,pred. MRTpo,human were assumed to be MRTiv,pred plus MAT or mean metabolite formation time (MFT). Human Css was calculated by dividing the corrected oral dose by Vss,pred.

3. Chronological sampling time and measured plasma concentrations were corrected by MRTpo,human and Css,human, respectively, and transformed to the corresponding values in humans.

4. The obtained concentration-time profile of PF-04937319 was superimposed well with the observed data after single and repeated oral administration to humans. The transformed plasma concentration of M1 was somewhat lower than the observed value, but a slow increase of the simulated metabolite reflected gradual increase of observed M1 on Day 1. Transformed M1 gave an almost-flat concentration–time profile on Day 14, which was consistent with the curve observed in humans. Application of this novel method to other MIST-related compounds is discussed.

Keywords:

• Chimeric mouse
• Css-MRT approach
• disproportionate metabolite
• humanized liver
• MIST guidance
• oral administration
• PK prediction

Disclosure statement

No potential conflict of interest was reported by the authors.