Simulation of human plasma concentration–time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling

Abstract

1. The partial glucokinase activator N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319) is biotransformed in humans to N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (M1), accounting for ∼65% of total exposure at steady state. 2. As the disproportionately abundant nature of M1 could not be reliably predicted from in vitro metabolism studies, we evaluated a chimeric mouse model with humanized liver on TK-NOG background for its ability to retrospectively predict human disposition of PF-04937319. Since livers of chimeric mice were enlarged by hyperplasia and contained remnant mouse hepatocytes, hepatic intrinsic clearances normalized for liver weight, metabolite formation and liver to plasma concentration ratios were plotted against the replacement index by human hepatocytes and extrapolated to those in the virtual chimeric mouse with 100% humanized liver. 3. Semi-physiological pharmacokinetic analyses using the above parameters revealed that simulated concentration curves of PF-04937319 and M1 were approximately superimposed with the observed clinical data in humans. 4. Finally, qualitative profiling of circulating metabolites in humanized chimeric mice dosed with PF-04937319 or M1 also revealed the presence of a carbinolamide metabolite, identified in the clinical study as a human-specific metabolite. The case study demonstrates that humanized chimeric mice may be potentially useful in preclinical discovery towards studying disproportionate or human-specific metabolism of drug candidates.

Pharmacokinetics and metabolism of pemafibrate, a novel selective peroxisome proliferator‐activated receptor‐alpha modulator, in rats and monkeys

“…It was able to be assumed that the plasma exposures of M1 would be low in all species tested because the M1 and/or M1 conjugate were readily excreted into bile. Moreover, because M1 was detected in feces from rats and monkeys in this study (Table 3) (Kamimura et al, 2017). The high circulating concentrations of metabolites M2/3, M4 and M5 in humans may be reproducible in these mice.…”

“…M3, M4 and M5 are possibly secondary metabolites, which could be difficult to predict in in vitro systems. Recently, chimeric mice with humanized livers have demonstrated their usefulness in predicting circulating human‐specific or disproportionate metabolites (Kamimura et al, ). The high circulating concentrations of metabolites M2/3, M4 and M5 in humans may be reproducible in these mice.…”

<p>A Recent Achievement In the Discovery and Development of Novel Targets for the Treatment of Type-2 Diabetes Mellitus</p>

“…Some agents like AZD6370, piragliatin, DS-7309, and ARRY-403 also terminated their drug development due to toxicity and loose of effectiveness with long-term administration. [47][48][49][50][51] Some examples of the GK activator presented in Table 3 with their stage of development and company.…”

Utility of Chimeric Mice with Humanized Liver for Predicting Human Pharmacokinetics in Drug Discovery: Comparison with <i>in Vitro</i>–<i>in Vivo</i> Extrapolation and Allometric Scaling

“…To improve predictability, correction methods using CL int, in vitro in humans and animals have been reported. 87,88) To improve prediction accuracy, use of in vitro data using hepatic microsomes in chimeric mice with humanized liver and humans might be effective. Kamimura et al 89) estimated CL t in humanized TK-NOG mice with 100% RI by extrapolating the values of CL t in humanized TK-NOG mice which showed different RIs for PF-04937319, a glucokinase activator.…”