UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study

Y-H Wang, M Trucksis, J J McElwee, P H Wong, C Maciolek, C D Thompson, T Prueksaritanont, G C Garrett, R Declercq, E Vets, K J Willson, R C Smith, J A Klappenbach, G J Opiteck, J A Tsou, C Gibson, T Laethem, P Panorchan, M Iwamoto, P M Shaw, J A Wagner, J C Harrelson, Y-H Wang, M Trucksis, J J McElwee, P H Wong, C Maciolek, C D Thompson, T Prueksaritanont, G C Garrett, R Declercq, E Vets, K J Willson, R C Smith, J A Klappenbach, G J Opiteck, J A Tsou, C Gibson, T Laethem, P Panorchan, M Iwamoto, P M Shaw, J A Wagner, J C Harrelson

Abstract

MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration-time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.

Figures

Figure 1
Figure 1
Plasma concentration–time profiles of MK-7246 after administration of a single 40-mg dose of MK-7246 in the fasted state in individuals in panels (a) A and (b) B of the first-in-human study. Eight subjects, including two who received the placebo, participated in each panel. Each symbol and line represents a separate individual who received MK-7246 within each panel.
Figure 2
Figure 2
Formation of acyl glucuronide M3 by recombinant human UGTs. MK-7246 at 5 and 50 µmol/l MK-7246 were incubated with UGTs in the presence of UDPGA for 90 min. Each bar and error bar represents the mean and standard deviation, respectively, of determinations carried out in triplicate. HLM, human liver microsome; UDPGA, uridine 5′-diphospho-glucuronic acid; UGT, uridine 5′-diphosphate-glucuronosyltransferase.
Figure 3
Figure 3
Dose-normalized individual (N = 13) and mean plasma concentration–time profiles of MK-7246 and its acyl glucuronide metabolite, M3, in UGT2B17 genotype groups of healthy volunteers after a single dose of MK-7246.

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