PT  - JOURNAL ARTICLE
AU  - Nan Wu
AU  - Bruce Hammock
AU  - Kin Sing Stephen Lee
AU  - Guohua An
TI  - Simultaneous Target-Mediated Drug Disposition (TMDD) Model for Two Small-Molecule Compounds Competing for Their Pharmacological Target: Soluble Epoxide Hydrolase
AID  - 10.1124/jpet.120.265330
DP  - 2020 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.120.265330
4099  - http://jpet.aspetjournals.org/content/early/2020/04/01/jpet.120.265330.short
4100  - http://jpet.aspetjournals.org/content/early/2020/04/01/jpet.120.265330.full
AB  - 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) and 1-(4-trifluoro-methoxy-phenyl)-3-(1-cyclopropanecarbonyl-piperidin-4-yl)-urea (TCPU) are potent inhibitors of soluble epoxide hydrolase (sEH) which have much better efficacy in relieving nociceptive response than the FDA-approved drug, gabapentin, in a rodent model of diabetic neuropathy. Experiments conducted in sEH-knock-out mice or with coadministration of a potent sEH displacer demonstrated that the pharmacokinetics of TPPU and TCPU were influenced by the specific binding to their pharmacologic target sEH, a phenomenon known as target-mediated drug disposition phenomenon (TMDD). To quantitatively characterize the complex pharmacokinetics of TPPU and TCPU and gain better understanding on their target occupancy, population pharmacokinetics analysis using a nonlinear mixed-effect modeling approach was performed in the current study. The final model was a novel simultaneous TMDD interaction model, where TPPU and TCPU compete for sEH, with TCPU binding to an additional unknown target pool with larger capacity which we refer to a refractory pool. The total amount of sEH enzyme (Rmax1) in mice was predicted to be 16.2 nmol, which is consistent with the experimental value of 10 nmol. The dissociate rate constants (koff) of TPPU and TCPU were predicted to be 2.24 h-1 and 2.67 h-1, respectively, which is close to the values obtained from in vitro experiments. Our simulation result predicted that, 90% of the sEH will be occupied shortly after a low dose of 0.3 mg/kg TPPU administration, with ≥ 40% of sEH remaining to be bound with TPPU for at least 7 days. Further efficacy experiments are warranted to confirm the predicted target occupancy.SIGNIFICANCE STATEMENT Although TMDD models have been well documented, most of them were established in a single compound scenario. Our novel model represents the first TMDD interaction model for two small-molecule compounds competing for the same pharmacological target.